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TWI304061B - Nitrogen-containing aromatic ring derivatives - Google Patents

Nitrogen-containing aromatic ring derivatives Download PDF

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Publication number
TWI304061B
TWI304061B TW090125928A TW90125928A TWI304061B TW I304061 B TWI304061 B TW I304061B TW 090125928 A TW090125928 A TW 090125928A TW 90125928 A TW90125928 A TW 90125928A TW I304061 B TWI304061 B TW I304061B
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Taiwan
Prior art keywords
group
substituent
compound
cyano
formula
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TW090125928A
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Chinese (zh)
Inventor
Tsuruoka Akihiko
Masayuki Matsukura
Haneda Toru
Fukuda Yoshio
Kamata Junichi
Keiko Takahashi
Matsushima Tomohiro
Kazuki Miyazaki
Nomoto Ken-Ichi
Watanabe Tatsuo
Hiroshi Obaishi
Suzuki Sachi
Nakamura Katsuji
Mimura Fusayo
Yamamoto Yui
Matsui Junji
Matsui Kenji
Yoshiba Takako
Itaru Arimoto
Yamaguchi Atsumi
Kenji Suzuki
Funahashi Yasuhiro
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Eisai R&D Man Co Ltd
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Publication of TWI304061B publication Critical patent/TWI304061B/en

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/72—Nitrogen atoms
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Abstract

The present invention concerns a process for preparing a compound represented by the following general formula (a- or a pharmacologically acceptable salt or hydrate thereof, which comprises reacting a compound repr with a compound represented by the following general formula (a-4) : wherein the residues R 1 , R 2 , R sa1 - R sa3 , R 300 , R 301 and Z are as defined in the claims.

Description

1304061 〜.- -A7 _________B7 五、發明説明（彳） 發明說明 技術範疇 本發明係關於一種在預防及治療伴隨血管新生之異常增 殖上有效之新穎化合物，以及含有該新穎化合物之血管新 生抑制劑及抗腫瘤劑等醫藥組合物。 背景技術 ： 血管新_生為胎兒期之血管樹形成及各器官之形態及機能 了 發達時不可欠缺之生物學現象。新生血管係經由内皮細胞 之移行、增殖及管腔形成等複數過程而構築，在該過程 中，巨細胞、淋巴球及間質細胞等之參與亦頗為重要（J· Folkman and Y. Shing, J. Biol. Chem., 267, 1093 1，· 1992)。 在成熟個體中，雖然在女性性週期發生生理性的血管新 生’但已知在成熟個體中血管新生之病態增加參與各種疾 病之發病或進行《具體而言，伴隨血管新生之異常之疾病· 例如有癌、〜風濕性關節炎、動脈粥腫性羚脈硬化症、糖尿 病性肩膜症、血管瘤及乾癬等（j. N. Engl. J. Med.， 1757，1995)。更特定而言，曾報告固形癌之增殖依存 於血管新生，以及期待血管新生抑制劑成為難治性固形癌 之新穎治療藥（Folkman J·，J. Natl· Cancer Inst♦，虹 4， 1990) 。 · 關於具有脲構造之化合物之先行技術，有W〇99003 57及 W〇 004336.6公報。 在WO 9900357號公報中，雖記載對於^raf^酶顯示抑制作 用而有抗腫瘤效果之聯苯脲衍生物，但未揭示其有血管新 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（2 ) 生抑制作用。在WO 0043366號公報中，雖然記載在試管中 對於A3 75黑色素瘤細胞之核形態變化作用弱，對於血管内 皮增殖因子（簡稱為VEGF)刺激之内皮細胞顯示增殖抑制作 用，及有抗腫瘤作用之喹啉衍生物及喹唑啉衍生物，但未 揭示對於VEGF以外之血管新生因子之作用。 發明之揭示 如上所述，亟望提供可做為醫藥之血管新生抑制化合 物。但是，尚未發現顯示優良血管新生抑制作用，而且做 為醫藥之有用性高、在臨床上能有效作用之化合物。 本發明之目的在於探索及尋找具有下列性質之血管新生 抑制化合物：（1)具有強力的血管新生抑制作用，或者藉由 強力的血管新生抑制作用及腫瘤細胞增殖抑制作用二者而 顯示抗腫瘤活性；（2)顯示在物性、體内動態及安全性等方 囬，可做為優質醫藥；以及在改善、預防及治療伴隨血 管新生之異濟增殖之各種疾病上有用。 對於上i者反覆鑑定及用心研究，結果、合成下列通式⑴ 表示之新穎化合物或其之鹽或彼等之水合物，同時發現下 列通式（I)之化合物或其之鹽或彼等之水合物顯示優異的血 f新生抑制作用，本發明於焉完成。 亦即，本發明係關於： <ι>-種通式⑴表示之化合物或其鹽或彼等之水合物： (() * 本紙張尺度適财國料料 13040611304061 ~.- -A7 _________B7 V. INSTRUCTION DESCRIPTION (彳) DESCRIPTION OF INVENTION Technical Field The present invention relates to a novel compound effective in preventing and treating abnormal proliferation accompanying angiogenesis, and an angiogenesis inhibitor containing the novel compound and A pharmaceutical composition such as an antitumor agent. BACKGROUND OF THE INVENTION: Vascular neo-generation is the formation of vascular trees in the fetal period and the morphology and function of various organs are biological phenomena that are indispensable when developed. The neovascular system is constructed through multiple processes such as migration, proliferation, and lumen formation of endothelial cells. In this process, the participation of giant cells, lymphocytes, and interstitial cells is also important (J·Folman and Y. Shing, J. Biol. Chem., 267, 1093 1, 1992). In mature individuals, although physiological angiogenesis occurs in the female sexual cycle, it is known that the morbidity of angiogenesis in mature individuals is involved in the onset of various diseases or in the "specifically, diseases associated with angiogenesis abnormalities, for example. There are cancer, rheumatoid arthritis, atherosclerotic atherosclerosis, diabetic shoulder disease, hemangioma and cognac (j. N. Engl. J. Med., 1757, 1995). More specifically, it has been reported that the proliferation of solid cancer depends on angiogenesis, and that an angiogenesis inhibitor is expected to be a novel therapeutic drug for refractory solid cancer (Folkman J., J. Natl. Cancer Inst ♦, Rainbow 4, 1990). · For the advance technology of compounds having a urea structure, there are W〇99003 57 and W〇 004336.6. In WO 9900357, although a biphenylurea derivative having an antitumor effect against an inhibitory action of ^raf^ enzyme is described, it is not disclosed that the vascular new paper scale is applicable to the Chinese National Standard (CNS) A4 specification ( 210X 297 mm) 1304061 A7 B7 V. Description of invention (2) Biosuppressive effect. In WO 0043366, it is described that in the test tube, the nuclear morphological change of A3 75 melanoma cells is weak, and the endothelial cells stimulated by vascular endothelial growth factor (abbreviated as VEGF) exhibit proliferation inhibition and antitumor effects. Quinoline derivatives and quinazoline derivatives, but did not reveal effects on angiogenic factors other than VEGF. Disclosure of the Invention As described above, it is expected to provide an angiogenesis inhibitory compound which can be used as a medicine. However, a compound which exhibits an excellent angiogenesis inhibitory effect and which is highly useful as a medicine and which is clinically effective has not been found. The purpose of the present invention is to explore and find an angiogenesis inhibitory compound having the following properties: (1) having potent angiogenesis inhibitory action, or exhibiting antitumor activity by both potent angiogenesis inhibition and tumor cell proliferation inhibition (2) It can be used as a high-quality medicine in terms of physical properties, in vivo dynamics, and safety. It is also useful for improving, preventing, and treating various diseases associated with angiogenesis. For the above-mentioned identification and careful study, the result is that a novel compound represented by the following formula (1) or a salt thereof or a hydrate thereof is synthesized, and a compound of the following formula (I) or a salt thereof or the like is found. Hydrate exhibits excellent blood f-suppressing action, and the present invention is completed in sputum. That is, the present invention relates to: <ι>- a compound represented by the formula (1) or a salt thereof or a hydrate thereof: (() * This paper size is suitable for the country of the material 1304061

[式中 八§為可有取代基之c^4芳基或可有取代基之5至14員雜環 基； 又§為單鍵、-〇-、_S_、伸烷基、-so-、-s〇2-或式 •N(Rg3H式中為氣原子、可有取代基之。"燒基或可有 取代基之_c2_7醯基）；[In the formula, § is a c4 aryl group which may have a substituent or a 5- to 14-membered heterocyclic group which may have a substituent; and § is a single bond, -〇-, _S_, an alkylene group, -so-, -s〇2- or formula: N (Rg3H is a gas atom, may have a substituent. " a burnt group or a _c2_7 fluorenyl group which may have a substituent);

Yg為各可有取代基之CrM芳基、5至14員雜環基、6_8烷 基、C3-8脂環族烴基、C0-M芳基Ci0烷基、5至14員雜芳基 Cb6烷基、式-(CH2)gS〇2-(式中g為1-8之整數）、式 -(CH2)fa-CH=CH-(CH2)fb-(式中仏及比各為 〇、1、2或3)、 式（CH2)fa-CH-CH-(CH2)fb-S02-(式中 fa&ft 各為〇、1、2 或3)、式-(〇112)^(：三（：-(<^2：^(式中:^及比各為〇、1、2 或 3)或式-(CH2)fa-CE C-(CH2)fb-S〇2(式中 fa及 fb各為 〇、 1、2或 3) ; 乂 Tgl 為、 (1)下述通式表示之基：Yg is a CrM aryl group each having a substituent, a 5- to 14-membered heterocyclic group, a 6-8 alkyl group, a C3-8 alicyclic hydrocarbon group, a C0-M aryl Ci0 alkyl group, and a 5- to 14-membered heteroaryl Cb6 alkane. The formula - (CH2)gS〇2- (wherein g is an integer from 1 to 8), and the formula -(CH2)fa-CH=CH-(CH2)fb- (wherein 仏 and ratio are each 〇, 1 , 2 or 3), formula (CH2)fa-CH-CH-(CH2)fb-S02- (wherein fa&ft is 〇, 1, 2 or 3), and -(〇112)^(:3 (:-(<^2:^(where: ^ and the ratio are 〇, 1, 2 or 3) or the formula -(CH2)fa-CE C-(CH2)fb-S〇2 (where fa And fb are each 〇, 1, 2 or 3); 乂Tgl is, (1) the base represented by the following formula:

Rgi 々V. {式中：-.Rgi 々V. {式:-.

Eg為單鍵或式-N(Rg2)-(其中Rg2為氫·原子、可有取代基 之烷基、可有取代基之〇2-6晞基、可有取代基之c26 -9- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（4 ) 炔基、可有取代基之C3-8脂環族烴基、可有取代基之C2_7 醯基或可有取代基之C2·7烷氧羰基）；Eg is a single bond or a formula -N(Rg2)- (wherein Rg2 is a hydrogen atom, an alkyl group which may have a substituent, a ruthenium 2-6 fluorenyl group which may have a substituent, and a c26 -9 group which may have a substituent Paper scale applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (4) Alkynyl group, C3-8 alicyclic hydrocarbon group which may have a substituent, C2_7 which may have a substituent a mercapto group or a C2·7 alkoxycarbonyl group which may have a substituent;

Rgl為氫原子、可有取代基之基、可有取代基之C2_ 6烯基、可有取代基之C2-6炔基、可有取代基之C3_8脂環 族烴基、可有取代基之c2_7醯基或可有取代基之c2.7烷氧 羰基；以及 ： 以為氫原子、可有取代基烷基、可有取代基之c2.6 烯基、可有取代基之C2-6炔基、可有取代基之C3-S脂環 族烴基、可有取代基之(：6_14芳基、可有取代基之C6-14芳… 基 Cb6烷基、式-〇R20G、式-SR2G〇、式-C〇R2⑻、式-S〇2R2G()(其中R2GG為氫原子、可有取代基之cN8烷基、可 有取代基之C3-8脂環族烴基、可有取代基之C6.14芳基、 可有取代基之C6.14芳基CN6烷基、可有取代基之5至14員 雜環基或可有取代基之5至14員雜環基CN6烷基）、可有-取代基七、5至14員雜環基或可有取代基之5至14員雜環基 ' C H燒基};或者 .、 (2)下述通式表示之基：Rgl is a hydrogen atom, a substituent group, a C2-6 alkenyl group which may have a substituent, a C2-6 alkynyl group which may have a substituent, a C3-8 alicyclic hydrocarbon group which may have a substituent, and a c2_7 which may have a substituent a mercapto group or a c2.7 alkoxycarbonyl group which may have a substituent; and: a hydrogen atom, a substitutable alkyl group, a c2.6 alkenyl group which may have a substituent, a C2-6 alkynyl group which may have a substituent, A C3-S alicyclic hydrocarbon group which may have a substituent, a substituent (6-14 aryl group, a C6-14 aryl group which may have a substituent, a Cb6 alkyl group, a formula -R20G, a formula -SR2G〇, a formula -C〇R2(8), a formula -S〇2R2G() (wherein R2GG is a hydrogen atom, a cN8 alkyl group which may have a substituent, a C3-8 alicyclic hydrocarbon group which may have a substituent, and a C6.14 aromatic group which may have a substituent a C6.14 aryl CN6 alkyl group which may have a substituent, a 5 to 14 member heterocyclic group which may have a substituent or a 5 to 14 member heterocyclic group CN6 alkyl group which may have a substituent), may have a substitution a 7-, 5 to 14 membered heterocyclic group or a 5- to 14-membered heterocyclic group 'CH-alkyl group} which may have a substituent; or (2) a group represented by the following formula:

{式中： ,{式: ,

RglAZg具有與上述之Rgi及zg相同之意義； 本紙珉尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7RglAZg has the same meaning as Rgi and zg above; This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7

五、發明説明（ 及Zg2可相同或相異，各為（1)單鍵，（2)在鏈之中或終 端可有從-〇-、-S-及氮原子選出之1個以上原子，或可被 酮基取代之Ci.6伸烷基，或者（3)可有取代基之缔 基}]。 <2〉一種通式（Π)表示之化合物或其鹽或彼等之水合物：5. Description of the invention (and Zg2 may be the same or different, each being (1) a single bond, and (2) having at least one atom selected from -〇-, -S- and a nitrogen atom in the chain or at the terminal, Or a Ci.6 alkyl group which may be substituted by a ketone group, or (3) a substituent which may have a substituent}]. <2> A compound represented by the formula (Π) or a salt thereof or a hydrate thereof :

[式中： A為可有取代基之5至14員芳香族雜環基； X為氧原子、硫原子、-SO-或-S02-; Y為可有取代基之(：6·14芳基、可有取代基之5至14員芳香族 雜環基或可逢取代基之Cu伸烷基； E為單鍵或'NR2-; 、 R1及R2各獨立為氫原子、可有取代基之CU6烷基、可有取 代基之Cl6烯基、可有取代基之C2-6炔基、可有取代基之 C3_8脂環族烴基、可有取代基之c2.7醯基或可有取代基之 C2-7烷氧羰基； Z為式-Ζπ-Ζ12{式中： zU為單鍵、氧原子、硫原子、-C0-、-S02-或可有取代 基之CU6伸烷基； : 212為氫原子、可有取代基之Cl 6烷基、可有取代基之匕一 ___ -11 - 本紙張尺度適標準(CNS) _a7規格(210 X 297公釐） 1304061 一一 A7 B7 五、發明説明（6 ) 晞基、可有取代基之^2·6決基、可有取代基之C3_8脂環族 烴基、可有取代基之C6· μ芳基、可有取代基之5至14員 雜環基、可有取代基之5至14員芳香族雜環基或如下式之 基：[In the formula: A is a 5- to 14-membered aromatic heterocyclic group which may have a substituent; X is an oxygen atom, a sulfur atom, -SO- or -S02-; Y is a substituent (6:14 Fang) a 5- to 14-membered aromatic heterocyclic group which may have a substituent or a Cu alkyl group which may be a substituent; E is a single bond or 'NR2-; R1 and R2 are each independently a hydrogen atom and may have a substituent CU6 alkyl, may have a substituted Cl6 alkenyl group, a C2-6 alkynyl group which may have a substituent, a C3_8 alicyclic hydrocarbon group which may have a substituent, a c2.7 fluorenyl group which may have a substituent or may be substituted a C 2-7 alkoxycarbonyl group; Z is a formula - Ζ π - Ζ 12 { wherein: zU is a single bond, an oxygen atom, a sulfur atom, -C0-, -S02- or a CU6 alkyl group which may have a substituent; 212 is a hydrogen atom, a C 6 alkyl group which may have a substituent, and a substituent which may have a substituent ___ -11 - this paper scale standard (CNS) _a7 specification (210 X 297 mm) 1304061 one A7 B7 five (6) A mercapto group, a ^2·6-ruthenyl group which may have a substituent, a C3_8 alicyclic hydrocarbon group which may have a substituent, a C6·μ aryl group which may have a substituent, and 5 which may have a substituent a 14-membered heterocyclic group, a 5 to 14 membered aromatic heterocyclic group which may have a substituent or The basis of the following formula:

(式中，Z31、Z33及Z34各獨立為亞甲基、-CO-、-NH-或 -0-，以及Z32為單鍵、亞甲基、-CO-、-NH-或-〇-)}; 再者，A可被選自下述（1)〜（4)所組成群中之1至6個基取 代： (1) 氰基:J (2) 鹵i原子； 、 (3) 硝基；及 (4) 式-VX1-VX2-VX22-VX3(式中： VX1，VX2及VX22各獨立為單鍵、氧原子、硫原子、 -CO-、-SO-、_s〇2-、式-NRX1，、_C〇NRX1-、式 -NRX1-C0-、式-S02NRX1-、式-NRX1S02- ' 式-O-CO· ' 式-C(〇）〇-、式-NRxiC(〇）〇-、式-NRx1C(0) NRX2-、式-0-C(0)NRxl-、式-Q-C(〇）〇-、可有取 代基之cN6伸烷基、可有取代基之c2_6烯基、可有取 -12- 裝 訂(wherein Z31, Z33 and Z34 are each independently methylene, -CO-, -NH- or -0-, and Z32 is a single bond, methylene, -CO-, -NH- or -〇-) Further, A may be substituted with 1 to 6 groups selected from the group consisting of (1) to (4): (1) cyano group: J (2) halogen atom; (3) nitrate And (4) Formula -VX1-VX2-VX22-VX3 (wherein: VX1, VX2 and VX22 are each a single bond, an oxygen atom, a sulfur atom, -CO-, -SO-, _s〇2-, -NRX1,, _C〇NRX1-, -NRX1-C0-, -S02NRX1-, -NRX1S02- 'form-O-CO· '-C(〇)〇-,式-NRxiC(〇)〇- , -NRx1C(0) NRX2-, formula-0-C(0)NRxl-, formula -QC(〇)〇-, a cN6 alkyl group which may have a substituent, a c2_6 alkenyl group which may have a substituent, Have -12- binding

線 本纸張尺度適用中國國家標準(CNS) A4規格(210χ297公釐） 1304061 A7 - __B7 1、發明説明（7 ) ~~~' --— 代基足c：2_6炔基、可有取代基之匕·8脂環族烴基、 可有取代基之C0·!4芳基、可有取代基之5至14員雜環 基或可有取代基之5至14員芳香族雜環某， V 、R及RX2各獨三為氫原子、可有取代某之〔 火元基、可有取代基之c：2·$缔基、可有取代某之q 6块 基、可有取代基之C3·8脂環族烴基、可有取代基之 C6-M芳基、可有取代基之5至14員雜環基、可有取代一 基之5至14員芳香族雜環基或可有取代基之Ci6烷氧二: 基)]。 ' &lt;3&gt; &lt;2〉記載之化合物或其鹽或彼等之水合物，其中χ為氧 原子或硫原子。 ''' &lt;4&gt; &lt;2&gt;或&lt;3&gt;記載之化合物或其鹽或彼等之水合物，其中 Ζ為可有取代基之環丙基、可有取代基之2〃塞唑基或下式表 示之基： &gt;Line paper size is applicable to China National Standard (CNS) A4 specification (210χ297 mm) 1304061 A7 - __B7 1. Invention description (7) ~~~' --- Substituting c: 2_6 alkynyl group, may have a substituent匕8 alicyclic hydrocarbon group, C0·!4 aryl group which may have a substituent, 5 to 14 membered heterocyclic group which may have a substituent or 5 to 14 membered aromatic heterocyclic ring which may have a substituent, V , R and RX2 are each a hydrogen atom, and may have a substitution of a fire atom group, a c-substitutable group having a substituent, a substituent group, a C 6 group having a substituent, and a C3 group having a substituent. · 8 alicyclic hydrocarbon group, C6-M aryl group which may have a substituent, 5 to 14 membered heterocyclic group which may have a substituent, 5 to 14 membered aromatic heterocyclic group which may have a substituted group or may be substituted Based on Ci6 alkoxy 2: group)]. &lt;3&gt; The compound described in <2> or a salt thereof or a hydrate thereof, wherein hydrazine is an oxygen atom or a sulfur atom. &lt;2&gt;&lt;2&gt;&lt;3&gt; or a salt thereof or a hydrate thereof, wherein hydrazine is a cyclopropyl group which may have a substituent, and a 2 oxazole which may have a substituent Base or formula: &gt;

(式中為腈基、甲磺醯基或-nhcoch3基卜 &lt; ：)&gt; &lt;2〉至&lt;4&gt;之任一項記載之化合物或其鹽或彼等之水合 物’其中E為式-NR2-代表之基（式中R2為具有與在&lt;2&gt;中2 R2相同之意.義）；Y為各可有取代基之苯基、吡啶基或下 表示之基： ^ __-13-(In the formula, a nitrile group, a methanesulfonyl group or a -nhcoch3 group, &lt;:)&gt;, a compound of any one of the above-mentioned items, or a salt thereof or a hydrate thereof, wherein E Is a group represented by the formula -NR2- (wherein R2 has the same meaning as 2R2 in &lt;2&gt;); Y is a phenyl group, a pyridyl group or a group represented by each: __-13-

本纸張尺度適用中國國豕標準(CNS) A4規格(21〇 χ 297公愛） 1304061 A7This paper scale applies to China National Standard (CNS) A4 specification (21〇 297 297 public) 1304061 A7

(式中W11及W&gt;2各獨立為可有取代基之碳原子或氮原子卜 :6&gt; &lt;2&gt;至&lt;二之任一項記載之化合物或其鹽或彼等之水 5物，其中E為單鍵，γ為可另有取代基之如下式表示之 基： _(wherein W11 and W&gt;2 are each independently a carbon atom or a nitrogen atom which may have a substituent: a compound according to any one of <2> to <2> or a salt thereof or a water of the same Wherein E is a single bond, and γ is a group represented by the following formula: _

(式中W13為可有取代基之碳原子或氮原子）。 &lt;7〉&lt;2〉至，中之任一項記載之化合物或其鹽 合物’其中A為如下式表示之基：(wherein W13 is a carbon atom or a nitrogen atom which may have a substituent). <7> The compound according to any one of the above 2, wherein A is a group represented by the following formula:

[式中： W為可有取代基之碳原子或氮原子； -14- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 一〜^ -A7 - --— _— B7 五、發明説明（9 )[wherein: W is a carbon atom or a nitrogen atom which may have a substituent; -14- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A~^-A7 - --- _ — B7 V. Description of invention (9)

Ral3為氫原子、鹵素原子、可有取代基之〇10烷基、可有取 代基之Ci·6烷氧基、胺基或硝基； R **為见基或下式表示之基： 〇 卜％”扣卜s〇2卞广卜〆叫一Lva12 卜p^12卜prir卜V〜2或卟1 &gt;13 1 卜- (式中Val1為-C〇U〇2-，val2，van及vaM各獨立為氫 原子、可有取代基之CN6烷基、可有取代基之c2.6烯基、 可有取代基之C2·6炔基、可有取代基之c3_8脂環族烴 基、可有取代基之Cl w芳基、可有取代基之5至14員雜 環基或可有取代基之5至14員芳香族雜環基）；以及 Ral1 為式 _Vf i-Vu2-Va23(式中： va21為可有取代基之Cu6伸烷基、單鍵或下式表示之基： /工、 va22為單鍵、氧原子、碟原子、- c〇-、-S〇-、-S02-、 式 _C〇N-Ra1、、式 _s〇2NRa14-、式-NRaI4S〇2-、式 _ -NRal4CO-或式-NRa14-(式中RaM為I原子、可有取代基 之CN6烷基或可有取代基之c3e8脂環族烴基）； 爾15- 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1304061 A7 --~-----^_ 五、發明説明（1〇 )Ral3 is a hydrogen atom, a halogen atom, a monodecyl group which may have a substituent, a Ci. 6 alkoxy group which may have a substituent, an amine group or a nitro group; R ** is a group represented by the formula or the following formula: 〇卜%"扣卜s〇2卞广卜〆一一 Lva12 卜p^12卜prir Bu V~2 or 卟1 &gt;13 1 Bu- (where Val1 is -C〇U〇2-, val2, van And vaM each independently a hydrogen atom, a CN6 alkyl group which may have a substituent, a c2.6 alkenyl group which may have a substituent, a C2·6 alkynyl group which may have a substituent, a c3_8 alicyclic hydrocarbon group which may have a substituent, a Cl w aryl group which may have a substituent, a 5 to 14 membered heterocyclic group which may have a substituent or a 5 to 14 membered aromatic heterocyclic group which may have a substituent; and Ral1 is a formula of _Vf i-Vu2-Va23 (wherein: va21 is a substitutable Cu6 alkyl group, a single bond or a group represented by the formula: /, va22 is a single bond, an oxygen atom, a dish atom, - c〇-, -S〇-, - S02-, Formula _C〇N-Ra1, Formula _s〇2NRa14-, Formula -NRaI4S〇2-, Formula _-NRal4CO- or Formula-NRa14- (wherein RaM is a I atom, CN6 which may have a substituent Alkyl or may have a substituted c3e8 alicyclic hydrocarbon group); er 15- This paper scale applies to Chinese national standards (CN S) A4 size (210X297 mm) 1304061 A7 --~-----^_ V. Description of invention (1〇)

Va23為氫原子、可有取代基iCl6烷基、可有取代基之 C1 2.6晞基·、可有取代基之c26炔基、可有取代基之c3.8脂 環族煙基、可有取代基之c6_14芳基、可有取代基之5至 14員雜環基或可有取代基之5至14員芳香族雜環基）]。 &lt;8&gt; &lt;2&gt;至&lt;6&gt;中之任一項記載之化合物或其鹽或彼等之水 合物’其中A為下式表示之基··Va23 is a hydrogen atom, a substituent iCl6 alkyl group, a C1 2.6 fluorenyl group which may have a substituent, a c26 alkynyl group which may have a substituent, a c3.8 alicyclic group which may have a substituent, may be substituted a c6_14 aryl group, a 5 to 14 membered heterocyclic group which may have a substituent or a 5 to 14 membered aromatic heterocyclic group which may have a substituent). &lt;8&gt; The compound described in any one of <2>, or a salt thereof or a hydrate thereof, wherein A is a group represented by the following formula:

(，中，w為可有取代基之碳原子或氮原子，Raii ,汉⑴及 Ral3具有與&lt;7&gt;中之Ra&quot; , R川及Rau相同之竟義）(wherein, w is a carbon atom or a nitrogen atom which may have a substituent, and Raii, Han (1) and Ral3 have the same meaning as Ra&quot;, R Chuan and Rau in &lt;7&gt;)

[式中， 或者（2)下式表示 W為可有取代基之碳原子或氮原子； Abn為（1)可有取代基之5至14員雜環基[wherein, or (2) the following formula represents that W is a carbon atom or a nitrogen atom which may have a substituent; and Abn is a (1) 5- to 14-membered heterocyclic group which may have a substituent

1 9Γ2:ΐ，中之任一項記載之化合物或:鹽或彼等之水 2 合物，其中Α為可另有取代基之如下式之基： !304061 A7 B7 五、 發明説明（ 11 之基： R' b11 ,々\ &gt;b12 (式中：The compound of any one of the following: or a salt or a water compound thereof, wherein hydrazine is a group of the following formula which may have another substituent: !304061 A7 B7 V. Description of the invention (11 Base: R' b11 , 々 \ &gt; b12 (where:

Vbu及Vbl2各獨立為單鍵、's〇2-、-NHC〇_或式-(CH2)b- C〇-(式中b為0至6之整數）； Rbl3 為單鍵、可有取代基之^.6伸烷基、可有取代基之 Cl8脂環族烴基或可有取代基之5至14員雜環基；Vbu and Vbl2 are each a single bond, 's〇2-, -NHC〇_ or a formula -(CH2)b-C〇- (where b is an integer from 0 to 6); Rbl3 is a single bond and can be substituted a 6-8 alkylene group, a C8 alicyclic hydrocarbon group which may have a substituent or a 5 to 14 membered heterocyclic group which may have a substituent;

R 及R各獨王為氫原子、羥基、_素原子、可有取代 基之C!·6烷基、可有取代基之^6缔基、可有取代基之 Cw炔基、可有取代基之脂環族烴基、可有取代基 之C^4芳、基、可有取代基之5至14員芳香族雜環基或可 有取代基之5至14員雜環基）]。 、 &lt; 10&gt; &lt;2〉至&lt;6〉中任一項記載之化合物或其鹽或彼等之水 合物，其中A為下式表示之基：Each of R and R is a hydrogen atom, a hydroxyl group, a _ atom, a C.·6 alkyl group which may have a substituent, a 6-membered group which may have a substituent, a Cw alkynyl group which may have a substituent, and a substituent An alicyclic hydrocarbon group, a C 4 aryl group which may have a substituent, a 5 to 14 membered aromatic heterocyclic group which may have a substituent or a 5 to 14 membered heterocyclic group which may have a substituent)]. The compound of any one of the above formulas, or a salt thereof, or a hydrate thereof, wherein A is a group represented by the following formula:

Rc -17 本纸張尺度適用中國國家標準(CNS) A4規^^7297公爱） 1304061Rc -17 This paper scale applies to China National Standard (CNS) A4 Regulation ^^7297 公爱) 1304061

[式中， w為可有取代基之碳原子或氮原子； Rcl3 為： (1) 氫原子， (2) 氰基， (3 )鹵素原子， (4) 甲醯基， (5) 可有取代基之c^6烷基， (6) 下式表示之基： —vc21 - Μ /V。22 、Vc23 (式中，Vc21為，CO-或亞甲基，Vc22及Vc23各獨立為 氫原寸、可有取代基之cU6烷基、可有取代基之c2.6 烯i、可有取代基之c2.6炔基、可有取代基之c3.8 脂環族烴基、可有取代基之5至14員雜環基、可有取 代基之5至14員芳香族雜環基或可有取代基之(：6_14芳 基），或 (7)式，-Vc21-〇-Vc22(式中Vc21及Vc22具有與上述Vc21及 ve22相同之意義）； R 為氫原子、可有取代基之Cle 6炫基或可有取代基之C3-8 脂環族烴基； 。Wherein w is a carbon atom or a nitrogen atom which may have a substituent; Rcl3 is: (1) a hydrogen atom, (2) a cyano group, (3) a halogen atom, (4) a formazan group, (5) Substituent c^6 alkyl, (6) The base represented by the formula: -vc21 - Μ /V. 22, Vc23 (wherein, Vc21 is, CO- or methylene, Vc22 and Vc23 are each independently hydrogen, cU6 alkyl which may have a substituent, c2.6 which may have a substituent, may have a substituent a c2.6 alkynyl group, a c3.8 alicyclic hydrocarbon group which may have a substituent, a 5 to 14 membered heterocyclic group which may have a substituent, a 5 to 14 membered aromatic heterocyclic group which may have a substituent or may have Substituent (: 6_14 aryl), or (7) formula, -Vc21-〇-Vc22 (wherein Vc21 and Vc22 have the same meanings as Vc21 and ve22 above); R is a hydrogen atom and may have a substituent Cle 6 leucoyl or a C3-8 alicyclic hydrocarbon group which may have a substituent;

Rel1 為式-vcll-vcl2-vcl3(式中： -18- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 〜A7 f____B7 五、發明説明（13 ) ^ 'Rel1 is of the formula -vcll-vcl2-vcl3 (in the formula: -18- This paper scale applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 ~ A7 f____B7 V. Invention description (13) ^ '

Veu為單键、氧原子、可有取代基之苯環、可有取代基 之5至14員芳香族雜環基或-C0·; vel2為單键、氧原子或可有取代基之烷基；Veu is a single bond, an oxygen atom, a benzene ring which may have a substituent, a 5- to 14-membered aromatic heterocyclic group which may have a substituent or -C0·; vel2 is a single bond, an oxygen atom or an alkyl group which may have a substituent ;

Vcl3為： U)可有取代基之C!.ό烷基， (2) 可有取代基之c2.6婦基， (3) 可有取代基之c2.6炔基， (4) 可有取代基之c3.8脂環族烴基， (5) 羥基， (6) 羧基， (7) 可有取代基之C2_7烷氧羰基， (8) 可有取代基之5至14員雜環基， (9) 可有取代基之5至14員芳香族雜環基， (10) 可有取代基之C6_14芳基， (11) 式-NJR。21 Rc22(式中Rc21及Rc22各獨立為氫原子或可 (12) 氫原子）]。 &lt;11〉一種通式（Ilia)表示之化合物或其鹽或分μ 4仮寺之水人 物： . &quot;Vcl3 is: U) C. which may have a substituent; όalkyl, (2) a c2.6 aryl group which may have a substituent, (3) a c2.6 alkynyl group which may have a substituent, (4) may have a c3.8 alicyclic hydrocarbon group of a substituent, (5) a hydroxyl group, (6) a carboxyl group, (7) a C2-7 alkoxycarbonyl group which may have a substituent, (8) a 5- to 14-membered heterocyclic group which may have a substituent, (9) A 5- to 14-membered aromatic heterocyclic group which may have a substituent, (10) a C6_14 aryl group which may have a substituent, and (11) a formula -NJR. 21 Rc22 (wherein Rc21 and Rc22 are each independently a hydrogen atom or a (12) hydrogen atom). &lt;11&gt; A compound represented by the formula (Ilia) or a salt thereof or a water human of the μ 4仮 Temple: .

本紙張尺度適用中國國家標準(CNS) Α4規格(210χ 297公爱) 1304061五、發明説明（14 A7 B7This paper scale applies to China National Standard (CNS) Α4 specifications (210χ 297 public) 1304061 V. Invention description (14 A7 B7

[式中： R1，R2 及 Z12 與 &lt;2&gt; 中之 R1 吡唑基之情沉除外）；[In the formula: R1, R2 and Z12 are excluded from the R1 pyrazolyl group in &lt;2&gt;);

Yal為下式表示之基：Yal is the base of the following formula:

{式中 WW!各獨立為可有取代基之碳 R 300芬p301夂傾、，乂长γ W 丁·， 及R各獨立為風原子 '商素原子、氰基、确基、 基、可有取代基之Cl·6燒基、可有取代其 ，一甘 &gt; 调取代基之Ch8脂環族 『烷氧 ，至☆、可有取代基之CN0烷氧基、可有取代基之5.7: 羰基或甲:·轉基、下式表示之基： 卜七° (式中V·及V3G1各獨立為氫原子或可有取代基之(^一烷 基）或可有取代基之c2.7醯基};WW in the formula: each independently is a carbon having a substituent R 300 fen p301 夂, 乂 γ W butyl, and R are each independently a wind atom's atom, cyano group, acetyl group, base group, a Cl.6 alkyl group having a substituent, a C8 alicyclic "alkoxy" which may have a substituent, a glycerin, a substituent, a CN0 alkoxy group which may have a substituent, and a substituent 5.7 : Carbonyl or A: · Transyl group, the base represented by the following formula: 卜7° (wherein V· and V3G1 are each independently a hydrogen atom or may have a substituent (^-alkyl group) or may have a substituent c2. 7醯基};

Ral1及Ral2具有與在&lt;7&gt;中之Ral^Rai2相同之意義； 限制條件為，在上述定義中以下述（1)或（2)之化合物除 外： ____ ~ 20 ~ 本紙張尺度適用中國@家標準(CNS) Μ規格(2Κ)χ 297公爱) 1304061 A7Ral1 and Ral2 have the same meaning as Ral^Rai2 in &lt;7&gt;; the limitation is that the compound of the following (1) or (2) is excluded from the above definition: ____ ~ 20 ~ This paper size is applicable to China@ Home Standard (CNS) ΜSpecifications (2Κ)χ 297 公爱) 1304061 A7

(l)Ra為下式表示之基：(l) Ra is the basis of the following formula:

卜 scv-tj^v41 (式中Val2及yal3義），Bu scv-tj^v41 (in the formula Val2 and yal3),

相同之意 R及R為氫原子，而且 z12為cv14芳基、6至14員雜環基或6至14 基； ^胥族雜環 (2) Ra 12為選自下式表示之基··The same meanings R and R are a hydrogen atom, and z12 is a cv14 aryl group, a 6 to 14 membered heterocyclic group or a 6 to 14 group; ^ a fluorene heterocyclic ring (2) Ra 12 is a group selected from the following formula:

具有與在&lt;7&gt;中之yall (式中 Van , Val2 , val3 及 Val4Has yall with &lt;7&gt; (where Van , Val2 , val3 and Val4

Val2，Val3及Val4相同之意義， R為風原子’而且 · Z12為（a)C6.14芳基，（b)5至14員雜環基，（c) 5至14員分 香族雜環基，（d)被5至10員雜環基或Csi()脂環族烴 代之淀基’（e)被5至10員雜環基或匕1()脂環族烴基 取代之Cm缔基，（f)被5至10員雜環差或Csi(^環族垣 基取代之Cl·6炔:基或者（g)被5至1〇員雜環基或^5 ^旨$ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（16 族烴基取代之C3-8脂環族烴基]。 &lt;12&gt; &lt;U&gt;記載之化合物或其鹽或彼等之水合物， 為甲基、2-甲氧乙基或下式表示之基：Val2, Val3 and Val4 have the same meaning, R is a wind atom 'and · Z12 is (a) C6.14 aryl, (b) 5 to 14 membered heterocyclic group, (c) 5 to 14 membered aromatic ring a group, (d) substituted by a 5 to 10 membered heterocyclic group or a Csi() alicyclic hydrocarbon, wherein the group '(e) is substituted with a 5 to 10 membered heterocyclic group or a hydrazine 1 () alicyclic hydrocarbon group. a group, (f) is a 5 to 10 member heterocyclic ring or Csi (a cyclohexyl group substituted by a Cl. 6 alkyne: group or (g) is 5 to 1 member heterocyclic group or ^5^ The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of the invention (16-membered hydrocarbon-substituted C3-8 alicyclic hydrocarbon group). &lt;12&gt;&lt;U&gt; Or a salt thereof or a hydrate thereof, which is a methyl group, a 2-methoxyethyl group or a group represented by the following formula:

或 (式中Ra53為甲基，環丙甲基或氰甲基；Ra51為氫、— 原子或羥基；Ra52為1-吡咯啶基、r六氫吡啶基、4 : 基、二甲胺基或二乙胺基）。 ^3〉&lt;H&gt;*&lt;12〉之化合物或其鹽或彼等之水合物，其 Z12為甲基、乙基、環丙基、2·噻唑基或4-氟苯基。、 &lt;14〉&lt;11&gt;至&lt;13&gt;中之任一項記載之化合物或其鹽或彼 之水合物，杀中Yal為下式表示之基：Or (wherein Ra53 is methyl, cyclopropylmethyl or cyanomethyl; Ra51 is hydrogen, - atom or hydroxyl; Ra52 is 1-pyrrolidinyl, rhexahydropyridyl, 4:yl, dimethylamino or Diethylamine). ^3>&lt;H&gt;*&lt;12&gt; A compound or a salt thereof or a hydrate thereof, wherein Z12 is a methyl group, an ethyl group, a cyclopropyl group, a 2 thiazolyl group or a 4-fluorophenyl group. The compound of any one of the above-mentioned compounds, or a salt thereof or a hydrate thereof, wherein Yal is a group represented by the following formula:

(式中Ra61，為氫原子、甲基、三氣甲基、氯原子或氣原子）。 &lt;15&gt; &lt;11&gt;至&lt;14&gt;中之任一項記載之化合物或其鹽或彼等 足水合物，其中Ral2為氰基或式_c〇NHRa62表示之基 R為氫原.子、可有取代基之cN6烷基、：可有取代基之c3 : 脂環族煙基、可有取代基&lt;Cn6烷氧基或可有取代基之。(In the formula, Ra61 is a hydrogen atom, a methyl group, a trimethyl group, a chlorine atom or a gas atom). The compound according to any one of the above-mentioned items, wherein Ral2 is a cyano group or a group represented by the formula _c〇NHRa62 is a hydrogen source, or a salt thereof or a salt thereof. The cN6 alkyl group which may have a substituent, the c3 which may have a substituent: an alicyclic group, may have a substituent &lt; Cn6 alkoxy group or may have a substituent.

,a62 V ^ T -22- 本紙張尺度制t g @家襟準(CNS) A4規格(210X297^17 1304061 A7 B7 五、發明説明（17 ) 環烷氧基）。 &lt;16&gt; —種.通式（nib)表示之化合物或其鹽或彼等之水合 物：, a62 V ^ T -22- This paper scale system t g @家襟准 (CNS) A4 specifications (210X297^17 1304061 A7 B7 V, invention description (17) cycloalkoxy). &lt;16&gt; - a compound represented by the formula (nib) or a salt thereof or a hydrate thereof:

[式中： Z21為氫原子、可有取代基之Cl ό烷基、可有取代基之c2-0 缔基、可有取代基之c2-6炔基或可有取代基之c3_8脂環族 烴基； R 為ίΐ基或下式表示之基： 〇 -0—va15 Νί~~ν®1 ^ &gt;[^14 ο 卜 C- Ν—V311—va12 ο 或 卜&amp;-N-Va ί ^13 (式中，Val)為可有取代基之Cu6烷基、可有取代基$c26 烯基、可有取代基之^;2·6炔基或可有取代基之脂環族 烴基，V川，, vai3及vau具有與在&lt;7&gt;中之yau， Val2 , Val3&amp;VaM相同之意義）； -23- 1304061 〜·’ A7[wherein: Z21 is a hydrogen atom, a C ό alkyl group which may have a substituent, a c2-0 alkyl group which may have a substituent, a c2-6 alkynyl group which may have a substituent, or a c3_8 alicyclic group which may have a substituent Hydrocarbyl; R is ί ΐ or a group represented by the following formula: 〇-0—va15 Νί~~ν®1 ^ &gt;[^14 ο 卜 C- Ν—V311—va12 ο or 卜&amp;-N-Va ί ^ 13 (wherein Val) is a substitutable Cu6 alkyl group, may have a substituent of the group Cc26 alkenyl group, may have a substituent; a 2·6 alkynyl group or an optionally substituted alicyclic hydrocarbon group, V Sichuan, vai3 and vau have the same meaning as yau, Val2, Val3&VaM in &lt;7&gt;; -23- 1304061 ~·' A7

R及1^〇1具有與在&lt;11&gt;中之&amp;30〇及尺3〇1 Ral1具有與在&lt;7&gt;中之Rall相同之意義； 相同之意義 附π條件為R2R and 1^〇1 have the same meaning as Rall1 in &lt;11&gt; and ruler 3〇1 Ral1 have the same meaning as Rall in &lt;7&gt;; the same meaning π condition is R2

R 及Ζ21具下列意義者被排除在外 ll2G為選自下列式表示之基：R and Ζ21 have the following meanings excluded: ll2G is a base selected from the following formula:

(式中，Va&quot;、Va丨2、van及val4具有與在&lt;7&gt;中之vau、 V⑴' V⑴及Va丨4相同之意義；以及vals具有與上述定義 相同之意義）；而且 z為卜）C3-8脂環族烴基，（b)被5至10員雜環基或c5⑺ 脂環族烴基取代之CU0烷基，（c)被5至10員雜環基或q ίο月εϊ %族普基取代之晞基或（d)被5至10員雜環基或 C% 1 〇脂環族fe基取代之c2.6決基]。 -、 &lt;17〉一種通式（nic)表示之化合物或其鹽或彼等之水合 物：(wherein, Va&quot;, Va丨2, van, and val4 have the same meaning as vau, V(1)' V(1) and Va丨4 in &lt;7&gt;; and vals have the same meaning as defined above; and z is a) a C3-8 alicyclic hydrocarbon group, (b) a CU0 alkyl group substituted with a 5 to 10 membered heterocyclic group or a c5(7) alicyclic hydrocarbon group, (c) a 5 to 10 membered heterocyclic group or a q ο 月 ε ϊ % a sulfhydryl group substituted with a fluorenyl group or (d) a c2.6 cleavage group substituted with a 5 to 10 membered heterocyclic group or a C% 1 alicyclic group. -, &lt;17> a compound represented by the formula (nic) or a salt thereof or a hydrate thereof:

-24- 本紙張尺度通用中國國家標旱(CNS) A4規格(210 X 297公釐） 1304061-24- The paper size is GM China National Standard Dry (CNS) A4 specification (210 X 297 mm) 1304061

[式中： z22為可有取代基之c：6·!4芳基，可有取代基之5至14員雜環 基或可有取代基之5至14員芳香族雜環基； 衣 R 各具有與在&lt; 11〉中之R300及R301相同之意義；Wherein z22 is a substitutable c: 6·! 4 aryl group, a 5 to 14 membered heterocyclic group which may have a substituent or a 5 to 14 membered aromatic heterocyclic group which may have a substituent; Each has the same meaning as R300 and R301 in <11>;

Vdl3選自下列式表示之基··Vdl3 is selected from the group represented by the following formula:

fsh-Va12 (式中Val2及Val3具有與在&lt;7&gt;中之Va!2及Vau相同之意 義）； 、fsh-Va12 (wherein Val2 and Val3 have the same meaning as Va!2 and Vau in &lt;7&gt;);

Vdu為可有取代基之。·6伸烷基或下式表示之基： 為⑴i-NRdHRmU中广及Rdl2為氣原子、可有取代 基之Ci·6烷基、可有取代基之C：3-8脂環族烴基、可有取代基 之芳基、可有取代基之5至14員雜環基或可有取代基之 5至14員芳香族雜環基）；或（2)可有取代基之5至14員雜環 基]。， &lt;18&gt; —種通式（nid)表示之化合物或其鹽或彼等之水合 物： -25- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（20 )Vdu is a substituent. · 6 alkyl group or a group represented by the following formula: (1) i-NRdHRmU and Rd2 is a gas atom, a Ci6 alkyl group which may have a substituent, a C: 3-8 alicyclic hydrocarbon group which may have a substituent, An aryl group which may have a substituent, a 5 to 14 membered heterocyclic group which may have a substituent or a 5 to 14 membered aromatic heterocyclic group which may have a substituent; or (2) 5 to 14 members which may have a substituent Heterocyclic group]. , &lt;18&gt; - a compound represented by the formula (nid) or a salt thereof or a hydrate thereof: -25- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (20)

0»d) [式中·· R，R2及Z12各具有與在&lt;2〉中之Ri , R2及zu相同之意義； W11為可有取代基之碳原子或氮原子； R300具有與在&lt;11&gt;中之r3〇〇相同之意義； 裝0»d) [wherein R, R2 and Z12 each have the same meaning as Ri, R2 and zu in <2>; W11 is a carbon atom or a nitrogen atom which may have a substituent; R300 has and The same meaning of r3〇〇 in &lt;11&gt;;

Ral1具有與在&lt;7&gt;中之Μ&quot;相同之意義；Ral1 has the same meaning as &lt;&lt;7&gt;;

Ral20具有與在&lt;16&gt;中之Rm〇相同之意義； 限制條件為上述定義中，下述（1)或（2)之化合物被除外： (1)R 12(5為下式表示之基：Ral20 has the same meaning as Rm〇 in &lt;16&gt;; the limitation is that in the above definition, the compound of the following (1) or (2) is excluded: (1) R 12 (5 is a base represented by the following formula) :

線 (式中val2及V川各具有與在&lt;7&gt;中之vaU及yan相同之意 義），. 〜 R及R為氫原子，而且 12 Z為C6-〖4^r基、6至14員雜環其七^ γ 基； 貝雖衣基或6至14貝芳香族雜環 (2) 為選自下式表示之基： : 26- 本纸張尺歧财國國冢標準(CNS) A4規格(21GX297公愛f !304061 A7 B7 五 、發明説明（ 21 卜 SC^-V®12 ο -C~〇-Va12 9 -C- Y —V^11— va12 卜 0~,ya1S y/al3 -N~V^^V312 Va13 -N—V^1 &gt;13Line (where val2 and V are each of the same meaning as vaU and yan in &lt;7&gt;), . . . R and R are hydrogen atoms, and 12 Z is C6-[4^r base, 6 to 14 Heterocyclic heterocyclic ring γ γ group; shell although the base or 6 to 14 shell aromatic heterocyclic ring (2) is selected from the group represented by the following formula: : 26- This paper ruler is the national standard (CNS) A4 specification (21GX297 public love f!304061 A7 B7 V. Invention description (21 Bu SC^-V®12 ο -C~〇-Va12 9 -C- Y —V^11— va12 Bu 0~, ya1S y/al3 -N~V^^V312 Va13 -N-V^1 &gt;13

Va1i 及 卜 c一 ν-\ΛΙ2 N-V31 (式中Va丨丨，V⑴，Va丨3及浐丨4具有與在&lt;7&gt;中之, val2 ’ val3及val4相同之意義，v⑴具有與在&lt;16&gt;中之 val5相同之意義）； R2為氫原子；而且 Z12為（a)C6-14芳基，（1))5至14員雜環基，（c) 5至14員芳 香族雜環基，（d)被5至10員雜環基或q iq脂環族烴基= 代之cN0烷基，（e)被5至10員雜環基或脂環族烴基 取代之C2.6缔基，⑺被5至1〇員雜環基或C)·，脂環族煙 基取代之:、C2.6炔基或者（g)被5至1〇員雜環基或脂環 族fe基取代之C3· s脂環族烴基]。 .、 &lt;19&gt; 一種如下列通式表示之化合物或其鹽或彼等之人 物： °Va1i and 卜c_ν-\ΛΙ2 N-V31 (where Va丨丨, V(1), Va丨3 and 浐丨4 have the same meaning as in var7' val3 and val4 in &lt;7&gt;, v(1) has In the same meaning as val5 in &lt;16&gt;; R2 is a hydrogen atom; and Z12 is (a) C6-14 aryl, (1)) 5- to 14-membered heterocyclic group, (c) 5- to 14-membered aromatic a heterocyclic group, (d) is a 5 to 10 membered heterocyclic group or a q iq alicyclic hydrocarbon group = a CN0 alkyl group, (e) a C 2 substituted with a 5 to 10 membered heterocyclic group or an alicyclic hydrocarbon group. 6, (7) substituted by 5 to 1 member heterocyclic group or C), an alicyclic group; C2.6 alkynyl or (g) 5 to 1 member heterocyclic or alicyclic Fe-substituted C3·s alicyclic hydrocarbon group]. . &lt;19&gt; A compound represented by the following formula or a salt thereof or the like:

[式中： __— -27-[where: __- -27-

本紙張尺度適用中國國豕標準(CNS) A4規格(21〇 X 297公袭) 1304061 A7 B7 五、發明説明（This paper scale applies to China National Standard (CNS) A4 specification (21〇 X 297 public attack) 1304061 A7 B7 V. Description of invention (

W4W各獨立為可有取代基之碳原子或氮原 為W41及w不可同時為氮原子； ^條件 xyl選自各可有取代基之下列式表示之化合物：W4W is independently a carbon atom which may have a substituent or a nitrogen atom is W41 and w may not be a nitrogen atom at the same time; ^Condition xyl is selected from the group consisting of the following compounds which may have a substituent:

(式中’ Zu具有與在&lt;2&gt;中之Z12相同之意義；以及 W11為可有取代基之碳原子或氮原子）；以及 Abu具有與在&lt;9：&gt;中之Abu相同之意義]。 &lt;20&gt; —種通式（Illf)表示之化合物或其鹽或彼等之水合物：(wherein 'Z has the same meaning as Z12 in &lt;2&gt;; and W11 is a carbon atom or a nitrogen atom which may have a substituent); and Abu has the same as Abu in &lt;9:&gt; significance]. &lt;20&gt; - A compound represented by the formula (Illf) or a salt thereof or a hydrate thereof:

[式中：[where:

Rcl3具有與在&lt;1〇&gt;中之Rcl3相同之意義；Rcl3 has the same meaning as Rcl3 in &lt;1〇&gt;;

Xy2選自纟可有取代基之下列式表示之化合物：Xy2 is selected from the group consisting of a compound represented by the following formula:

-28- 1304061 A7 B7 五、發明説明（ (式中，Z12，R1及R2各具有與在&lt;2&gt;中之Zi2，…及“相 同之意義，以及Wu為可有取代基之碳原子或氮原子）； RCll&amp;RCl2各具有與在&lt;10&gt;中之Rcl1及Rcl2相同之竟義· 限制條件為上述定義中，下述（1)或（2)之化合物除外： (1) R1及R2為氫原子，而且 Z為（a)C6-14芳基’（b)5至14員雜環基，（c)被5至14 員芳香族雜環基、5至10員雜環基或c5_ 1G脂環族烴基 取代之C!·6烷基，（d)被5至10員雜環基或C5iG脂環 族烴基取代之C2·6婦基，（e)被5至1〇員雜環基或q ίο脂環族煙基取代之C：2·6決基或（f)被5至1〇員雜環基 或c 5 - 1 〇脂球族經基取代之c 3 - 8脂環族煙基； (2) Xy2為下式表示之基：-28- 1304061 A7 B7 V. DESCRIPTION OF THE INVENTION (wherein Z12, R1 and R2 each have the same meaning as Zi2, ... and " in &lt;2&gt;, and Wu is a carbon atom which may have a substituent or The nitrogen atom); RC11 & RCl2 each have the same meaning as Rcl1 and Rcl2 in &lt;10&gt;. The limitation is the above definition, except for the following compounds (1) or (2): (1) R1 and R2 is a hydrogen atom, and Z is (a) C6-14 aryl '(b) 5 to 14 membered heterocyclic group, (c) is 5 to 14 membered aromatic heterocyclic group, 5 to 10 membered heterocyclic group or C5_1G alicyclic hydrocarbon group substituted C!·6 alkyl group, (d) C2·6 cation group substituted by 5 to 10 membered heterocyclic group or C5iG alicyclic hydrocarbon group, (e) is 5 to 1 〇 a C 3 -8 aliphatic group substituted by a cyclic group or a q ί alicyclic group or (f) a c 3 - 8 ester substituted with a 5 to 1 member heterocyclic group or a c 5 - 1 steroid group Ring family of cigarettes; (2) Xy2 is the base of the following formula:

(式中，Z12為（a)C6.l4芳基，（b)5至14員雜環基，（c) 5至14員芳香族雜環基，（d)被5至10員雜環基或c5.1〇 脂環族烴基取代之CN6烷基，（e)被5至10員雜環基或 C5.1G脂環族烴基取代之（：2-6晞基，（f)被5至10員雜 環基或脂環族基取代之C2-6块基或（g) C3-8脂 環族烴基）]。 」 &lt;21&gt;&lt;10&gt;或&lt;20〉之化合物或其鹽或彼等之水合物，其中 -29- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（ R 為下式表示之基： vf12_Vf1UQn(wherein Z12 is (a) C6.l4 aryl, (b) 5 to 14 membered heterocyclic group, (c) 5 to 14 membered aromatic heterocyclic group, and (d) is 5 to 10 membered heterocyclic group Or a C5.1 cycloaliphatic hydrocarbon-substituted CN6 alkyl group, (e) substituted by a 5 to 10 membered heterocyclic group or a C5.1G alicyclic hydrocarbon group (: 2-6 fluorenyl group, (f) is 5 to a compound having a 10-membered heterocyclic group or an alicyclic group substituted with a C2-6 block or (g) a C3-8 alicyclic hydrocarbon group]] &lt;21&gt;&lt;10&gt; or &lt;20&gt; Or their hydrates, where -29- this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (R is the base of the following formula: vf12_Vf1UQn

[式中：[where:

Vfu為單鍵、可有取代基iCi-6伸烷基或下式表示之基·· vfl2表示（1)氫原子，（2)羥基，（3)可有取代基之5至14員雜 環基，（4)可有取代基之5至14員芳香族雜環基，（5)可有 取代基之C6· 14芳基或（6)式-NRf21Rf22(式中Rf21&amp;Rf22各獨立 為氫原子或可有取代基之烷基）]。 &lt;22〉一種绰式（IIIg)表示之化合物或其鹽或彼等之水合 物·· ' .Vfu is a single bond, may have a substituent iCi-6 alkyl group or a group represented by the following formula: vfl2 represents (1) a hydrogen atom, (2) a hydroxyl group, (3) a 5- to 14-membered heterocyclic ring which may have a substituent a group, (4) a 5- to 14-membered aromatic heterocyclic group which may have a substituent, (5) a C6·14 aryl group which may have a substituent or a formula (6)-NRf21Rf22 (wherein Rf21 &amp; Rf22 are each independently hydrogen Atom or an alkyl group which may have a substituent)]. &lt;22> A compound represented by the formula (IIIg) or a salt thereof or a hydrate thereof.

[式中： X具有與在&lt;2&gt;中之X相同之意義； ： R300及R301具有與在&lt;11〉中之R300及R301相同之意義； -30- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） l3〇4〇61[wherein: X has the same meaning as X in &lt;2&gt;; : R300 and R301 have the same meaning as R300 and R301 in &lt;11>; -30- This paper scale applies to Chinese national standards (CNS) A4 size (210 X 297 mm) l3〇4〇61

A3i選自下列式表示之基：A3i is selected from the group represented by the following formula:

(式中：(in the formula:

Rcl3具有與在&lt;1〇&gt;中之Rcn相同之意義； W’R 及R 具有與在&lt;7&gt;中之\^，11&amp;11及1^13相同之意 義；Rcl3 has the same meaning as Rcn in &lt;1〇&gt;; W'R and R have the same meanings as \^, 11&11 and 1^13 in &lt;7&gt;;

Ab&quot;具有與在&lt;9&gt;中之Ab&quot;相同之意義；Ab&quot; has the same meaning as Ab&quot; in &lt;9&gt;;

Rcl2具有與在&lt;10〉中之Rcu相同之意義；及 Re&quot;為下式表示之基：Rcl2 has the same meaning as Rcu in <10>; and Re&quot; is the base of the following formula:

Vf12—\/代〇Vf12—\/代〇

(式中，Vfll&amp;Vf12具有與在&lt;21&gt;中之vm及相同之意 義；限.制條件為\^12不為氫原子）]。 &lt;23&gt; —種通式（nih)表示之化合物或其鹽或彼等之水合 物： -31 · 1304061 AT B7 五、發明説明（26(wherein, Vfll &amp; Vf12 has the same meaning as vm in &lt;21&gt;; the condition is that \^12 is not a hydrogen atom)]. &lt;23&gt; - A compound represented by the formula (nih) or a salt thereof or a hydrate thereof: -31 · 1304061 AT B7 V. Description of the invention (26

[式中： Z12，R1及R2各具有與在&lt;2&gt;中之 Z12，R1及R2相同之意 義； R3GG及R3G1各具有與在&lt;11&gt;中之R3GG及R3G1相同之意義； A32選自下列式表示之基：[wherein: Z12, R1 and R2 each have the same meaning as Z12, R1 and R2 in &lt;2&gt;; R3GG and R3G1 each have the same meaning as R3GG and R3G1 in &lt;11&gt;; Based on the following formula:

(式中：(in the formula:

Ren具有與在&lt;10〉中之Rel3相同之意義； W，Ral1，Ral2及Ral3分別具有，與在&lt;7〉中之W，Ral1， Ral2及Ral3相同之意義；Ren has the same meaning as Rel3 in &lt;10>; W, Ral1, Ral2 and Ral3 have the same meanings as W, Ral1, Ral2 and Ral3 in &lt;7>, respectively;

Abn具有與在&lt;9&gt;中之Abn相同之意義；及 Rel2具有與在&lt;10〉中之Rel2相同之意義）]。 &lt;24〉&lt; 1&gt;或&lt;2&gt;記載之化合物或其藥理厚上容許之鹽或彼 等之水合物，其選自下列化合物中之任一種： 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 、-- A7 _____________B7 五、發明説明（27 ) N-(4-(6-氰基- 7-(3-(4-吡啶基）丙氧基卜喹啉基）氧苯 基）-N’-(4-.甲氧苯基）脲， Ν·(4·(6-氰基- 7-(2-( 1，2,3-三唑-2-基）乙氧基）-4-喹啉基） 氧苯基）-N，-(4-氟苯基）脲， Ν· (4-(6-氰基-7-(2-( 三唑-卜基）乙氧基卜4•喹啉基） 氧苯基）-N’-(4-氟苯基）脲， 冰（4-(6-氰基-7-(2-( 1，2,3-三唑-2_基）乙氧基卜4-喹啉基） 氧苯基）-Nf-(2,4-二氟苯基）脲，- 队（4-(6-氰基-7-(2-(1，2,3-三唑_1-基）乙氧基广4-喹啉基） 氧苯基）-N，-(2,4-二氟苯基）脲， N_ (4-(6-氰基-7-(2-甲氧基乙氧基卜4^奎啉基）氧苯基卜N，_ (4-氟苯基）脲， Ν·(4-(6-氰基-7-(2-曱氧基乙氧基）-4-喹啉基）氧苯基）-N，-(1，3-嘍唑-2-基）脲， N_(4-(6-氰泰·7·(2-曱氧基乙氧基）_4·喹啉基）氧苯基）-N，-(3 -氰基苯基）躲， 、 Ν·(4-(6-氰基-7-(2-曱氧基乙氧基）-4-喹啉基）氧苯基）-N，-(2-(曱磺醯基）苯基）脲， N-(4-(6-氰基_7-( 2-曱氧基乙氧基.）-4-喹啉基）氧苯基）-N，-環丙脲，. &amp;(4-(6-氰基-7-(2-甲氧基乙氧基）-‘喹啉基）氧-:氟苯 基）_Ν’-(ΐ，3-α 塞峻基）脲， &amp;(4-(6-氰基-7-(2-甲氧基乙氧基卜4&quot;奎啉基）氧-2-氟苯 基）-Ν’-環丙基脲， _ - 33 - 本紙張尺度適财g g家標準(CNS) Α4規格(21Qχ 297公爱) 裝 訂Abn has the same meaning as Abn in &lt;9&gt;; and Rel2 has the same meaning as Rel2 in &lt;10&gt;)]. &lt;24&gt;&lt;1&gt; or &lt;2&gt; or a pharmacologically thick salt or a hydrate thereof, which is selected from any of the following compounds: The paper scale applies to the Chinese national standard ( CNS) A4 size (210 X 297 mm) 1304061, --- A7 _____________B7 V. Description of invention (27) N-(4-(6-Cyano- 7-(3-(4-pyridyl))propoxyb Quinolinyl)oxyphenyl)-N'-(4-.methoxyphenyl)urea, Ν·(4·(6-cyano-7-(2-(1,2,3-triazole-2) -yl)ethoxy)-4-quinolyl)oxyphenyl)-N,-(4-fluorophenyl)urea, Ν·(4-(6-cyano-7-(2-(triazole) -Bu)Ethyloxy-4-quinoyloxyphenyl)-N'-(4-fluorophenyl)urea, ice (4-(6-cyano-7-(2-(1,2) ,3-triazol-2-yl)ethoxy brom 4-quinolinyl)oxyphenyl)-Nf-(2,4-difluorophenyl)urea,-team (4-(6-cyano)- 7-(2-(1,2,3-triazol-1-yl)ethoxypoly-4-quinolinyl)oxyphenyl)-N,-(2,4-difluorophenyl)urea, N_ (4-(6-Cyano-7-(2-methoxyethoxyb 4^ quinolyl)oxyphenyl) N,_(4-fluorophenyl)urea, Ν·(4-(6 -Cyano-7-(2-decyloxyethoxy)-4-quinolyl Oxyphenyl)-N,-(1,3-oxazol-2-yl)urea, N_(4-(6-cyanoethoxy)7(2-decyloxyethoxy)-4 quinolinyl Oxyphenyl)-N,-(3-cyanophenyl), Ν·(4-(6-cyano-7-(2-decyloxyethoxy)-4-quinolinyl) Oxyphenyl)-N,-(2-(nonylsulfonyl)phenyl)urea, N-(4-(6-cyano-7-(2-decyloxyethoxy))-4-quinoline Phenyl)oxyphenyl)-N,-propanylurea,. &amp;(4-(6-Cyano-7-(2-methoxyethoxy)-'quinolinyl)oxy-:fluorobenzene (), Ν'-(ΐ,3-α 塞 基) urea, &amp;(4-(6-cyano-7-(2-methoxyethoxyb 4&quot; quinolyl)oxy-2- Fluorophenyl)-Ν'-cyclopropylurea, _ - 33 - This paper scales GS standard (CNS) Α4 specifications (21Qχ 297 public) Binding

1304061 、 …〜.- A7 - __ ______ B7 五、發明説明1 ~~) —- N-( 4-(6-氰基_7·(2-甲氧基乙氧基卜4-喹啉基）氧苯基）-N，_ 環丙甲基脲， N- (4- ( 6-氰基-7- ( 3-(嗎福琳·4-基）丙氧基）v奎琳·4_基氧）· 2_氟苯基）-&gt;1，-(2，‘二氣苯基）脲， Ν-(4-(6-氰基-7-(3_(二乙胺）丙氧基卜4_喹啉氧基）苯基 Nf-(4-氟苯基）脲， N- (4- ( 6-氰基-7- (3- (4-嗎福啉基）丙氧基）· 4-喳啉基）氧苯 基）-N’-(4-氟苯基）脉， N-(4-(6-氰基-7-(2-甲氧基乙氧基卜4_奎啉基）氧·2·氟苯 基）-Ν’-(3-(甲磺醯基）苯基）脲， Ν-(4-(6-氰基-7-(3-(二乙胺基）丙氧基）-4-喹啉基）氧氟 苯基）·Ν’-(2,4-二氟苯基）脲， Ν-(4-(6-氰基-7-(3-( 1-(4-乙基六氫吡啩基））丙氧基卜心喹 淋基）氧苯基）-N，-(4-甲氧苯基）脲， N- (4- ( 6-氰:棊-7- (3 -氰基丙氧基）-4· 4^林基）氧-2-氟苯基）· Ν’-(2,4-二氟苯基）脲， ·、 Ν·(4-(6-氰基-7-(2-(曱磺醯基）乙氧基）-4-喹啉基）氧_2-氟 苯基）-&gt;Γ-(2,4-二氟苯基）脲， Ν·(4-(6-氰基- 7-(2-(甲磺醯基）乙氧基）-4-喹啉基）氧苯 基）-N’-(4-氟苯基）脲， N- (4- ( 6-氰基-7- (2-曱氧基乙氧基）-4-峻琳基）氧苯基）·ν·-苯基脲， Ν-(4-(6-氰基-7-(2-曱氧基乙氧基）-4-殪啉基）氧-2-氟苯 基）-Ν·-(2,4-二氟苯基）脲， -34- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 13040611304061 , ...~.- A7 - __ ___ B7 V. INSTRUCTION DESCRIPTION 1 ~~) —- N-( 4-(6-Cyano-7·(2-methoxyethoxybu 4-quinolinyl) Oxyphenyl)-N,_cyclopropylmethylurea, N-(4-(6-cyano-7-(3-(moffene-4-yl)propoxy)v-quinein-4-yl Oxygen)· 2_fluorophenyl)-&gt;1,-(2,'di-phenylphenyl)urea, Ν-(4-(6-cyano-7-(3-(diethylamine)propoxy) 4_quinolineoxy)phenyl Nf-(4-fluorophenyl)urea, N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)·4 - porphyrinyl)oxyphenyl)-N'-(4-fluorophenyl) vein, N-(4-(6-cyano-7-(2-methoxyethoxy) 4- quinolyl Oxygen·2·fluorophenyl)-Ν'-(3-(methylsulfonyl)phenyl)urea, Ν-(4-(6-cyano-7-(3-(diethylamino))propyl Oxy)-4-quinolinyl)oxyfluorophenyl)·Ν'-(2,4-difluorophenyl)urea, Ν-(4-(6-cyano-7-(3-( 1- (4-ethylhexahydropyridinyl))propoxycycloquinolyl)oxyphenyl)-N,-(4-methoxyphenyl)urea, N-(4-(6-cyanide: fluorene) -7-(3-Cyanopropoxy)-4·4^linyl)oxy-2-fluorophenyl)·Ν'-(2,4-difluorophenyl)urea, ·, Ν·(4 -(6-cyano -7-(2-(oxasulfonyl)ethoxy)-4-quinolinyloxy-2-fluorophenyl)-&gt;Γ-(2,4-difluorophenyl)urea, Ν· (4-(6-Cyano-7-(2-(methylsulfonyl)ethoxy)-4-quinolinyl)oxyphenyl)-N'-(4-fluorophenyl)urea, N- (4-(6-Cyano-7-(2-decyloxyethoxy)-4-junyl)oxyphenyl)·ν·-phenylurea, Ν-(4-(6-cyano) -7-(2-decyloxyethoxy)-4-indolyl)oxy-2-fluorophenyl)-indole-(2,4-difluorophenyl)urea, -34- paper scale Applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1304061

AT _______B7 五、發明説明（29 ) N-(4-(6-氰基-7-(3-甲氧羰基丙氧基）-4-喹啉基）氧苯基）· N、（4-甲氧，苯基）脲， N-(4-(6-氰基-7-(3_羧基丙氧基）_4-喹啉基）氧苯基）-：^-(4-甲氧苯基）脲， N-(4-( 6-氰基-7-(2-(2-羥基乙氧基）乙氧基）-4^奎啉基）氧 苯基）-N’-(4-甲氧苯基）脲， N-(4-(6-氰基-7-(3-(二乙胺基）丙氧基）_心喹啉氧基）苯 基）-N'-(3-(甲續酿）苯基）脲， N-(4-(6-氰基-7-(3-(4-嗎福啉基）丙氧基）-4-峻啉基）氧苯 基）-N’-(3-(甲磺醯基）苯基）脲， N-( 4-(6-氰基-7-(3-二乙胺基）丙氧基）-4-喹啉氧）笨基）-苯基脲， N- (4- ( 6-氰基-7- ( 3· (4-嗎福啉基）丙氧基）-4-喹啉基）氧苯 基）-Ν^苯基脲， Ν-(4-(6'^^·7-(3-(4_嗎福啉基）丙氧基）·4^奎啉基）氧苯 基）-Ν’-(2-酮基-1,2,3,4-四氫-6-喹啉基）脲， N-(4-(6-氰基- 7-(2-甲氧乙氧基）-4-喹啉基）氧苯基）-N，- (3-乙醯胺苯基）脲， N-(4-(6-氰基-7-苄氧基-4-喹啉基）氧-2-氟苯基）-N，-(2,4-二氟苯基）脲， 义（4-(6-氰基-7-(2-甲氧乙氧基）-4-喹啉基）氧-2-氟苯基）_ N\(4-氟苯基）脲， N-(4-(6-氰基-7-(2-甲氧乙氧基）-4-喹啉基）氧-2-氟苯基卜 Ν’-苯基脲， -35- 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐） 13〇4〇61 '、 A7 ^___ B7 五、發明説明（3〇 ) 4-(‘（（4-氟苯胺基）羰基）胺苯氧基）-7-(2-甲氧乙氧基）-6-喹啉羧醯胺， 7-(2-甲氧乙氧基）-4-( 4-((1,3-噹唑-2-基胺基）羰基）胺基苯 氧基）-6-峻琳基幾酿胺， 4-(4-((苯胺羰基）胺基）-3-氟苯氧基）-7-(2-甲氧乙氧基）- 6- 喹啉羧醯胺， 4-(4-((4-氟苯胺基）羰基）胺基苯氧基）-7-甲氧基-6-喹啉羧 醯胺， 4-(4-((環丙胺基）羰基）胺基苯氧基）-7-( 2-甲氧乙氧基）-6-喹啉羧醯胺， 7- 甲氧基-4-(4-((1,3-嘍唑-2-基胺基）羰基）胺基苯氧基）-6-喹啉羧醯胺， 4-(4-((2,4-二氟苯胺基）羰基）胺基-3-氟苯氧基）-7-甲氧 基-6-喹琳幾醯胺， 4-(4-((環丙》胺基）羰基）胺苯氧基）-7-曱氧基-6-喹啉羧醯 胺， - % 4-(5-((苯胺羰基）胺基）-2-吡啶氧基）-7-甲氧基-6-喹啉羧 醯胺， 4-(4-(苯胺羰基）胺基苯氧基）-7-曱氧基-6-喹啉羧醯胺， 4-(4-(苯胺羰基）胺基苯氧基）-7-( 2-甲氧基乙氧基）-6-喹啉 羧醯胺， 4-(4-((2,4-二氟苯胺基）羰基）胺基-3-氟苯氧基）-7-(2-甲氧 基乙氧基）-6-喹啉羧醯胺， .· 4-(4-((4-氟苯胺基）羰基）胺基-3-氟苯氧基）-7-(2-甲氧基 -36- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 _ A7 * 一 · _ ____ B7 五、發明説明（31 ) '~&quot; 乙氧基）_6-，奎琳叛酿胺， 7-(2-曱氧基乙氧基）-4-(4-((1，3_嘍唑基胺基）羰基）胺 基-3-氟苯氧基）-6-〃奎淋幾酿胺，及 4-(4-((4-氟苯胺基）羰基）胺基氟苯氧基卜甲氧基 峻淋幾醯胺。 &lt;25&gt; &lt;1&gt;或&lt;2&gt;之化合物或其藥理學上容許之鹽或彼等之 水合物，其選自下列化合物中之任一種： 1^(4-(6-氰基-7-(2-曱氧乙氧基）_4_喹啉基）氧-2-氟苯基）·.·^^: N'-(4-氟苯基）脲， ·· N-(2-氯-4-((6-氰基-7-(( 1_曱基·心六氫吡啶基）甲氧基卜 4-喹啉基）氧）苯基）-Nf-環丙基脲， N-(4-((6-氰基-7-(((2R)-3-(二乙胺基卜2_羥基丙基）氧）· 4-喹啉基）氧）苯基）-N，-(4-氟苯基）脲， N-(4-((6-氰基- 7-(( (2R)-2-羥基- 3-(1-吡咯啶基）丙基）· 氧）-心4啉棊）氧）苯基）-N\(4_氟苯基）脲， N- { 4- [ 6-氰基-7- (2-羥基-3-吡咯啶-1 —基a丙氧基）-喹啉·心 基氧]-2-甲基苯基丨-N'-環丙基脲， 4-(4-(4-氟苯胺基）羰基）-4-甲胺基苯氧基）-7-曱氧基-6-4 啉羧醯胺， 4-(3-氯-4-(環丙胺談基）胺苯氧基）-7-甲氧基6-峻琳幾酶 胺， 4-(3-氯-4-(環丙胺羰基）胺苯氧基）-7-(2-曱氧基乙氧基）· - ♦ 6 - β奎琳幾酿胺， ： Ν6-環丙基-4-(3-氯-4-(((環丙胺）羰基）胺基）苯氧基甲 -37- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) ' ~ 1304061 — 、.- A7 ___B7____ 五、發明説明（32 ) 氧基-6-4：琳複醯胺， N6-(2-曱氧乙基）-4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧 基）-7-甲氧基-6-。奎淋幾酿胺， N6-(2-吡啶基）-4-(3_氯-4-(((環丙胺基）羰基）胺基）苯氧 基）-7-曱氧基-6-0奎淋幾酿胺， N6-(2-氟乙基）-4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧 .· 基）-7-曱氧基-6-峻淋幾酿胺， N6-曱氧基4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧基）-7… 甲氧基-6-4：琳幾酿胺， N6-甲基-4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧基）-7-曱 氧基-6-〃奎琳幾醯胺， N6-乙基-4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧基）-7-曱 氧基-6-4:淋幾醯胺， 6-胺曱醯基-4-(1-乙基胺曱醯基-1H-啕哚-5-基氧）-7-甲氧 - 基π奎琳，；， 6-胺曱醯基-7-甲氧基-4-(1-丙基胺甲醯基-1Η-吲哚-5-基 氧]-P奎琳， 6-胺曱醯基-7-甲氧基-4-[ 1-(1-甲基）乙基胺甲醯基-1H-啕 嗓-5 -基氧]嗜琳， N4-(4-{4·-[(苯胺羰基）胺基]-3-氯苯氧基}-2-吡啶基）-l-甲基-4-六氫p比咬幾酿胺， N1-苯基-3-氯-5-[(2-{[(卜甲基-4-六氫吡啶基）羰基]胺… 基卜4-吡啶基）氧]-1H-1-峭哚羧醯胺，： N4-[4-(3-氯-4-{[(4-氟苯胺基）羰基]胺基}苯氧基）-2-吡 -38- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061AT _______B7 V. Inventive Note (29) N-(4-(6-Cyano-7-(3-methoxycarbonylpropoxy)-4-quinolinyl)oxyphenyl)·N, (4-A Oxygen, phenyl)urea, N-(4-(6-cyano-7-(3-carboxypropoxy)-4-quinolinyl)oxyphenyl)-:^-(4-methoxyphenyl) Urea, N-(4-(6-cyano-7-(2-(2-hydroxyethoxy)ethoxy)-4^ quinolyl)oxyphenyl)-N'-(4-methoxy Phenyl)urea, N-(4-(6-cyano-7-(3-(diethylamino)propoxy)-quinolineoxy)phenyl)-N'-(3-(A Phenyl)urea, N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-trendyl)oxyphenyl)-N' -(3-(methylsulfonyl)phenyl)urea, N-(4-(6-cyano-7-(3-diethylamino)propoxy)-4-quinolineoxy)phenyl) -phenylurea, N-(4-(6-cyano-7-(3·(4-morpholinyl)propoxy)-4-quinolinyl)oxyphenyl)-indole-phenylurea , Ν-(4-(6'^^·7-(3-(4-))-propoxy)·4^ quinolyloxyphenyl)-Ν'-(2-keto- 1,2,3,4-tetrahydro-6-quinolinyl)urea, N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxybenzene Base)-N,-(3-acetamidophenyl) Urea, N-(4-(6-cyano-7-benzyloxy-4-quinolinyl)oxy-2-fluorophenyl)-N,-(2,4-difluorophenyl)urea, (4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxy-2-fluorophenyl)_N\(4-fluorophenyl)urea, N-( 4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxy-2-fluorophenylindolide--phenylurea, -35- This paper size is applicable to China Standard (CNS) Α4 size (210X297 mm) 13〇4〇61 ', A7 ^___ B7 V. Description of invention (3〇) 4-('((4-Fluoroanilinyl)carbonyl)amine phenoxy)- 7-(2-methoxyethoxy)-6-quinolinecarboxamide, 7-(2-methoxyethoxy)-4-(4-((1,3-oxazol-2-ylamine) (carbonyl)aminophenoxy)-6-junolinyl, 4-(4-((phenylaminocarbonyl)amino)-3-fluorophenoxy)-7-(2-methoxyB Oxy)- 6-quinoline carboxamide, 4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-methoxy-6-quinoline carboxamide, 4- (4-((Cyclopropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide, 7-methoxy-4-(4-( (1,3-oxazol-2-ylamino)carbonyl)aminophenoxy)-6-quinolinecarboxylate , 4-(4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-methoxy-6-quinolinamine, 4-(4-( (cyclopropyl)amino)carbonyl)aminephenoxy)-7-decyloxy-6-quinolinecarboxamide, -% 4-(5-((phenylaminocarbonyl)amino)-2-pyridyloxy - 7-methoxy-6-quinoline carboxamide, 4-(4-(anilinecarbonyl)aminophenoxy)-7-decyloxy-6-quinoline carboxamide, 4-(4 -(anilinecarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide, 4-(4-((2,4-difluoroanilino)carbonyl) Amino-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide, .. 4-(4-((4-fluoroanilino)carbonyl) Amino-3-fluorophenoxy)-7-(2-methoxy-36- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 _ A7 * 一· _ ____ B7 V. INSTRUCTIONS (31) '~&quot; Ethoxy)_6-, 奎琳叛胺, 7-(2-decyloxyethoxy)-4-(4-((1,3_喽) Azylamino)carbonyl)amino-3-fluorophenoxy)-6-quinone quinone, and 4-(4-((4-fluoroanilino)carbonyl)aminofluorophenoxy Methoxy uranium Amine. &lt;25&gt;&lt;1&gt; or &lt;2&gt; or a pharmacologically acceptable salt thereof or a hydrate thereof, which is selected from any one of the following compounds: 1^(4-(6-cyano) -7-(2-oxime ethoxy)_4_quinolinyloxy-2-fluorophenyl)···^^: N'-(4-fluorophenyl)urea, ··· N-(2 -Chloro-4-((6-cyano-7-((1-indolyl)-hexahydropyridyl)methoxy b- 4-quinolinyl)oxy)phenyl)-Nf-cyclopropylurea, N-(4-((6-Cyano-7-((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)· 4-quinolinyl)oxy)phenyl)-N ,-(4-fluorophenyl)urea, N-(4-((6-cyano-7-((2R)-2-hydroxy-3-(1-pyrrolidinyl)propyl))oxy) -Hetal 4 棊 棊)oxy)phenyl)-N\(4-fluorophenyl)urea, N- { 4-[ 6-cyano-7-(2-hydroxy-3-pyrrolidin-1-yl) Propoxy)-quinoline·cardenyloxy]-2-methylphenylhydrazine-N'-cyclopropylurea, 4-(4-(4-fluoroanilino)carbonyl)-4-methylaminobenzene Oxy)-7-decyloxy-6-4 carboxycarboxamide, 4-(3-chloro-4-(cyclopropylamine)amine phenoxy)-7-methoxy 6-junolin Amine, 4-(3-chloro-4-(cyclopropylaminecarbonyl)amine phenoxy)-7-(2-decyloxyethoxy)· - ♦ 6 - β-quineline amine, : 6-cyclopropyl-4-(3-chloro-4-(((cyclopropylamine)carbonyl))amino)phenoxymethyl-37- This paper scale applies to Chinese national standards (CNS) A4 size (210 X 297 mm) ' ~ 1304061 — ,.- A7 ___B7____ V. Description of invention (32) Oxy-6-4: linaloamine, N6-(2-decyloxyethyl) -4-(3-Chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-.Queridine, N6-(2-pyridyl) 4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-decyloxy-6-0 quinone, N6-(2-fluoroethyl -4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy).yl)-7-decyloxy-6-anthracene, N6-decyloxy 4 -(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7...methoxy-6-4: lining amine, N6-methyl-4-(3- Chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-decyloxy-6-quineline decylamine, N6-ethyl-4-(3-chloro-4- (((Cyclopropylamino)carbonyl)amino)phenoxy)-7-decyloxy-6-4: decylamine, 6-aminoindol-4-(1-ethylamine fluorenyl) -1H-啕哚-5-yloxy)-7-A Oxy-based π-quinein;; 6-aminoindolyl-7-methoxy-4-(1-propylaminemethanyl-1Η-吲哚-5-yloxy)-P-quineline, 6 -Aminomethyl-7-methoxy-4-[1-(1-methyl)ethylamine-carbamoyl-1H-indol-5-yloxy]-lin, N4-(4-{4 ·-[(Acetylcarbonyl)amino]-3-chlorophenoxy}-2-pyridyl)-l-methyl-4-hexahydrop is a bit of chitosan, N1-phenyl-3-chloro- 5-[(2-{[(i-methyl-4-hexahydropyridinyl)carbonyl]amine] phenyl 4-pyridyl)oxy]-1H-1-throindolecarboxamide, N4-[4-(3 -Chloro-4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-2-pyridin-38- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061

淀基]-1-甲基-4-六氫吡啶幾醯胺， 1气2-氯-4-{6-[4-(2-二乙胺基乙氧基）_苯基]·7Η•吡咯幷 [2,3-d]嘧咬-4-基氧}苯基）-3·環丙基脲， 1- {2-氯-4-[6-[4-((2R)-2-羥基·3·二乙胺基丙氧基卜苯 基]-7Η-吡咯并[2,3-d]嘧啶-4-基氧卜苯基卜3_環丙基脲， 1-(2-氯-4-{6-[4-((211)-2-羥基_3-吡咯啶丙氧基）_苯基]-7H-吡咯并[2,3-d]嘧啶-4-基氧卜苯基卜3·環丙基脲，以及 1-(2-氯-4-{6-[4-(2-二乙胺丙氧基）·苯基]·7Η·吡咯幷 [2,3-d]嘧啶-4-基氧}苯基）-3-環丙基脲。 &lt;26&gt; &lt;1&gt;或&lt;2&gt;之化合物或其藥理學上容許之鹽或彼等之 水合物，其選自下列化合物中之任一種： 4-(3-氯-4-(環丙胺羰基）胺苯氧基甲氧基―卜喹啉羧醯 胺， 4-(3-氯-4-(乙胺羰基）胺苯氧基曱氧基-6-喹啉羧醯 胺， :人 N6-甲氧基-4-(3-氯-4-(((環丙胺基）羰基j、胺基）苯氧基卜7-曱氧基-6-0奎淋致酿胺， 4-(3-氯-4-(甲胺羰基）胺苯氧基）-7-甲氧基-6-喹啉複醯 胺，以及 N6-甲氧基-4-(3-氣-4-(((乙胺基）羰基）胺基）苯氧基）-7•甲 氧基-6-4：淋幾酿胺。 &lt;27&gt; —種醫藥，其以&lt;1&gt;至&lt;6〉之任一項記載之化合物或 其藥理學上容許之鹽或彼等之水合物作為有效成分。 &lt;28&gt; —種具有血管新生抑制活性之醫藥，其以至&lt;6&gt; ____-39- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（34 之任一項記載之化合物或其藥理學上容許之鹽或彼等之水 合物作為有效成分9 &lt;29&gt; —種醫藥組合物，其包含下列通式（Π)表示之化合物 或其藥理學上容許之鹽或彼等之水合物’以及藥理學上容 許之載體： (II) V' [式中 Α為可有取代基之5至14員芳香族雜環基； X為氧原子、硫原子、-SO-或-S02-; Y為可有取代基之Cl μ芳基、可有取代基之5至14員芳香族 雜環基或有取代基之烷基； E為單鍵或-NR2-; -、 R1及R2各獨立為氫原子、可有取代基之Cl6烷基、可有取 代基之C2·6烯基、可有取代基之C2.6炔基、可有取代基之 C3·8脂環族烴基、可有取代基之·C2 7醯基或可有取代基之 C2-7貌氧羰基； Z為式-zu-z12{式中： Z11為單鍵、氧原子、硫原子、_c〇-、-S〇2-或可有取代 基之CN6伸烷基； _ z 2為氫原子、可有取代基之^一烷基、可有取代基之C2 ό -40- 本紙張尺度適用中國國家標準(CNS) Α4規格(21〇χ297公釐） Ϊ304061淀]]-1-methyl-4-hexahydropyridine decylamine, 1-gas 2-chloro-4-{6-[4-(2-diethylaminoethoxy)-phenyl]·7Η• Pyrrole [2,3-d] pyridin-4-yloxy}phenyl)-3.cyclopropylurea, 1- {2-chloro-4-[6-[4-((2R)-2- Hydroxy·3·diethylaminopropoxyphenyl]-7Η-pyrrolo[2,3-d]pyrimidin-4-yloxybuphenyl 3-cyclopropylurea 1-(2-chloro -4-{6-[4-((211)-2-hydroxy-3-pyrrolidinyloxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxybenzene Kib3·cyclopropylurea, and 1-(2-chloro-4-{6-[4-(2-diethylaminepropoxy)·phenyl]·7Η·pyrrole[2,3-d And a pharmaceutically acceptable salt thereof or a hydrate thereof Any one selected from the group consisting of 4-(3-chloro-4-(cyclopropylaminecarbonyl)amine phenoxymethoxy-p-quinolinecarboxamide, 4-(3-chloro-4-(ethylamine) Carbonyl)amine phenoxymethoxy-6-quinoline carboxamide, human N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl), amino)phenoxy Keb 7-decyloxy-6-0 quinone-branched amine, 4-(3-chloro-4-(methylaminocarbonyl)amine phenoxy) -7-methoxy-6-quinoline decylamine, and N6-methoxy-4-(3-carb-4-(((ethylamino)carbonyl))amino)phenoxy)-7• Methoxy-6-4: a pharmaceutically acceptable salt, or a pharmacologically acceptable salt thereof, or a compound thereof, or a pharmacologically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. The hydrate is used as an active ingredient. &lt;28&gt; - A medicine having an angiogenesis inhibitory activity, which is applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) on a paper scale of &lt;6&gt; </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Π) a compound or a pharmacologically acceptable salt thereof or a hydrate thereof' and a pharmacologically acceptable carrier: (II) V' [wherein Α is a 5 to 14 member aromatic impurity which may have a substituent a ring group; X is an oxygen atom, a sulfur atom, -SO- or -S02-; Y is a Cl μ aryl group which may have a substituent, a 5- to 14-membered aromatic heterocyclic group which may have a substituent or a substituent Alkyl; E a single bond or -NR2-; -, R1 and R2 are each independently a hydrogen atom, a C6 alkyl group which may have a substituent, a C2·6 alkenyl group which may have a substituent, a C2.6 alkynyl group which may have a substituent, a C3·8 alicyclic hydrocarbon group having a substituent, a C2 7 fluorenyl group which may have a substituent or a C2-7 oxycarbonyl group which may have a substituent; Z is a formula -zu-z12 wherein: Z11 is a single bond , an oxygen atom, a sulfur atom, _c〇-, -S〇2- or a CN6 alkyl group which may have a substituent; _ z 2 is a hydrogen atom, a monoalkyl group which may have a substituent, and a C2 which may have a substituent ό -40- This paper size is applicable to China National Standard (CNS) Α4 specification (21〇χ297 mm) Ϊ304061

五、發明説明（ A7 B7V. Description of the invention (A7 B7

烯基、可有取代基之C2·6炔基、可有取代基之C：3·8脂環 族烴基、可有取代基之C6· 14芳基、可有取代基之5至14 員雜環基、可有取代基之5至14員芳香族雜環基或如下式 之基：Alkenyl group, C2·6 alkynyl group which may have a substituent, C:3·8 alicyclic hydrocarbon group which may have a substituent, C6·14 aryl group which may have a substituent, 5 to 14 members which may have a substituent a cyclic group, a 5 to 14 membered aromatic heterocyclic group which may have a substituent or a group of the formula:

(式中，Z31、z33及Z34各獨立為亞甲基、-c〇·、-NH•或 …Z32為單键、亞〒基、- CO-、-NH-或-〇-)}; 再者，A可被選自下述（1)〜（4)所組成群中之1至6個基取 代： (1) 氰基； (2) #素·原子； (3) 硝;i ;及 、 (4) 式-VX1-VX2-VX22-VX3(式中： νχι，VX2及VX22各獨立為單鍵、氧原子、硫原子、 • C〇_、_s〇-、-s〇2-、式-NRX1-、_C〇NRX1-、式 -NRX1C〇-、式-S02NRX1-、式-NRX1S02-、式-〇-CO-、式-C(0)〇-、式-NRxlC(〇）〇-、式-NRX1(0) NRX2:、式-〇-C(0)NRxl-、式-〇_c(〇)〇-、可有取 代基之Cu伸烷基、可有取代基冬（：2-6晞基、可有取 代基之c2.6炔基、可有取代基之c3.8脂環族烴基、 -41 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1304061 - . A7 — B7 五、發明説明（36 ) 可有取代基之C6-14芳基、可有取代基之5至14員雜環 基或.可有取代基之5至14員芳香族雜環基， VX3、RX1及RX2各獨立為氫原子、可有取代基之(：卜6 烷基、可有取代基之C2-6婦基、可有取代基之C2-6炔 基、可有取代基之C3_8脂環族烴基、可有取代基之 C6-M芳基、可有取代基之5至14員雜環基、可有取代 基之5至14員芳香族雜環基或可有取代基之Cl6烷氧 基)]。 &lt;30&gt; —種血管新生抑制作用能發揮效用之疾病之預防及治 療劑，其以&lt;1&gt;或&lt;2&gt;之化合物或其藥理學上容許之鹽或彼 等之水合物作為有效成份。 &lt;31&gt; —種血管新生抑制劑，其以&lt;1：&gt;或&lt;2&gt;之化合物或其 藥理學上容許之鹽或彼等之水合物作為有效成份。 &lt;32&gt; —種抗腫瘤劑，其以&lt;1&gt;或&lt;2&gt;之化合物或其藥理學 上容許之寧:或彼等之水合物作為有效成份。 &lt;33&gt; —種血管瘤治療劑，其以&lt;1&gt;或&lt;2&gt;之化合物或其藥 理學上谷许之鹽或彼等之水合物作為有效成份。 &lt;34&gt; —種癌轉移抑制劑，其以&lt;1：&gt;或&lt;2&gt;之化合物或其藥 理學上容許之鹽或彼等之水合物作為有效成份。 &lt;35〉一種網膜血管新生症治療劑或糖尿病性網膜症治療 劑，其以&lt;1&gt;或&lt;2〉之化合物或其藥理學上容許之鹽或彼等 之水合物作為有效成份。 &lt;36&gt; —種炎症性疾病治療劑，其以&lt;;ι&gt;或&lt;2&gt;之化合物或 其樂理學上容許足鹽或彼等之水合物作為有效成份。 -42- 本纸張尺度適用中國國家標準(CNS) A4規格(21〇 X 297公釐） A7 B7(wherein Z31, z33 and Z34 are each independently methylene, -c〇·, -NH• or ... Z32 is a single bond, an anthranylene group, -CO-, -NH- or -〇-)}; A may be substituted with 1 to 6 groups selected from the group consisting of (1) to (4): (1) cyano; (2) #素·原子; (3) nitrate; i; (4) Formula -VX1-VX2-VX22-VX3 (wherein: νχι, VX2 and VX22 are each a single bond, an oxygen atom, a sulfur atom, • C〇_, _s〇-, -s〇2-, -NRX1-, _C〇NRX1-, formula -NRX1C〇-, formula -S02NRX1-, formula -NRX1S02-, formula -〇-CO-, formula -C(0)〇-, formula -NRxlC(〇)〇-, Formula -NRX1(0) NRX2:, formula -〇-C(0)NRxl-, formula -〇_c(〇)〇-, Cu which may have a substituent, alkyl group, may have a substituent in winter (: 2- 6 fluorenyl, c2.6 alkynyl group which may have a substituent, c3.8 alicyclic hydrocarbon group which may have a substituent, -41 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1304061 - A7 - B7 V. Inventive Note (36) A C6-14 aryl group which may have a substituent, a 5- to 14-membered heterocyclic group which may have a substituent, or a 5- to 14-membered aromatic heterocyclic group which may have a substituent , VX3, RX1 and RX2 are each independently a hydrogen atom, a substituent (: a 6 alkyl group, a C2-6 group which may have a substituent, a C2-6 alkynyl group which may have a substituent, a C3_8 alicyclic hydrocarbon group which may have a substituent, and a C6 which may have a substituent a -M aryl group, a 5 to 14 membered heterocyclic group which may have a substituent, a 5 to 14 membered aromatic heterocyclic group which may have a substituent or a C6 alkoxy group which may have a substituent)]. &lt;30&gt; A preventive and therapeutic agent for a disease capable of exerting an angiogenesis inhibitory effect, which comprises the compound of <1> or <2> or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient. &lt;31&gt; An angiogenesis inhibitor comprising the compound of &lt;1:&gt; or &lt;2&gt; or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient. &lt;32&gt; And a compound of <1> or <2> or a pharmacologically acceptable compound thereof or a hydrate thereof as an active ingredient. &lt;33&gt; - An angiomas therapeutic agent, which is &lt;1&gt; Or a compound of &lt;2&gt; or a pharmacologically a salt thereof or a hydrate thereof as an active ingredient. &lt;34&gt; - a cancer metastasis inhibitor, which is &lt; A compound of 1:&gt; or &lt;2&gt; or a pharmacologically acceptable salt or a hydrate thereof as an active ingredient. &lt;35&gt; A therapeutic agent for retinal angiogenesis or a therapeutic agent for diabetic retinopathy, which comprises the compound of &lt;1&gt; or &lt;2&gt; or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient. &lt;36&gt; A therapeutic agent for an inflammatory disease, which comprises, as an active ingredient, a compound of &lt;;ι&gt; or &lt;2&gt; or a physiologicly acceptable foot salt or a hydrate thereof. -42- This paper size applies to Chinese National Standard (CNS) A4 specification (21〇 X 297 mm) A7 B7

1304061 五、發明説明（37 &lt;37〉一種包含變形性關節炎、風濕性關節炎、乾癖或延遲 性過敏反應·之炎症性疾病之治療劑，其以〈卜或之化合 物或其藥理學上容許之鹽或彼等之水合物作為有效成份。 &lt;38〉一種粥腫性動脈硬化症治療劑，其以&lt;1：&gt;或&lt;2〉之化 合物或其藥理學上容許之鹽或彼等之水合物作為有效成 份。 &lt;39&gt; —種胰臟癌治療劑、胃癌治療劑、大腸癌治療劑、乳 癌治療劑、前列腺癌治療劑、肺癌治療劑、腎癌治療劑、 腦腫瘤治療劑、血液癌治療劑、或卵巢癌治療劑，其以申 請專利範圍&lt;1&gt;或&lt;2&gt;之化合物或其藥理學上容許之鹽或彼 等之水合物作為有效成份。 &lt;40&gt; —種基於血管新生抑制活性之抗腫瘤劑，其以〈卜或 &lt;2&gt;之化合物或其藥理學上容許之鹽或彼等之水合物作為 有效成份。 &lt;41&gt; 一種〜藤由血管新生抑制作用而預防及治療疾病之方 法，其包含投與患者藥理學上有效量之&lt;：r、〉4&lt;2&gt;i化合物 或其藥理學上容許之鹽或彼等之水合物。 &lt;42&gt; &lt;1&gt;或&lt;2&gt;之化合物或其藥理學上容許之鹽或彼等之 水合物’其被用於製造血管新生抑制作用能發揮效用之疾 病之預防及治療劑。 實施發明之最佳形態 以下將詳細說明本發明之内容。 在本說明書中，化合物之構造，雖為了方便以一定之異 構體表不’但在本發明中，化合物構造上產生之所有幾何 I---- --- -43- 本纸張尺度適用t目目家辟(CNS) A^i^_297公爱)1304061 V. INSTRUCTION OF THE INVENTION (37 &lt; 37> A therapeutic agent comprising an inflammatory disease of deformed arthritis, rheumatoid arthritis, dryness or delayed allergic reaction, which is a compound or pharmacology thereof The above-mentioned salt or the hydrate thereof is used as an active ingredient. <38> A therapeutic agent for atherosclerotic atherosclerosis, which is a compound of &lt;1:&gt; or &lt;2&gt; or pharmacologically acceptable thereof a salt or a hydrate thereof as an active ingredient. &lt;39&gt; - a pancreatic cancer therapeutic agent, a gastric cancer therapeutic agent, a colorectal cancer therapeutic agent, a breast cancer therapeutic agent, a prostate cancer therapeutic agent, a lung cancer therapeutic agent, a renal cancer therapeutic agent, A brain tumor therapeutic agent, a blood cancer therapeutic agent, or a ovarian cancer therapeutic agent, which is a compound of the patent application &lt;1&gt; or &lt;2&gt; or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient. &lt;40&gt; An anti-tumor agent based on an angiogenesis inhibitory activity, which comprises a compound of <br> or <2> or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient. &lt;41&gt; ~ vine by angiogenesis A method for preventing and treating a disease comprising administering to a patient a pharmacologically effective amount of a <:r, >4&lt;2&gt;i compound or a pharmacologically acceptable salt thereof or a hydrate thereof. 42&lt;1&gt; or a compound of <2> or a pharmacologically acceptable salt thereof or a hydrate thereof, which is used for the prophylaxis and treatment of a disease capable of exerting an angiogenesis inhibitory effect. BEST MODES OF THE INVENTION The contents of the present invention will be described in detail below. In the present specification, the structure of the compound, although convenient for a certain isomer, is shown in the present invention, all the geometrical structures produced by the compound I-- -- --- -43- This paper size is applicable to the t-mesh (CNS) A^i^_297 public)

13040611304061

異構物、因不對稱碳產生之光學異構體、立體異構體及互 變異構體等全部異構體以及異構體混合物均被包含在内， 並不限^為了方便而列出之結構式所記載者。X，本發明 化口物尚包含在身體内經氧化、還原、加水分解及結合等 二謝後顯示期望活性之化合物；本發明亦包含在身體内經 氧化、還原及加水分解等代謝後生成本發明化合物之化合 物。再者，本發明亦包含主要為水合物之溶媒合物。 以下·’為本發明所用術語之定義。 在本說明書中，所謂「鹵素原子」係指氟原子、氯原 子、》臭原子及琪原子等函素原？，以氟原子、氯原子及溴 原子為較佳。 在本說明書中，所謂「CN6烷基」表示碳數為卜6之直鏈 或分枝鏈狀之烷基，具體而言為甲基、乙基、正丙基、異 丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、 異戊基、戊基、第三戊基、新戊基、卜甲基丁基、2_ 甲基丁基、1，1-二甲基丙基、二甲基丙基、正己基、異 己基、1-曱基戊基、2-甲基戊基、3-甲基戊基、丨，^二甲基 丁基、1，2-二甲基丁基、2,2-二甲基丁基、1&gt;3-二甲基丁 基、2,3-二曱基丁基、3,3-二甲基丁基、^乙基丁基、2_乙 基丁基、’1，1,2-三甲基丙基、三甲基丙基、^乙基-^ 甲基丙基、1-乙基-2-曱基丙基等；以甲基、乙基、正丙 基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正 戊基、異戊基 '第二戊基、第三戊基、、·新戊基' 甲基丁 基、2-甲基丁基、1，1·二甲基丙基、丨，2-二曱基丙基、正己 ____-44- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（39 基及異己基等為較佳；以甲基、乙基、正基、 正丁基、異丁基、第二丁基、第三丁基、正戊=戊 基、第二戊基、第三戊基、新戊基、丨·甲基丁基、2-甲基 丁基、1，1-二甲基丙基及二甲基丙基為更佳；以甲基、 乙基、正丙基、異丙基、正丁基、異丁基、第二丁基及第 三丁基為特佳；以甲基、乙基、正丙基及異丙基為最佳。All isomers, optical isomers, stereoisomers and tautomers derived from asymmetric carbon, and all isomers and isomer mixtures are included, and are not limited to The structure is described. X, the chemical substance of the present invention further comprises a compound which exhibits desired activity after being oxidized, reduced, hydrolyzed and combined in the body; the present invention also includes the metabolism after oxidation, reduction and hydrolysis in the body. A compound of the inventive compound. Further, the present invention also encompasses a solvent which is mainly a hydrate. The following 'is a definition of the terms used in the present invention. In the present specification, the term "halogen atom" means a fluorine atom, a chlorine atom, a odor atom, and a genomic element such as a qi atom. Preferably, a fluorine atom, a chlorine atom and a bromine atom are preferred. In the present specification, the "CN6 alkyl group" means a straight or branched chain alkyl group having a carbon number of 6, especially methyl, ethyl, n-propyl, isopropyl, n-butyl. , isobutyl, tert-butyl, tert-butyl, n-pentyl, isopentyl, pentyl, third amyl, neopentyl, methylbutyl, 2-methylbutyl, 1,1-di Methylpropyl, dimethylpropyl, n-hexyl, isohexyl, 1-decylpentyl, 2-methylpentyl, 3-methylpentyl, hydrazine, dimethyl butyl, 1, 2 - dimethylbutyl, 2,2-dimethylbutyl, 1&gt; 3-dimethylbutyl, 2,3-didecylbutyl, 3,3-dimethylbutyl, ^ethyl Butyl, 2-ethylbutyl, '1,1,2-trimethylpropyl, trimethylpropyl, ^ethyl-^methylpropyl, 1-ethyl-2-mercaptopropyl Etc.; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl, n-pentyl, isopentyl 'second pentyl, third Pentyl, neopentyl 'methylbutyl, 2-methylbutyl, 1,1 dimethylpropyl, hydrazine, 2-dimercaptopropyl, hexyl ____-44- paper Scale applies to China Home Standard (CNS) A4 Specification (210 X 297 mm) 1304061 A7 B7 V. Description of the Invention (39 bases and iso-hexyl groups are preferred; methyl, ethyl, n-butyl, n-butyl, isobutyl, Dibutyl, tert-butyl, n-pentyl-pentyl, second pentyl, third amyl, neopentyl, oxime methylbutyl, 2-methylbutyl, 1,1-dimethyl More preferably, propyl and dimethylpropyl; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and t-butyl are preferred; The base, ethyl, n-propyl and isopropyl groups are most preferred.

在本說明書中，所謂「Cld伸烷基」意指從上述「Cw烷 基」中去除1個氫原子所衍生之二價基，具體而言，例如為 亞甲基、伸乙基、甲基伸乙基、伸丙基、乙基伸乙基、 1，1-二甲基伸乙基、1，2-二甲基伸乙基、三亞甲基、^甲基 三亞甲基、1-乙基三亞甲基、2-曱基三亞曱基、二甲基 三亞曱基、四亞甲基、五亞甲基及六亞甲基等。 在本說明書中，所謂「C2.6晞基」意指碳數為2〜6之直鏈 或分枝鏈狀烯基，亦即碳數為2以上之上述rCi 6燒基」中 具有雙鍵·之1取代基。具體而言，例如為乙缔基、卜丙缔-卜 基、2-丙晞-1-基、3-丙烯-1-基、1-丁烯&gt;^基、^ 丁缔 基、1-丁晞-3-基、1-丁烯-4-基、2-丁烯·-基、孓丁烯-2· 基、1-曱基-1-丙晞-1-基、2-曱基_1-丙缔·ι基、^曱基· 2-丙晞-丨-基、2-甲基-2-丙晞-i-基、u曱基-1 丁烯 基、2-甲基-1-丁缔·1·基、3-甲基-1-丁缔基、^甲基· 2- 丁烯-1-基、2-曱基-2- 丁烯-1-基、3_甲基丁烯-卜 基、1-甲基-3- 丁烯-1-基、2-甲基-3- 丁缔_ 基、3·甲基· 3- 丁烯-1-基、1-乙基-1-丁烯_ 1-基、，孓乙基·卜丁烯_ ^ 基、3-乙基-1-丁烯-1-基、1-乙基-2-丁烯-丨·基、乙基 -45- 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 1304061 s - A7 B7五、發明説明（40 ) 2- 丁烯-1-基、3-乙基-2- 丁烯-1-基、1-乙基-3- 丁晞-1-基、2-乙基-3-丁晞-1-基、3-乙基-3-丁晞-1-基、1,1-二甲 基-1-丁婦-1-基、1，2-二甲基-1-丁烯-1-基、1,3-二甲基-1-丁烯-1-基、2,2-二甲基-1-丁晞-1-基、3,3-二甲基-1-丁烯-1-基、1,1-二甲基-2-丁烯-1-基、1，2-二甲基-2-丁烯-1-基、1，3-二甲基-2- 丁烯-1-基、2,2-二甲基-2- 丁烯-1-基、 3,3-二甲基-2-丁烯-1-基、1，1-二甲基-3-丁烯-1-基、1,2-二甲基：3-丁烯-1-基、1，3-二曱基-3-丁缔-1-基、2,2-二甲 基-3- 丁烯-1-基、3,3-二甲基-3- 丁婦-1-基、1-戊缔-1-基、2-戊晞-1-基、3-戊烯-1-基、4-戊烯-1-基、1-戊晞-2-基、2-戊晞-2-基、3-戊烯-2-基、4-戊烯-2-基、1-戊烯-3-基、2-戊烯-3-基、1-戊烯-1-基、2-戊缔-1-基、3-戊烯-1-基、4-戊婦-1 -基、1-戊缔-2-基、2 -戊婦-2 -基、3 -戊缔-2 _ 基、4-戊烯-2-基、1-戊烯-3-基、2-戊烯-3-基、1-甲基-1-戊烯-1-基曱基-1-戊婦-1-基、3-甲基-1-戊烯-1-基、 4-曱基-1-戊烯-1-基、1-甲基-2-戊烯-1-基、2-甲基-2-戊 烯-1-基、3-曱基-2-戊烯-1-基、4-甲基-2-戊烯-1-基、1-曱基-3-戊烯-1-基、2-甲基-3-戊烯-1-基、3-甲基-3-戊烯-1-基' 4-甲基-3-戊烯-1-基、1-甲基-4-戊晞-1-基、2-甲 基-4-戊烯-1-基、3-曱基-4-戊烯-1-基、4-甲基-4-戊烯-1-基、1-甲基-1-戊烯-2-基、2-曱基-1-戊缔-2-基、3-甲基- 1- 戊烯-2-基、4-曱基-1-戊晞-2-基、1-曱基-2-戊烯-2-基、2-甲基-2-戊烯-2-基、3-甲基-2-戊烯-2-基、4-甲基- 2- 戊晞-2-基、1-甲基-3-戊烯-2-基、2-甲基-3-戊烯-2- -46- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 s.- A7 B7五、發明説明（41 ) 基、3-甲基-3-戊缔-2-基、4-甲基-3-戊晞-2-基、1-甲基-4-戊缔-2-基、2-甲基-4-戊烯-2-基、3-甲基-4-戊烯-2-基、4-曱基-4-戊烯-2-基、1-甲基-1-戊晞-3-基、2-甲基- 1- 戊烯-3-基、3-甲基-1-戊烯-3-基、4-甲基-1-戊烯- 3-基、1-甲基-2-戊烯-3-基、2-甲基-2-戊婦-3-基、3-甲基- 2- 戊缔-3-基、4-甲基-2-戊晞-3-基、1-己烯-1-基、1-己 烯-2-基、1-己稀-3-基、1-己烯-4-基、1-己烯-5-基、卜己 烯-6-基、2-己烯-1-基、2-己缔-2-基、2-己烯-3-基、2-己 = 烯-4-基、2-己缔-5-基、2-己晞-6-基、3-己缔-1-基、3 -己 烯-2-基及3-己烯-3-基等；以乙烯基、1-丙烯-1-基、2-丙 缔-1 -基、3 -丙缔-1 -基、1 - 丁婦-1 -基、1 - 丁稀 - 2 -基、1 - 丁 烯-3-基、1-丁烯-4-基、2-丁晞-1-基、2-丁烯-2-基、1-曱 基-1-丙晞-1-基、2-甲基-1-丙晞-1-基、1-甲基-2-丙缔-1-基、2-甲基-2-丙埽-1-基、1-甲基-1-丁烯-1-基、2-甲基--1- 丁烯-1二基、3-甲基-1- 丁烯-1-基' 1-甲基-2- 丁烯-1-基、2-甲基-2-丁烯-1-基、3-甲基-2-丁烯-1-基、1-甲基- 3- 丁婦-1-基、2-甲基-3- 丁烯-1-基、3-甲基-3- 丁晞-1-基、1-乙基-1-丁烯-1-基、2-乙基-1-丁烯-1-基、3-乙基-1-丁烯· 1-基、1-乙基-2-丁烯-1-基、2-乙基-2- 丁烯-1-基、3-乙基-2-丁缔-1-基、1-乙基-3-丁婦-1-基、2-乙基· 3 - 丁烯-1-基、3-乙基-3- 丁烯-1-基、1，1-二甲基-1- 丁晞-1-基、1,2-二甲基-1- 丁烯-1-基、1,3-二甲基-1- 丁烯-1-基、2,2-二甲基-1-丁烯-1-基、3,3-二甲基-1-丁烯-1-基、 1，1-二甲基-2-丁烯-1-基、1,2-二甲基-2-丁烯-1-基、1，3- -47- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 :、 〜- A7 B7 五、發明説明（42 ) 二甲基-2-丁烯-1-基、2,2-二甲基-2-丁烯-1-基、3,3-二甲 基-2-丁烯-1-基、1，1-二甲基-3-丁烯-1-基、1，2-二甲基-3-丁烯-1-基、1，3-二甲基-3-丁烯-1-基、2,2-二甲基-3-丁烯-1-基、3,3-二甲基-3- 丁烯-1-基為較佳；以乙烯基、1-丙 烯-1-基、2-丙烯-1-基、3-丙烯-1-基、1-丁埽-1-基、1-丁 烯-2-基、1-丁晞-3-基、1-丁烯-4-基、2-丁稀-1-基、2-丁 婦-2 -基、1 -甲基-1 -丙錦^ - 1 -基、2 -甲基-1 -丙輝τ - 1 -基、1 -甲基-2'丙晞-1-基、2-甲基-2-丙烯-1-基、1-甲基-l-丁婦- 1- 基、2-甲基-1-丁婦-1-基、3-曱基-1-丁烯-1-基、1-甲 基-2-丁烯-1-基、2-甲基-2-丁烯-1-基、3-甲基-2-丁烯-1-基、1-甲基-3-丁烯-1-基、2-曱基-3-丁烯-1-基及3-曱基-3 - 丁烯-1-基為更佳；以乙烯基、1-丙晞-1-基、2-丙烯-1-基、3-丙晞-1-基、1-丁烯-1-基、1-丁烯-2-基、1-丁婦-3-基、1-丁烯-4-基、2-丁烯-1-基及2-丁晞-2-基為最佳。 在本說哂書中，所謂「C2_6炔基」意指碳數為2〜6乏直鏈 或分枝鏈狀炔基，亦即碳數為2以上之上述「匕_6烷基」中 具有參鍵之取代基。具體而言，例如為乙炔基、1-丙決-1-基、2-丙決-1-基、3 -丙块-1-基、1-丁块-1-基、1-丁块- 2· 基、1-丁炔-3·基、1-丁炔-4-基、2-丁炔-1-基、2-丁炔-2-基、1-甲’基-1-丙炔-1-基、2-甲基-1-丙炔-1-基、1-甲基- 2- 丙炔-1-基、2-甲基-2-丙炔-1-基、1-甲基-1- 丁炔-1-基、2-甲基-1- 丁炔-1-基、3-甲基-1- 丁炔-1-基、1-甲基-2- 丁炔-1-基、2-甲基-2- 丁炔-1-基、3-甲基-2- 丁炔-1-基、1-曱基-3- 丁炔-1-基、2-甲基-3- 丁炔-1-基、3-甲基- -48- 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 裝 訂In the present specification, the term "Cld alkylene group" means a divalent group derived by removing one hydrogen atom from the above "Cw alkyl group", specifically, for example, a methylene group, an ethyl group, and a methyl group. Ethyl, propyl, ethyl ethyl, 1,1-dimethylmethyl, 1,2-dimethylethyl, trimethylene, methyltrimethylene, 1-ethyl Trimethylene, 2-mercaptotrientylene, dimethyltrientylene, tetramethylene, pentamethylene and hexamethylene. In the present specification, the term "C2.6 mercapto" means a straight or branched chain alkenyl group having a carbon number of 2 to 6, that is, a double bond having the carbon number of 2 or more and the above rCi 6 alkyl group. · 1 substituent. Specifically, it is, for example, an ethyl group, a propyl group, a 2-propen-1-yl group, a 3-propen-1-yl group, a 1-butene group, a butyl group, and a 1- Butyl-3-yl, 1-buten-4-yl, 2-butenyl-yl, fluoren-2-yl, 1-mercapto-1-propan-1-yl, 2-indenyl _1-Binyl·Im base, 2-mercapto-2-propanyl-fluorenyl-, 2-methyl-2-propionium-i-yl, u-mercapto-1 butenyl, 2-methyl- 1-Butyl-1, 3-methyl-1-butylidene, ^methyl-2-buten-1-yl, 2-mercapto-2-buten-1-yl, 3-methyl Butylene-buyl, 1-methyl-3-buten-1-yl, 2-methyl-3-butan-1-yl, 3-methyl-3-buten-1-yl, 1-B -1-butene-1-yl, fluorenylethylbutenyl-^, 3-ethyl-1-buten-1-yl, 1-ethyl-2-butene-fluorenyl , Ethyl-45- This paper scale is applicable to China National Standard (CNS) Α4 specification (210X297 mm) 1304061 s - A7 B7 V. Description of invention (40) 2-buten-1-yl, 3-ethyl-2 - Buten-1-yl, 1-ethyl-3-butan-1-yl, 2-ethyl-3-butan-1-yl, 3-ethyl-3-butan-1-yl, 1,1-Dimethyl-1-butan-1-yl, 1,2-dimethyl-1-buten-1-yl, 1,3-dimethyl-1-buten-1-yl , 2,2-Dimethyl-1-butan-1-yl, 3,3-dimethyl-1-buten-1-yl, 1,1-dimethyl-2-buten-1-yl 1,2-dimethyl-2-buten-1-yl, 1,3-dimethyl-2-buten-1-yl, 2,2-dimethyl-2-butene-1- , 3,3-dimethyl-2-buten-1-yl, 1,1-dimethyl-3-buten-1-yl, 1,2-dimethyl:3-butene-1 -yl, 1,3-dimercapto-3-butan-1-yl, 2,2-dimethyl-3-buten-1-yl, 3,3-dimethyl-3-butyl- 1-yl, 1-pentan-1-yl, 2-pentan-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-pentan-2-yl, 2 -penta-2-yl, 3-penten-2-yl, 4-penten-2-yl, 1-penten-3-yl, 2-penten-3-yl, 1-pentene-1 -yl, 2-pentan-1-yl, 3-penten-1-yl, 4-pentan-1-yl, 1-pent-2-yl, 2-pentyl-2-yl, 3- Penta-2-yl, 4-penten-2-yl, 1-penten-3-yl, 2-penten-3-yl, 1-methyl-1-penten-1-ylindolyl- 1-pentyl-1-yl, 3-methyl-1-penten-1-yl, 4-mercapto-1-penten-1-yl, 1-methyl-2-penten-1-yl , 2-methyl-2-penten-1-yl, 3-mercapto-2-penten-1-yl, 4-methyl-2-penten-1-yl, 1-indolyl-3- Penten-1-yl, 2-methyl-3-penten-1-yl, 3-methyl- 3-penten-1-yl' 4-methyl-3-penten-1-yl, 1-methyl-4-pentan-1-yl, 2-methyl-4-penten-1-yl , 3-mercapto-4-penten-1-yl, 4-methyl-4-penten-1-yl, 1-methyl-1-penten-2-yl, 2-mercapto-1- Pentam-2-yl, 3-methyl-1-penten-2-yl, 4-mercapto-1-pentan-2-yl, 1-mercapto-2-penten-2-yl, 2 -methyl-2-penten-2-yl, 3-methyl-2-penten-2-yl, 4-methyl-2-pentan-2-yl, 1-methyl-3-pentene -2-yl, 2-methyl-3-pentene-2-46- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 s.- A7 B7 V. Invention (41) group, 3-methyl-3-pentan-2-yl, 4-methyl-3-pentan-2-yl, 1-methyl-4-pentan-2-yl, 2-methyl 4-penten-2-yl, 3-methyl-4-penten-2-yl, 4-mercapto-4-penten-2-yl, 1-methyl-1-pentanthene-3 -yl, 2-methyl-1-penten-3-yl, 3-methyl-1-penten-3-yl, 4-methyl-1-pentene-3-yl, 1-methyl- 2-penten-3-yl, 2-methyl-2-pentyl-3-yl, 3-methyl-2-pentane-3-yl, 4-methyl-2-pentan-3-yl , 1-hexen-1-yl, 1-hexen-2-yl, 1-hexyl-3-yl, 1-hexen-4-yl, 1-hexene-5-yl, hexene- 6 -yl, 2-hexen-1-yl, 2-hexan-2-yl, 2-hexen-3-yl, 2-hex=en-4-yl, 2-hexa-5-yl, 2 -hexyl-6-yl, 3-hexan-1-yl, 3-hexen-2-yl and 3-hexen-3-yl, etc.; with vinyl, 1-propen-1-yl, 2- Propion-1-yl, 3-propan-1-yl, 1-butan-1-yl, 1-butadien-2-yl, 1-buten-3-yl, 1-butene-4- , 2-butan-1-yl, 2-buten-2-yl, 1-mercapto-1-propan-1-yl, 2-methyl-1-propen-1-yl, 1- Methyl-2-propan-1-yl, 2-methyl-2-propen-1-yl, 1-methyl-1-buten-1-yl, 2-methyl--1-butene -1 diyl, 3-methyl-1-buten-1-yl' 1-methyl-2-buten-1-yl, 2-methyl-2-buten-1-yl, 3-methyl 2-buten-1-yl, 1-methyl-3-butan-1-yl, 2-methyl-3-buten-1-yl, 3-methyl-3-butan-1 -yl, 1-ethyl-1-buten-1-yl, 2-ethyl-1-buten-1-yl, 3-ethyl-1-butene-1-yl, 1-ethyl- 2-buten-1-yl, 2-ethyl-2-buten-1-yl, 3-ethyl-2-butan-1-yl, 1-ethyl-3-butan-1-yl , 2-ethyl-3-buten-1-yl, 3-ethyl-3-buten-1-yl, 1,1-dimethyl-1-butan-1-yl, 1,2- Dimethyl-1-butene-1 -yl, 1,3-dimethyl-1-buten-1-yl, 2,2-dimethyl-1-buten-1-yl, 3,3-dimethyl-1-butene- 1-yl, 1,1-dimethyl-2-buten-1-yl, 1,2-dimethyl-2-buten-1-yl, 1,3- -47- This paper size is applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) 1304061 :, ~- A7 B7 V. Description of Invention (42) Dimethyl-2-buten-1-yl, 2,2-dimethyl-2 -buten-1-yl, 3,3-dimethyl-2-buten-1-yl, 1,1-dimethyl-3-buten-1-yl, 1,2-dimethyl- 3-buten-1-yl, 1,3-dimethyl-3-buten-1-yl, 2,2-dimethyl-3-buten-1-yl, 3,3-dimethyl -3-buten-1-yl is preferred; vinyl, 1-propen-1-yl, 2-propen-1-yl, 3-propen-1-yl, 1-butan-1-yl, 1-buten-2-yl, 1-butan-3-yl, 1-buten-4-yl, 2-butyl-1-yl, 2-butan-2-yl, 1-methyl- 1 - propyl hydrazine ^ - 1 -yl, 2-methyl-1-propanol- 1 -yl, 1-methyl-2'propan-1-yl, 2-methyl-2-propene-1- , 1-methyl-l-butan-1-yl, 2-methyl-1-butan-1-yl, 3-mercapto-1-buten-1-yl, 1-methyl-2 -buten-1-yl, 2-methyl-2-buten-1-yl, 3-methyl-2-butyl -1-yl, 1-methyl-3-buten-1-yl, 2-mercapto-3-buten-1-yl and 3-mercapto-3-buten-1-yl are more preferred; With vinyl, 1-propen-1-yl, 2-propen-1-yl, 3-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 1- D-butyl-3-yl, 1-buten-4-yl, 2-buten-1-yl and 2-butan-2-yl are preferred. In the present specification, the term "C2_6 alkynyl" means a straight or branched chain alkynyl group having 2 to 6 carbon atoms, that is, the above-mentioned "匕_6 alkyl group" having a carbon number of 2 or more. Substituent substituents. Specifically, for example, ethynyl, 1-propen-1-yl, 2-propen-1-yl, 3-propan-1-yl, 1-butan-1-yl, 1-butyl- 2·yl, 1-butyn-3-yl, 1-butyn-4-yl, 2-butyn-1-yl, 2-butyn-2-yl, 1-methyl'yl-1-propyne -1-yl, 2-methyl-1-propyn-1-yl, 1-methyl-2-propyn-1-yl, 2-methyl-2-propyn-1-yl, 1-methyl -1-butyn-1-yl, 2-methyl-1-butyn-1-yl, 3-methyl-1-butyn-1-yl, 1-methyl-2-butyne-1 -yl, 2-methyl-2-butyn-1-yl, 3-methyl-2-butyn-1-yl, 1-mercapto-3-butyn-1-yl, 2-methyl- 3-butyn-1-yl, 3-methyl--48- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) Binding

線 1304061 〜 〜A7 B7 五、發明説明（43 ) 3 -丁決-1-基、1-乙基-1-丁块-1-基、2-乙基-1- 丁块-1 · 基、3 -乙基-1 - 丁決-1 -基、1 -乙基-2 - 丁块-1 -基、2 -乙基-2 - 丁決-1 -基、3 -乙基-2 *•丁块-1 -基、1 -乙基-3 - 丁块：-1 -基、2-乙基-3-丁炔-1-基、3-乙基-3-丁炔-1-基、1,1-二甲 基-1-丁炔-1-基、1，2-二曱基-1-丁炔-1-基、1，3-二甲基-1-丁炔-1-基、2,2-二甲基-1-丁炔-1-基、3,3-二甲基-1-丁炔-1-基、1，1-二甲基-2-丁炔-1-基、1，2-二甲基-2-丁炔-1-基、1，3.-二甲基-2-丁炔-1-基、2,2-二曱基-2-丁炔-1-基、 3,3-二甲基-2-丁炔-1-基、1，1-二甲基-3-丁炔-1-基、1，2-二甲基-3-丁炔-1-基、1,3-二甲基-3-丁炔-1-基、2,2-二甲 基-3- 丁炔-1-基、3,3-二曱基-3- 丁炔-1-基、1-戊炔-1-基、2-戊炔-1-基、3-戊块-1-基、4-戊炔-1-基、1-戊炔-2-基、2-戊炔-2-基、3-戊炔-2-基、4-戊炔-2-基、1-戊炔-3-基、2-戊炔-3-基' 1-戊炔-1-基、2-戊決-1-基、3-戊炔-1-基、4-戊巷基、1-戊炔-2-基、2-戊块-2-基、3-戊炔-2-基、4-戊炔-2-基、1-戊炔-3-基、2-戊炔:、3-基、1-甲基-1-戊炔-1-基、2-曱基-1-戊炔-1-基、3-曱基-1-戊炔-1-基、 4-甲基-1-戊決-1-基、1-甲基-2-戊炔-1-基、2-甲基-2-戊 炔-1-基、3-甲基-2-戊炔-1-基、4-曱基-2-戊炔-1-基、1-甲基-3-戊炔-1-基、2-甲基-3-戊炔-1-基、3-甲基-3-戊炔-1-基、4-甲基-3-戊炔-1-基、1-甲基-4-戊炔-1-基、2-甲 基-4-戊炔-1-基、3-甲基-4-戊炔-1-基、4-甲基-4-戊炔-1-基、1-甲基-1-戊炔-2-基、2-甲基-1-戊炔-2-基、3-甲基-1-戊炔-2-基、4-甲基-1-戊炔-2-基、1-甲基-2-戊炔-2- -49- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（44 ) 基 、2-甲基-2-戊炔-2- 基 、3-甲基-2- 戊決-2 -基、4 · 甲基- 2- 戊炔-2-基、1-甲基 -3- 戊炔-2-基 、2-甲基-3-戊 決-2 - 基 、3-甲基-3-戊炔-2- 基 、4-曱基-3- 戊炔-2-基、1- 甲基- 4- 戊炔-2-基、2-曱基 -4- 戊炔-2-基 、3-甲基-4-戊 块-2 _ 基 、4-甲基-4-戊炔-2- 基 、1-甲基-1- 戊炔-3-基、2- 甲基- 1- 戊決-3-基、3-甲基 -1- 戊決-3 -基 、4-甲基-1-戊 決-3 · 基 、1-甲基-2-戊炔-3- 基 、2-甲基-2- 戊炔-3-基、3- 甲基- _ 2- 戊炔：· 3-基、4-曱基- -2- 戊炔-3-基、 1-己炔-1-基、 • 峰 • 1-己一- 決 -2-基、1-己炔-3-基 ' 1 -己決-4-基 、1•己炔-5-基’ 、1-己 炔 -6 -基、2 -己块-1 -基 、2-己炔-2-基 、2-己決-3-基’ 、2-己 炔 -4-基、2-己炔-5-基 、2 -己決-6 -基 、3 -己決-1 -基’ 、3-己 块 -2-基及3-己炔-3-基等 :以乙炔基 、1 -丙決-1 -基’ 、2-丙 決 -1 - 、3 -丙 ^： - 1 - ' 1 -丁決-1 -基 、1-丁炔-2-基 、1-丁 決 -3-基、1-丁炔-4-基 、2·•丁炔-1-基 、2-丁炔-2-基’ 、1-甲· 基-1-丙炔：1-基、2-曱 基- 1-丙決-1-基 .、1 -甲基-2 -丙 炔-1- 基 、2 -甲基-2 -丙块：-1 · 基 、1-甲基-1- 丁炔-1-基、2- 曱基- 1- 丁炔-1-基、3-曱基 -1- 丁炔-1 -基 、1-曱基-2- 丁 炔-1- 基 、2-甲基-2- 丁炔-1- 基 、3-甲基-2- 丁炔-1 -基、1- 甲基- 3- 丁炔-1-基、2-甲基 -3- 丁炔-Γ-基 、3-甲基-3- 丁 炔-1- 基 、1-乙基-1- 丁炔-1- 基 、2-乙基-1- 丁炔-1-基 ' 3- 乙基- 1- 丁決-1 -基、1 -乙基 -2- 丁炔-1-基 、2-乙基-2- 丁 炔-1 - 基 、3-乙基-2- 丁炔-1- 基 、1-乙基-3- 丁決-1 -基、2 - 乙基_ 3- 丁炔-1-基、3-乙基- 3- 丁炔-1 -基、 1; 1 -二甲基-1 - 丁炔- 1- 基、1,2-二甲基-1- · 丁炔-1-基、1,3-二甲基-1- 丁 炔-1- -50- 裝 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 訂Line 1304061 ~ ~A7 B7 V. Description of the invention (43) 3-buten-1-yl, 1-ethyl-1-butan-1-yl, 2-ethyl-1-butyl block-1 · group, 3-ethyl-1 -butyl-1-yl, 1-ethyl-2-butan-1-yl, 2-ethyl-2-buten-1-yl, 3-ethyl-2*• Butyl-1 -yl, 1-ethyl-3-butan:-1-yl, 2-ethyl-3-butyn-1-yl, 3-ethyl-3-butyn-1-yl, 1,1-dimethyl-1-butyn-1-yl, 1,2-dimercapto-1-butyn-1-yl, 1,3-dimethyl-1-butyn-1-yl 2,2-Dimethyl-1-butyn-1-yl, 3,3-dimethyl-1-butyn-1-yl, 1,1-dimethyl-2-butyn-1- 1,1,2-dimethyl-2-butyn-1-yl, 1,3.-dimethyl-2-butyn-1-yl, 2,2-dimercapto-2-butyne- 1-yl, 3,3-dimethyl-2-butyn-1-yl, 1,1-dimethyl-3-butyn-1-yl, 1,2-dimethyl-3-butyne -1-yl, 1,3-dimethyl-3-butyn-1-yl, 2,2-dimethyl-3-butyn-1-yl, 3,3-diinden-3-yl Alkyn-1-yl, 1-pentyn-1-yl, 2-pentyn-1-yl, 3-pent-1-yl, 4-pentyn-1-yl, 1-pentyn-2-yl , 2-pentyn-2-yl, 3-pentyn-2-yl, 4-pentyn-2-yl, 1-pentyn-3-yl, 2-pentyn-3-yl' 1-pentyne -1-base , 2-penten-1-yl, 3-pentyn-1-yl, 4-pentenyl, 1-pentyn-2-yl, 2-pentyl-2-yl, 3-pentyne-2- , 4-pentyn-2-yl, 1-pentyn-3-yl, 2-pentyne:, 3-yl, 1-methyl-1-pentyn-1-yl, 2-mercapto-1 -Pentyn-1-yl, 3-mercapto-1-pentyn-1-yl, 4-methyl-1-penten-1-yl, 1-methyl-2-pentyn-1-yl, 2-methyl-2-pentyn-1-yl, 3-methyl-2-pentyn-1-yl, 4-mercapto-2-pentyn-1-yl, 1-methyl-3-pentyl Alkyn-1-yl, 2-methyl-3-pentyn-1-yl, 3-methyl-3-pentyn-1-yl, 4-methyl-3-pentyn-1-yl, 1- Methyl-4-pentyn-1-yl, 2-methyl-4-pentyn-1-yl, 3-methyl-4-pentyn-1-yl, 4-methyl-4-pentyne- 1-yl, 1-methyl-1-pentyn-2-yl, 2-methyl-1-pentyn-2-yl, 3-methyl-1-pentyn-2-yl, 4-methyl 1-pentyn-2-yl, 1-methyl-2-pentyne-2-49- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention Description (44) group, 2-methyl-2-pentyn-2-yl, 3-methyl-2-penten-2-yl, 4 · methyl-2-pentyn-2-yl, 1- Methyl-3-pentyn-2-yl, 2-methyl-3-pentyl-2-yl, 3-methyl-3-pentyne-2- , 4-mercapto-3-pentyn-2-yl, 1-methyl-4-pentyn-2-yl, 2-mercapto-4-pentyn-2-yl, 3-methyl-4 -pentyl-2 _ group, 4-methyl-4-pentyn-2-yl, 1-methyl-1-pentyn-3-yl, 2-methyl- 1-pent-3-yl, 3-methyl-1-pentyl-3-yl, 4-methyl-1-pent-3-enyl, 1-methyl-2-pentyn-3-yl, 2-methyl-2-pentyl Alkyn-3-yl, 3-methyl- -2- 2-pentyne: 3-yl, 4-mercapto--2-pentyn-3-yl, 1-hexyn-1-yl, • Peak • 1 -hexyl-demethyl-2-yl, 1-hexyn-3-yl '1-hexen-4-yl, 1 ·hexyne-5-yl', 1-hexyne-6-yl, 2-hexyl Block-1 -yl, 2-hexyn-2-yl, 2-hex-3-yl', 2-hexyn-4-yl, 2-hexyne-5-yl, 2-hexyl-6 , 3-hexyl-1 -yl', 3-hexyl-2-yl and 3-hexyn-3-yl, etc.: ethynyl, 1-propyl-l-yl', 2-propene- 1 - , 3 - propyl ^: - 1 - ' 1 -buten-1-yl, 1-butyn-2-yl, 1-butan-3-yl, 1-butyn-4-yl, 2· • butyn-1-yl, 2-butyn-2-yl', 1-methyl-1-propyne: 1-yl, 2-mercapto- 1-propan-1-yl., 1 - Methyl-2-propyn-1-yl, 2 -Methyl-2-propane block: -1 · group, 1-methyl-1-butyn-1-yl, 2-mercapto- 1-butyn-1-yl, 3-mercapto-1-yl Alkyn-1-yl, 1-mercapto-2-butyn-1-yl, 2-methyl-2-butyn-1-yl, 3-methyl-2-butyn-1-yl, 1- Methyl-3-butyn-1-yl, 2-methyl-3-butynyl-fluorenyl, 3-methyl-3-butyn-1-yl, 1-ethyl-1-butyne- 1-yl, 2-ethyl-1-butyn-1-yl' 3-ethyl-1-butan-1-yl, 1-ethyl-2-butyn-1-yl, 2-ethyl 2-butyne-1-yl, 3-ethyl-2-butyn-1-yl, 1-ethyl-3-butan-1-yl, 2-ethyl-3-butyne-1- , 3-ethyl-3-butynyl-1-yl, 1; 1 -dimethyl-1-butynyl-1-yl, 1,2-dimethyl-1-butyn-1-yl , 1,3-dimethyl-1-butyne-1- -50- paper size applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

線 l3〇4〇6lLine l3〇4〇6l

i 基、3,3_二甲基小丁块·卜基、 u-二甲基-2-丁炔小基、…甲基_2· 丁炔·卜基、。· 一甲基-2-丁块-1-基、22 -二甲基7 盆 ， T 暴-2-丁炔-1-基、3,3-二甲 基丁決-1-基、1 ，—甲基丁炔-1-基、1，2·二甲基-3- 以]V，3·二甲基乂丁炔+基、2,2-二甲基-3-丁块· 3,3 —甲基丁炔基為較佳；以乙炔基、1-丙 決，1-基、2-丙块-1·基 ^ 3-丙炔 基、1· 丁炔-1-基、1-Τ 炔^2-基、1-丁块-3-基、·| 丁枚/甘 · 丞 1-丁炔·4·基、2-丁炔-1-基、2· 丁 決-2,基、I甲基-1丙炔 J厌·卜i、2-甲基-1-丙炔·ι基、^ 甲基，2 -丙決-1-基、2-甲宜〇工α 4 签2甲基_2·丙炔-1-基、卜甲基-1-丁炔- 土、2-甲基]-丁炔小基、3_甲基]•丁炔·卜基、1·曱 mi' 2H2m·基、3-甲基·2·丁決.卜 土 1-甲基丁炔基、2•甲基_3_丁炔•基及弘甲基_ 3 丁炔小棊為更佳；U乙炔基、i•丙炔·卜基、2·丙炔]· 基、3_丙^^基、h 丁块小基、1-丁決-2-基' i-丁炔-3- 基丨-丁炔基、孓丁炔-；μ基及丁炔.，2-基為特佳；以 乙決基、1-丙炔-1-基、2-丙炔-；[-基及3一丙炔基為最 佳〇 :在本說明書中’所謂「€3-8環坑基」意指碳數3〜8之環狀 运基’具.體而言’例如為環丙基、環丁基、環戊基及環己 基。以環丙基為較佳。 在本說明書中，所謂「C38環烯基」意指碳數3〜8之環狀 缔基，具體而言，例如為環戊缔基及環已烯基。 在本說明書中，所謂「（：3.8環炔基」意指碳數3〜8之環狀 j___ -51 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1304061 五、發明説明（ A7 B7i group, 3,3-dimethylsobutyl bromide, u-dimethyl-2-butyne small group, methyl 2·butynyl group. · monomethyl-2-butan-1-yl, 22-dimethyl 7-pot, T-violet-2-butyn-1-yl, 3,3-dimethylbutan-1-yl, 1, —Methylbutyn-1-yl, 1,2·dimethyl-3-,]V,3·dimethylbutynyl+, 2,2-dimethyl-3-butyl·3, 3-methylbutynyl is preferred; ethynyl, 1-propionyl, 1-yl, 2-propion-1-yl-3-propynyl, 1·butyn-1-yl, 1- Τ alkyne^2-yl, 1-butan-3-yl,·|丁丁/甘·丞1-butyne·4·yl, 2-butyn-1-yl, 2·butyl-2 , I methyl-1 propyne J · · · i, 2-methyl-1-propyne · ι, ^ methyl, 2-propyl -1- group, 2- 甲 〇 α α 4 sign 2 Methyl-2·propyn-1-yl, benzyl-1-butyne-soil, 2-methyl]-butyne small group, 3-methyl]-butyne-diyl, 1·曱mi' 2H2m ·Base, 3-methyl·2·丁决.Bu soil 1-methylbutynyl, 2·methyl_3-butynyl group and Hong methyl _ 3 butyne oxime are more preferable; U acetylene , i•propyne·buyl, 2·propyne]·yl, 3—propyl group, h-butyl group, 1-butan-2-yl 'i-butyne-3-ylindole- Butynyl, indomethan-; μ-based and butyne-, 2-yl is particularly preferred; with ethyl, 1-propyne- 1-Based, 2-propyne-; [-based and 3-propynyl are the best hydrazine: in the present specification, the term "€3-8 ring pit base" means a ring number of carbon numbers 3 to 8. The base 'is, for example, 'is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. A cyclopropyl group is preferred. In the present specification, the "C38 cycloalkenyl group" means a cyclic group having 3 to 8 carbon atoms, and specifically, for example, a cyclopentyl group and a cyclohexenyl group. In this specification, the term "(:3.8 Cycloalkynyl) means a ring of carbon number 3 to 8 j___ -51 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1304061 V. Invention Description (A7 B7

決基，具體而&quot;F，例如為環己決基。 在本說明書中，所謂「C3-8環烷氧基」意指上述(：3.8環烷 基之終端結合有氧原子者，具體而言，例如為環丙氧基、 環丁氧基、環戊氧基及環己氧基。 在本說明書中，所謂「C34脂環族烴基」意指碳數3〜8之 環狀烴基，亦即上述「c3-8環烷基」、「c3-8環烯基」及·: 「Cl s環炔基」所界定之取代基。以環丙基為較佳、 … . ——一 在本說明書中，所謂「Cl-6烷氧基」意指上述「Cl.6烷 基」結合在氧原子上之取代基，具體而言，例如為甲氧 基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧 基、第二丁氧基、第三丁氧基、正戊氧基、異戊氧基、第 二戊氧基、第三戊氧基、新戊氧基、1-甲基丁氧基、甲 基丁乳基、1，1- 一甲基丙氧基、1,2 -二甲基丙氧基、正己氧 基、異己氧基、1-曱基戊氧基、2-甲基戊氧基、3-甲基戊-氧基、1，1广二甲基丁氧基、12-二甲基丁氧基、2,2-二甲基 ， 丁氧基、1，3 -二甲基丁氧基、2,3-二甲基丁氧基、3,3 -二甲 基丁氧基、1-乙基丁氧基、2-乙基丁氧基、ι，ι，2-三曱基丙 氧基、1，2,2-三甲基丙氧基、1-乙基-丨·甲基丙氧基及卜乙 基· 2-甲基丙氧基等；以甲氧基、乙氧基、正丙氧基、異丙 氧基、正·丁氧基、異丁氧基、第二丁氧基、第三丁氧基、 正戊氧基、異戊氧基、第二戊氧基、第三戊氧基、新戊氧. 基、1-甲1 丁氧基、2-甲基丁氧基、ι，ΐ-二甲基丙氧基、-: 1，2-二甲基丙氧基、正己氧基及異己氧:基等為較佳；以甲 氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧 -52- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜 A7 _ B7 五、發明説明（47 ) 基、第二丁氧基、第三丁氧基、正戊氧基、異戊氧基、第 二戊氧基、·第三戊氧基、新戊氧基、丨-甲基丁氧基、2_甲 基丁氧基、1，1-二甲基丙氧基及1,2-二甲基丙氧基為更佳； 以甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異 丁氧基、第一丁氧基及第三丁氧基為特佳；以及以甲氧 基、乙氧基、正丙氧基及異丙氧基為最佳。 在說明書中，所謂「Cl7醯基」意指在上述r Ci /烷 基」、.·「Cn缔基」及「Cu炔基」之終端結合有羰基之取二 代基，具體而言，例如為乙醯基、丙醯基、丁醯基、異丁 酿基、戊醯基、異戊醯基？特戊醯基、己醯基、辛醯基、 丙缔酿基、甲基丙缔醯基、巴豆醯基及苄醯基等。以乙醯 基、丙醯基、丁醯基、異丁醯基、戊醯基、異戊醯基、特 戊醯基、己醯基、辛醯基、丙缔醯基' 甲基丙烯醯基、巴 旦酸基及芊酿基為較佳；以乙醯基、丙醯基、丁醯基、異· 丁醯基、-喪趨基、異戊醯基、特戊醯基、己醯基、辛醯基 及爷酿基為更佳；以乙酿基、丙醯基、下酿基、異丁酿基 及；酿基為特佳；以及以乙醯基、丙醯基及苄醯基為最 佳。 在本說明書中，所謂「c2-7烷氧羰基」意指與上述「Ci 6 燒氧基」·結合之羰基，具體而言例如為甲氧羰基、乙氧羰 基、正-丙氧羰基、異丙氧羰基、第二丙氧羰基、正丁氧羰. 基、異丁氧羰基、1，2-二曱基丙氧羰基及2-乙基丙氧羰基- 等。 ^ 在本說明書中，所謂「正-」（η-)意指常態型或1級取代 ___ - 53 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公爱） 一 13〇4〇61The basis, specific and "F," for example, the ring base. In the present specification, the term "C3-8 cycloalkoxy" means the above (: 3.8 cycloalkyl group is bonded to an oxygen atom at the terminal, specifically, for example, a cyclopropoxy group, a cyclobutoxy group, or a cyclopentane group. In the present specification, the "C34 alicyclic hydrocarbon group" means a cyclic hydrocarbon group having 3 to 8 carbon atoms, that is, the above-mentioned "c3-8 cycloalkyl group" and "c3-8 ring". "Alkenyl" and ": a substituent defined by "Cl s cycloalkynyl". Preferably, cyclopropyl is used, ... - In this specification, "Cl-6 alkoxy" means "the above" a substituent of a C.6 alkyl group bonded to an oxygen atom, specifically, for example, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, Dibutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, second pentyloxy, third pentyloxy, neopentyloxy, 1-methylbutoxy, methyl butyl 1,1,1-methylpropoxy, 1,2-dimethylpropoxy, n-hexyloxy, isohexyloxy, 1-decylpentyloxy, 2-methylpentyloxy, 3- Methyl pentyloxy, 1,1 dimethyl dimethyloxy, 12-dimethylbutoxy , 2,2-dimethyl, butoxy, 1,3 -dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethyl Butoxy, 2-ethylbutoxy, ι,ι,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-fluorenylmethylpropoxy And ethyl ethyl 2-methylpropoxy group; methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, third Butoxy, n-pentyloxy, isopentyloxy, second pentyloxy, third pentyloxy, neopentyloxy, 1-methyl-1-butoxy, 2-methylbutoxy, ι, Ϊ́-dimethylpropoxy, -: 1,2-dimethylpropoxy, n-hexyloxy and isohexyloxy: and the like are preferred; methoxy, ethoxy, n-propoxy, iso Propyloxy, n-butoxy, isobutoxy-52- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ~ A7 _ B7 V. Description of invention (47) Base, Dibutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, second pentyloxy, third pentyloxy, neopentyloxy, fluorenyl-methylbutoxy, 2-methyl Butoxy, 1,1-dimethylpropoxy and 1,2-dimethylpropoxy are more preferred; methoxy, ethoxy, n-propoxy, isopropoxy, n-butyl The oxy group, the isobutoxy group, the first butoxy group and the third butoxy group are particularly preferred; and the methoxy group, the ethoxy group, the n-propoxy group and the isopropoxy group are most preferred. The term "Cl7 fluorenyl" means a second-generation group having a carbonyl group bonded to the terminal of the above-mentioned r Ci /alkyl", "Cn-based" and "Cu alkynyl group", specifically, for example, an ethyl group. , propyl sulfhydryl, butyl sulfhydryl, isobutyl aryl, pentamidine, isoamyl hydrazino, pentylene, hexyl decyl, octyl decyl, propyl aryl, methyl propyl sulfhydryl, crotonyl and benzamidine Base. Ethylene, propyl, butyl, isobutyl, pentylene, isoamyl, pentylene, hexyl, octyl, propyl-methyl methacrylate, sulphate and The brewing base is preferred; it is preferably an ethyl sulfonium group, a propyl fluorenyl group, a butyl sulfhydryl group, an isobutyl fluorenyl group, a sulphonyl group, an isovaleryl group, a pentylene group, a hexanyl group, a octyl group, and a geranyl group; It is best to use ethyl ketone, propyl sulfonyl, decyl, isobutyl and broth; and ethyl hydrazide, propyl hydrazide and benzhydryl. In the present specification, the "c2-7 alkoxycarbonyl group" means a carbonyl group bonded to the above "Ci 6 alkoxy group", and specifically, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a n-propyloxycarbonyl group or a different group. Propoxycarbonyl, second propoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, 1,2-dimercaptopropoxycarbonyl and 2-ethylpropoxycarbonyl- and the like. ^ In this specification, the so-called "positive-" (η-) means normal or 1st-order ___ - 53 - This paper scale applies to the Chinese National Standard (CNS) Α 4 specification (210 X 297 public). 4〇61

、發明説明（ 基’ 「第二」（sec-)意指2級取代基，「第三」（卜）意指3級 取代基；以及「異」（i)意指異型取代基β 在本說明書中，所謂r Ci 6伸烷二氧基」意指從上述 境基」除去1個氫原子而衍生之二價基之二終端各具 有氧原子之取代基，具體而言，例如為亞甲二氧基、伸乙 —氧基、伸丙二氧基、伸丁二氧基、伸戊二氧基及伸己二 氧基等。 、在本說明書中，所謂rC6_14芳基」可為碳數6至14之芳香 族％式基，具體而言，例如為苯、戊嗒烯、氫茚、莕、甘 匍藍烴、庚嗒埽、亞聯苯基、苯并二茚、見晞、芴基、 苯欺審及惹等，以苯、戊塔烯、氫莽、莫及甘菊藍烴 為較佳。 例如為氧 錫、錯、 意指構成 在本說明書中，所謂r雜原子」，具體而言 原子、硫原子、氮原子、_、_、#1 硼及汞等，氧原子U子及氮原子為較佳。 在本說明書中，所謂「5至14員芳香族 :子一，且構成該環式基二= 式美。JL W，、縣子及I原子等雜原子之芳香族環 式基具植而言，例如為吡咯環、吡咬 «、鄉㈣環”㈣、咪：厂比㈣環、塔 料、異•環，環'嗜呤環、；:::、：唉 %、異喹啉環、喹畊環、S大畊環 '莫啶戸 唑衣、喹啉 唑啉環”亭啉環、堞啶環、咪唑二喳喏啉環、喳 環、㈣并^環K環K環=、,幷三呼 唑環、咔唑啉 j_____— -54- 本纸張尺1適用中國國家標準(CNS) A4^i^l&lt;297^y 13〇4〇61 五、 發明説明（ 49 %、^環、啡琳環、啡b井環&quot;号二峻環 = 環及環含氮=族 吡喃产 衣及+并嚯吩環等含硫芳香族雜環卜夫喊環' 含心:::r:b:= 气唑璜、# ^. 吞哩衣異嚯唑環、苯并 唑衣苯并嚜唑環'苯并嘍二唑環、啡嘍，井環、晨 衣、咬咕環、啡十井環、吨棱并^ 地7工 噻吩并咕咗护,.^ 木唉并噻唑環、 咬产i |、吱心^環K并外環、吱喃并外 衣、呋喃并嘧啶環、噻吩并嘧啶環及哼唑環 原子、硫原子及氧原子中潠屮夕 α有從氮 雜環基。1「tr 上之雜原子之芳香族 環:广5至14貞芳香族雜環基」以峨唉環”比相 、=環、咪㈣”㈣環、料環、異料環十井 環^井、環、茶唉環”奎七林環、.林環”丫淀環、啡咬 環、、：:::？、吱喃環，環、苯并吱喃 哈并rt 、啡七井環”比嘻并㈣環”比 吩并麵環等為較佳;.w環、嗅吩 衣奉幵嘎吩環、噻唑環、苯并 環、4琳環”比嘻并喃咬環、·，、二㈣”奎唾琳 吩并射環等為更I ❻、心W咬環及遠 成書中，所謂「5至14員非芳香族雜環基」意指構 2式基之環之原子數為5至14，且構成該環式基之環之原 子巧個以上氮原子、较原子及氧原子等雜原子之非芳香_ 族％式基。具體而f，例如為吨哈咬基.”比嘻琳基 '六氫 吡呢基、六氫吡呼基'N.甲基六氣t井基、咪唑啉基、吡 _______-55« 本纸張尺用中g g家標準(CNS) ^規格(21Qx 297公g 裝 訂 1304061 A7 ______ ___ B7 五、發明説明（50 ) 峻咬基 '咪峻淀基、嗎福啉基、四氫吡喃基、吖丁啶基、 氧雜環丁烷基、氧硫雜環戊烷基、吡啶酮環、2-吡咯啶酮 壤、環亞乙基腺、1，3·二氧戊環基、丨^二，号烷環、丨，心二 、坑壤、献酿亞胺環及琥珀醯亞胺環等非芳香族雜環基。 ^ 5至14員非芳香族雜環基」以吡咯啶基、六氫吡啶基及 嗎福啉基等為較佳；以吡咯啶基、六氫吡啶基、嗎福啉基 及吡咯環為更佳。 、^本說明書中，所謂「5至14員雜環基」意指構成環式基 足裱疋原子數為5至14，且構成該環式基之環之原子包含i 個以亡氮原子、硫原子及氧原子等雜原子之芳香族或非芳 香族％式基’其巾前者4「5至14貝芳香族雜環基」，後者 為「5至14員非芳香族雜環基」。因此，「5幻4員雜環 之具體例’例如為上述「5至14員芳香族雜環基」之具 月豆例錢上述「5至14員非芳香族雜環基」之具體例。 二5至1州基」例如爾咬基、六氯⑽、嗎 福林基、p比嘻環、@ ?| ,iS ^ 疋衣、吡啶酮環、嘧啶環、咪唑環、 r…”環、異峻琳環、七井環 t七林環、4料、以環、以環、嚷吩環 t、味喃環”比喃環、苯并峡喃環，塞咬環 環為較佳；，《、六μι 馬钿啉基、吡咯環、咐 、 ^ 、苯并心環，環、=奎=林吩/ \苯心塞吩環、 酮環為更佳，·以噻唑環、喳、衣、啤啉環及喹喏 喏酮環為特佳。 衣&quot;三唑啉環、呀啉環及喹 莕啶環、 苯并α塞吩 苯并p塞咬 卩比, invention description (base "second" (sec-) means a level 2 substituent, "third" (b) means a level 3 substituent; and "extra" (i) means a heterotype substituent β in In the specification, the term "r Ci 6 alkylenedioxy" means a substituent having an oxygen atom at the terminal of each of the divalent groups derived by removing one hydrogen atom from the above-mentioned environment, and specifically, for example, a methylene group a dioxy group, an exoethyloxy group, a propylene dioxy group, a butyl dioxy group, a pentylene dioxy group, and a hexylene dioxy group. In the present specification, the so-called rC6_14 aryl group may be a carbon number. An aromatic % group of 6 to 14, specifically, for example, benzene, pentacene, hydroquinone, hydrazine, cinerein, hydrazine, biphenylene, benzodiazepine, see ruthenium, osmium Base, benzene bullying, and arsenic, etc., preferably benzene, pentadiene, hydroquinone, and chamomile blue hydrocarbon. For example, oxygen tin, wrong, meaning in the present specification, the so-called r hetero atom, Specifically, an atom, a sulfur atom, a nitrogen atom, _, _, #1, boron, mercury, etc., and an oxygen atom U and a nitrogen atom are preferable. In the present specification, the so-called "5 to 14 member fragrance" : sub-, and constitutes the ring-based group II = formula. JL W,, county and I atom and other heteroatoms of the aromatic ring-based plant, such as pyrrole ring, pyridine «, town (four) ring "(4), Mi: Plant ratio (four) ring, tower material, iso-ring, ring 'isophilic ring,;:::,: 唉%, isoquinoline ring, quinacine ring, S large cultivating ring 'Moridazole Benzene, quinazoline ring "tinolin ring, acridine ring, imidazoporphyrin ring, anthracene ring, (d) and ring K ring K ring =, 幷trioxazole ring, oxazoline j_____--54 - This paper ruler 1 is applicable to China National Standard (CNS) A4^i^l&lt;297^y 13〇4〇61 V. Description of invention (49%, ^ ring, 琳琳环, 啡b well ring &quot;号二Junction ring = ring and ring nitrogen-containing = family pyran-producing clothes and + porphin ring and other sulfur-containing aromatic heterocyclic buff ring "with heart:::r:b:= azrazil, # ^.嚯 嚯 Isoxazole ring, benzoxazole-coated benzoxazole ring 'benzo oxadiazole ring, morphine, well ring, dressing gown, bite ring, brown well ring, ton edge and ^ 7 thiophene And protect, .^ 唉 唉 thiazole ring, bite production i |, 吱 heart ^ ring K and outer ring, 吱 并 and coat, furan pyrimidine ring, thiophene The pyrimidine ring and the carbazole ring atom, the sulfur atom and the oxygen atom have a nitrogen heterocyclic group. The "aromatic ring of a hetero atom on the tr: a broad 5 to 14 fluorene aromatic heterocyclic group"唉 ring" ratio phase, = ring, microphone (four)" (four) ring, material ring, heterogeneous ring ten well ring ^ well, ring, tea 唉 ring "Kui Qilin ring, Lin ring" 丫 环 ring, brown bite ring, ,::::?, 吱 环 ring, ring, benzopyrene and rt, 七七环环"比嘻和(四)环" is better than the 吩 面面面, etc.; w ring, olfactory The porphin ring, the thiazole ring, the benzo ring, the 4 lin ring, the 嘻 嘻 喃 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 奎 奎 奎 奎 奎 为 为 为 为 为 为 为 为 为 为 为 为 为 为 为The phrase "5 to 14 member non-aromatic heterocyclic groups" means that the number of atoms of the ring of the formula 2 is 5 to 14, and the atoms constituting the ring of the ring group are more than one atom, more atom and oxygen. Non-aromatic _ family % base of heteroatoms such as atoms. Specifically, f, for example, is a ton of bite base." than 嘻琳基' hexahydropyryl, hexahydropyryl 'N. methyl hexa-t-well, imidazolinyl, pyr _______-55« Paper ruler used in the gg standard (CNS) ^ specification (21Qx 297 g g binding 1304061 A7 ______ ___ B7 V, invention description (50) 咬 基 ' 'Mijiujiu, morpholinyl, tetrahydropyranyl , azetidinyl, oxetanyl, oxathiolanyl, pyridone ring, 2-pyrrolidone, cycloethylene gland, 1,3 dioxolanyl, oxime, Non-aromatic heterocyclic groups such as alkane ring, anthracene, heart two, pit soil, flavonoid ring and amber quinone ring. ^ 5 to 14 members of non-aromatic heterocyclic group" with pyrrolidinyl group, hexahydro A pyridyl group, a morpholinyl group and the like are preferred; a pyrrolidinyl group, a hexahydropyridyl group, a morpholinyl group and a pyrrole ring are more preferred. In the present specification, the phrase "5 to 14 membered heterocyclic group" means The atom constituting the ring-based group has 5 to 14 atoms, and the atom constituting the ring of the ring group contains i aromatic or non-aromatic % of a hetero atom such as a nitrogen atom, a sulfur atom and an oxygen atom. Base 'the former 4" 5 to 14 aromatic aromatic heterocyclic groups, the latter being "5 to 14 member non-aromatic heterocyclic groups". Therefore, the "specific example of the 5 magic 4 member heterocyclic ring" is, for example, the above-mentioned "5 to 14 member aromatic hetero The specific example of the above-mentioned "5 to 14-member non-aromatic heterocyclic group" of the ring-shaped Beans. The two-to-one-state bases such as ergo, hexachloro (10), phlophin, and p. Ring, @?|, iS ^ 疋, pyridone ring, pyrimidine ring, imidazole ring, r..." ring, heterojune ring, seven well ring t seven forest ring, 4 material, ring, ring, porphin ring t, 味环环" is more preferred than the ring, benzotrim ring, plug ring ring;, ", liu 钿 钿 钿 、, pyrrole ring, 咐, ^, benzo heart ring, ring, = 奎= Lin phene / \ benzoxin ring, ketone ring is better, · thiazole ring, hydrazine, clothing, porphyrin ring and quinacridone ring is particularly good. Clothing &quot; triazoline ring, porphyrin ring And quinacridine, benzo-α-phene benzopyrene

裝 訂Binding

線 本紙張尺度適财目@家標準(CNS) ' 56 - 1304061Line Paper size scales @家标准(CNS) ' 56 - 1304061

「在本說明書中，所謂「6至14員芳香族雜環基」意指上述 「5至14員芳香族雜環基」所定義之取代基之中，構成環式 基之環之原子數為6至14之取代基。具體而言，例如為吡啶 環、吡啶酮環、嘧啶環、啕哚環、喹啉環、異喹啉環、喹 畊環、酞哜環、莕啶環、喹唑啉環、崎啉環、吖啶環、苯 并嘍吩裱、苯并呋喃環、嘍唑環、苯并嘍唑環及啡噻畊環· 等。 在本說明書中，所謂「6至14員雜環基」意指上述「5至·$ 14員雜環基」所定義之取代基之中，構成環式基之環之原 子數為6至14之取代基。具體而言，例如為六氫吡啶基、六 氫吡畊基、N-甲基六氫吡畊基、嗎福啉基、四氫吡喃基、 1,4-二呤烷環及酞醯亞胺環等。 在本說明書中，所謂「C6-M芳基CN6烷基（=芳烷基）」意 伯上述「Cu垸基」中，可被取代之部份被上述「c6 i4芳· 基」取代基，具體而言，例如為苄基、苯乙基、3_苯丙 基、4-苯丁基、5_苯戊基、心苯己基、卜萘甲基、萘甲 基、1-莕乙基、2-莕乙基、1-莕丙基及2-莕丙基等。以苄 基、苯乙基、3-苯丙基、4-苯丁基、5-苯戊基、6-苯己 基、1-審甲基、2-莕曱基、1-莕乙基、2_莕乙基、^萘丙 基及2-蒸丙基為較佳；以芊基、苯乙基、3·苯丙基、‘苯 丁基、5'苯戊基、6_苯己基、丨_莕曱基及2_莕甲基為更 佳；以苄基、苯乙基、3-苯丙基及4-苯丁基為特佳；以苄_ : 基及苯乙基為最佳。 ·· 在本說明書中，所謂「5至14員雜環基匕·6烷基」意指上 -57-"In the present specification, the "6 to 14 member aromatic heterocyclic group" means the number of atoms of the ring constituting the ring group among the substituents defined by the above "5 to 14 member aromatic heterocyclic group". Substituents of 6 to 14. Specifically, for example, a pyridine ring, a pyridone ring, a pyrimidine ring, an anthracene ring, a quinoline ring, an isoquinoline ring, a quinoline ring, an anthracene ring, an acridine ring, a quinazoline ring, a pyridyl ring, Acridine ring, benzoxanthene, benzofuran ring, carbazole ring, benzoxazole ring, and thiophene ring. In the present specification, the "6 to 14 membered heterocyclic group" means a substituent defined by the above "5 to - 14 membered heterocyclic group", and the number of atoms constituting the ring group is 6 to 14 Substituent. Specifically, for example, a hexahydropyridyl group, a hexahydropyridinyl group, an N-methylhexahydropyridinyl group, a morpholinyl group, a tetrahydropyranyl group, a 1,4-dioxane ring, and a quinone Amine ring and the like. In the present specification, the "C6-M aryl CN6 alkyl (= aralkyl group)" is a substituent which is substituted by the above "c6 i4 aryl group" in the above "Cu fluorenyl group". Specifically, for example, a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, a 5-phenylpentyl group, a cardinyl group, a naphthylmethyl group, a naphthylmethyl group, a 1-fluorenylethyl group, 2-荇ethyl, 1-mercaptopropyl and 2-mercaptopropyl. Benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1-methyl, 2-indenyl, 1-indenyl, 2荇 荇 ethyl, ^ naphthylpropyl and 2-vaporated propyl are preferred; fluorenyl, phenethyl, 3-phenylpropyl, 'phenylbutyl, 5' phenylpentyl, 6-phenylhexyl, fluorene More preferably, the benzyl group and the 2-methyl group are particularly preferred; the benzyl group, the phenethyl group, the 3-phenylpropyl group and the 4-phenylbutyl group are particularly preferred; and the benzyl group: benzyl group and the phenethyl group are most preferred. ·· In this specification, the phrase “5 to 14 members of heterocyclic 匕·6 alkyl” means upper -57-

13040611304061

述「cN0烷基」中，可被取代之部份被上述「5至14員雜環 基」取代之基，具體而τ，例如為吡啶甲基、吡啶甲 基及2-喹啉甲基等。 在本說月曰中，做為「脫離基」者，只要為有機合成上 =知為脫離基之基，將無特殊之限制，具體而言，例如為 虱原子、溴原子及碘原子等鹵素原子，曱硫基、乙硫基及.· 丙硫基等燒硫基’苯硫基、甲苯硫基及2“比症硫基等芳疏 基，甲磺醯氧基、三氟甲磺醯氧基、乙磺醯氧基及丙磺醃三:· 氧基等烷磺醯氧基，苯磺醯氧基及對甲苯磺酿氧基等芳磺… 酿乳基，乙酿氧基及三氟乙酿氧基等㈣氧基，甲氧基' 乙氧基及丙氧基等烷氧基，甲胺基、乙胺基、丙胺基及丁 胺基等燒胺基’二甲胺基、二乙胺基、二丙胺基、甲基乙 胺、乙基丙胺及曱基丙胺等二貌胺基，二苯氧鱗酿氧基等 經取代磷醯氧基等；以氯原子、溴原子及碘原子等卣素原· 子以及二卷&lt;*甲橫酿氧基等為較佳。 _ 在本說明書中’所謂r可有取代基」意指「在可被取代 之部位上，可具有以任意方式組合之〗或複數個取代基」， 該取代基，具體而言例如為（1)函素原子，（2)羥基，（3)硫 醇基，（4)硝基，（5)腈基，（6)酮基，（7)疊氮基，（8)胍 基，（9)胼基，（1〇)異氰基，（11)氰酸酯基，（12)異氰酸酯 基，（13)硫氰酸酯基，（14)異硫氰酸酯基，（15)亞硝基， (16)胺曱醞基（脲基），（17)曱醯基，（i8)Ci 6醯亞胺基，_ : (19)各可，函素化或#至基化之燒基u基、決 基、C3.6¥烷基、c3 δ環烯基、c36環炔基、ci6烷氧基、 - ----- -58- 本紙張尺度適用中國國家標準(CNS) 1304061 A7 B7 五、發明説明（53 ) C2.6晞氧基、C2.6炔氧基、C3.6環烷氧基、Ci.6烷硫基、C2.6 烯硫基、C.2.6炔硫基、C3-6環烷硫基或c!.6伸烷二氧棊， (20)C6.14芳基，（21)5至14員雜環基，（22)羧基，（23)三氟 甲基，（24)C6-14芳基Cu燒基，（25)5至14員雜環烷 基或（26)式-VXX1-VXX2-VXX3-VXX4(式中，VXX1，VXX2 及 VXX3各獨立為1)單鍵、2)氧原子、3)硫原子、4)式-CO-、5) 式-SO-、6)式-S02-、7)式-NRXX1-、8)式-C〇NRXX1-、9)... 式-NRXX21CO-、10)式-S02NRXX1-、11)式-NRXX1S02-、12)二: 式-0-C0-、13)式-C(0)0-、14)式-NRXX1C(0)0-、15)式 -NRXX1C(0)NRXX2-、16)式-0-C(0)NRxxl-、17)式-0-C(0)0-、18)CU6 伸烷基、19)C2.6 烯基、20)(^.6 炔基、 21)C3.8脂環族烴基、22)C6_14芳基、23)5至14員雜環族基或 24)5至14員芳香族雜環基；以及VXX4，RXXi及RXX2各獨立 為1)氫原子、2)(^.6燒基、3) C2-6烯基、4) Cw炔基、-5)C3-8脂族烴基、6)C6-14芳基、7)5至14員雜環基、8)5 至14員芳香族雜環基或9) CN6烷氧基）。、 因此，所謂「可有取代基」意指可被下列等取代基取 代：#i基，硫醇基，硝基，嗎福琳基，硫代碼福淋基，氟 原子、氯原子、溴原子及琪原子等函素原子，腈基，疊氮 基，曱醒、基，曱基、乙基、丙基、異丙基及丁基等垸基， 乙烯基、烯丙基（allyl)、丙烯基（pr〇penyl)等烯基，乙決 基、丁炔:基及丙块基等块基，對應於低碳燒基之甲氧基、 乙氧基、丙氧基及丁氧基等燒氧基，氟-·甲基、二氟甲基、 三氟甲基及氟乙基等函代烷基，羥甲基、羥乙基及經丙基 -59- 各紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） !3〇4〇61 Α7 Β7 五、發明説明（54 ) 等羥烷基，胍基，甲醯亞胺基，乙醯亞胺基，胺甲醯基， 硫代胺曱醯基，胺甲醯甲基及胺甲醯乙基等胺甲醯烷基， 曱基胺曱醯基及二甲基胺曱醯基等烷基胺甲醯基，脲基， 乙醯基等烷醯基，胺基，甲胺基、乙胺基及異丙胺基等烷 胺基，二甲胺基、甲基乙胺基及二乙胺基等二烷胺基，胺 甲基、胺乙基及胺丙基等胺烷基，羧基，甲氧羰基、乙氧 羰基及丙氧羰基等烷氧羰基，甲氧羰曱基、乙氧羰曱基、 丙氧幾·甲基、甲氧談乙基、乙氧談乙基及丙氧談乙基等燒 -氧羰烷基，甲氧甲基、甲氧乙基、乙氧甲基及乙氧乙基等 烷氧烷基，甲硫甲基、甲硫乙基 '乙硫甲基及乙硫乙基等 垸硫烷基，胺曱基胺曱基及胺乙基胺甲基等胺烷基胺烷 基’甲羰氧基、乙羰氧基及異丙羰氧基等烷羰氧基，羥甲 基’芊氧基乙氧乙基等芳烷氧基烷氧烷基，經乙氧甲基及 經乙氧乙基等羥烷氧烷基，芊氧甲基、芊氧乙基及芊氧丙， 基等芳垸〜氧:挽基，三甲基銨基、甲基乙基甲基銨基及三乙 銨基等第四級銨基，環丙基、環丁基、環戊基及環己基等 %烷基，環丙缔基、環丁烯基、環戊烯基及環己烯基等環 缔基，苯基、吡啶基、〃塞吩基、呋喃基及吡咯基等芳基， 甲硫基、乙硫基、丙硫基及丁硫墓等烷硫基，苯硫基、吡 哫硯基、、塞吩硫基、呋喃硫基及吡咯硫基等芳硫基，芊 基、三苯甲基及二曱氧三苯甲基等芳基低碳烷基，磺醯 基，甲磺醯基及對甲苯磺醯基等經取代磺醯基，芊醯基等^ 芳醯基，氟苯基及溴苯基等函代芳基，-以及亞甲二氧基等 氧烷氧基。 -60- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 55 五、發明説明（ 在本說明書中，所謂「c&quot;醯亞胺基」例 基、己醯亞胺基及琥珀醯亞胺基等。 ，甲醯亞胺 在本說明書中，環八為5至14員 列者中所° $為從下 異峻.環，—環二幷他 喹喏啉環、吡啶并吡症严u 5疋并嘧啶環、 環、吲嗓環、峨峻并峨二、二：比二、咐哈并嘧咬 ^吩并㈣環、苯并❹環 ^并❹ ㈣環、苯并咪《、㈣料〜^4、嗔嗅并 …一.環、苯 喃并㈣、苯并w基…并心環、二ζν夫 &amp;基♦木壤、，比吐并峻如林環、峨唉并 :奎蝴、㈣并Β奎啦環、異啊琳_ :氮： 環、異黃萌、萃并：虱雜 2-酮環、U-二酮基二氣異♦朵環、.:3:= :“網環、2,3-二氫-…如林-2-_環：：:2并 二广、尊環、呤嗤環、異1Ή環、異噻吐環及喳吐Γ 4-㈣。以如林環、㈣環、峨洛并喊基 峻琳環、⑽并㈣環、⑽并㈣環口奎 州錢環、吱喃并心環及㈣并錢環等為較二 以例^奎琳環' W環、心并μ環、嚷吩并錢=、. 續料及吱喃并心環等為更佳，但不限於此等基。 況 又，在Υ為5至14員雜環基等具有雜原子之基之情 ______-61 · 本纸張尺度適财S S家料(CNS) Α4舰$〇 X 297公$ 1304061In the "cN0 alkyl group", the moiety which may be substituted is substituted by the above-mentioned "5 to 14 member heterocyclic group", and specifically, τ is, for example, a pyridylmethyl group, a pyridylmethyl group, a 2-quinolinylmethyl group or the like. . In this syllabary, as a "disengagement base", there is no special restriction as long as it is a basis for organic synthesis. It is, for example, a halogen such as a halogen atom, a bromine atom or an iodine atom. Atom, sulfonylthio group, ethylthio group and propylthio group, such as thiol-phenylthio, tolylthio and 2" thiol groups, methanesulfonyloxy, trifluoromethanesulfonate Oxyl, acesulfonyloxy and propyl sulfonate three: · alkane sulfonyloxy such as oxy, phenylsulfonyloxy and p-toluenesulfonic acid, etc. a tetraalkyloxy group such as a fluoroethyleneoxy group; an alkoxy group such as a methoxy group; an ethoxy group; an amino group such as a methyl group; an ethylamine group; an ethylamine group; an ethylamine group; a propylamino group; a di-ammonium group such as diethylamine, dipropylamine, methylethylamine, ethylpropylamine or mercaptopropylamine; a substituted phosphoniumoxy group such as a diphenyloxy aryloxy group; a chlorine atom, a bromine atom and It is preferred that the iodine atom and the like have a bismuth atom and a two-volume &lt;* ketoneoxy group. _ In the present specification, 'there is a substituent which may have a substituent 』 means that it may have a moiety at a position which may be substituted Arbitrarily Or a plurality of substituents, specifically, for example, (1) a hydroxyl atom, (2) a hydroxyl group, (3) a thiol group, (4) a nitro group, and (5) a nitrile group. , (6) keto group, (7) azido group, (8) fluorenyl group, (9) fluorenyl group, (1 〇) isocyano group, (11) cyanate group, (12) isocyanate group, (13) Thiocyanate group, (14) isothiocyanate group, (15) nitroso group, (16) amine fluorenyl group (ureido group), (17) fluorenyl group, (i8) Ci 6 醯Amino, _: (19) each, functionalized or # to alkylated alkyl group, thiol, C3.6, alkyl, c3 δ cycloalkenyl, c36 cycloalkynyl, ci6 alkoxy , - ----- -58- This paper scale applies to China National Standard (CNS) 1304061 A7 B7 V. Description of invention (53) C2.6 晞oxy, C2.6 alkynyloxy, C3.6 naphthenic oxygen a group, a Ci.6 alkylthio group, a C2.6 alkenethio group, a C.2.6 alkynylthio group, a C3-6 cycloalkylthio group or a c..6 alkylene dioxane, (20) a C6.14 aryl group, (21) 5 to 14 membered heterocyclic group, (22) carboxy group, (23) trifluoromethyl group, (24) C6-14 aryl Cu alkyl group, (25) 5 to 14 membered heterocycloalkyl group or (26) )-VXX1-VXX2-VXX3-VXX4 (where VXX1, VXX2 and VXX3 Independently 1) single bond, 2) oxygen atom, 3) sulfur atom, 4) formula -CO-, 5) formula -SO-, 6) formula -S02-, 7) formula -NRXX1-, 8) formula-C 〇NRXX1-,9)... Formula-NRXX21CO-, 10)-S02NRXX1-, 11)-NRXX1S02-, 12) Two: Equation-0-C0-, 13)-C(0)0-, 14) Formula -NRXX1C(0)0-, 15) Formula -NRXX1C(0)NRXX2-, 16) Formula-0-C(0)NRxxl-, 17) Formula-0-C(0)0-, 18) CU6 alkyl, 19) C2.6 alkenyl, 20) (^.6 alkynyl, 21) C3.8 alicyclic hydrocarbon, 22) C6_14 aryl, 23) 5 to 14 membered heterocyclic or 24 5 to 14 membered aromatic heterocyclic group; and VXX4, RXXi and RXX2 are each independently 1) a hydrogen atom, 2) (^.6 alkyl, 3) C2-6 alkenyl, 4) Cw alkynyl, -5 C3-8 aliphatic hydrocarbon group, 6) C6-14 aryl group, 7) 5 to 14 membered heterocyclic group, 8) 5 to 14 membered aromatic heterocyclic group or 9) CN6 alkoxy group). Therefore, the phrase "may have a substituent" means that it can be substituted with the following substituents: #i group, thiol group, nitro group, whuflin group, sulfur code phoryl group, fluorine atom, chlorine atom, bromine atom And atomic atoms such as nitrile, nitrile group, azido group, awakening, sulfhydryl, ethyl, propyl, isopropyl and butyl groups, vinyl, allyl, propylene An alkenyl group such as pr〇penyl, a blocking group such as a vinyl group, a butyne group or a propyl group, and a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like which is a lower alkyl group. Alkyl groups such as oxy, fluoro-methyl, difluoromethyl, trifluoromethyl and fluoroethyl, hydroxymethyl, hydroxyethyl and propyl-59- apply to Chinese national standards for each paper scale ( CNS) A4 size (210 X 297 mm) !3〇4〇61 Α7 Β7 V. Description of invention (54) Isohydroxyalkyl group, fluorenyl group, formazan imino group, acetammine group, amine mercapto group , an alkylamino group such as a thioamine group, an amine formamidine methyl group and an amine formamyl group, an alkylamine group such as a mercaptoamine group and a dimethylamino group, a urea group , ethenyl group, alkyl group, amine group, A Alkylamino groups such as ethylamine, ethylamino and isopropylamine, dialkylamino groups such as dimethylamino, methylethylamino and diethylamine, and amine alkyl groups such as amine methyl, amine ethyl and amine propyl Alkoxycarbonyl group such as carboxyl group, methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, propoxymethyl group, methoxyethyl, ethoxyethyl and Alkoxyalkyl, methoxycarbonyl, methoxymethyl, methoxymethyl, ethoxymethyl and ethoxyethyl, methylthiomethyl, methylthioethyl Aminoalkylamino group such as methyl sulfonyl group such as methyl and ethyl thioethyl group, amine alkyl mercapto fluorenyl group and amine ethyl amine methyl group, methylcarbonyloxy group, ethoxycarbonyloxy group, isopropoxycarbonyloxy group, etc. An alkoxycarbonyl group, an aralkoxy alkoxyalkyl group such as a hydroxymethyl 'methoxy ethoxyethyl group, a hydroxyalkyloxy group such as an ethoxymethyl group and an ethoxyethyl group; Oxyethyl and acetophenone, aryl fluorene-oxyl: cyclyl, trimethylammonium, methylethylmethylammonium and triethylammonium, etc., fourth-order ammonium, cyclopropyl, cyclobutyl %, cyclopentyl and cyclohexyl, etc., alkyl, cyclopropyl, cyclobutenyl, ring a cyclopentyl group such as a pentenyl group and a cyclohexenyl group; an aryl group such as a phenyl group, a pyridyl group, a decyl group, a furyl group or a pyrrolyl group; an alkyl group such as a methylthio group, an ethylthio group, a propylthio group or a toluene tomb; Arylthio groups such as thiol, phenylthio, pyridyl, thiophenethio, furanthio and pyrrolethio; aryl low carbon such as mercapto, trityl and dioxotrityl a substituted sulfonyl group such as an alkyl group, a sulfonyl group, a methanesulfonyl group or a p-toluenesulfonyl group; a fluorenyl group such as a fluorenyl group; a aryl group such as a fluorophenyl group and a bromophenyl group; Dioxy isocyanyloxy. -60- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1304061 55 V. Description of invention (In this specification, the so-called "c&quot; sulfhydryl group" base, hexamethylene imine group and Amber quinone imine and the like. In the present specification, the ring VIII is in the range of 5 to 14 members. The value is from the lower succinct ring, the cyclodextta quinoxaline ring, and the pyridine. Pyridoxine u 5 疋 pyrimidine ring, ring, anthracene ring, 峨 峨 峨 、 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二Mimi ", (four) material ~ ^ 4, 嗔 sniff and ... a ring, benzopyrene (tetra), benzoh-based ... and heart ring, two ζ 夫 夫 &amp; base ♦ wood soil, than spit and as strong as the forest ring,峨唉 :: Kui Butterfly, (4) and Β 啦 环 ring, different ah _: nitrogen: ring, different yellow Meng, extraction and: 2-ketone ring, U-diketone two gas ♦ ring,. :3:= : "Net ring, 2,3-dihydro-...such as Lin-2-_ ring:::2 and Erguang, Zunhuan, Qionghuan, Yiyi ring, isothiophene ring and vomiting Γ 4-(4). For example, Lin Huan, (4) Ring, Qi Luo and Shouting Ji Junlin Ring, (10) and (4) Ring, (10) and (4) Ring Mouth Qian Huan, 吱 并 心 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 四 四 四 四 四 四 四 四 四 四 四 四 四 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 奎 奎 奎 奎 奎 奎However, it is not limited to such a base. Moreover, in the case of a hetero atom having 5 to 14 members of a heterocyclic group, ______-61 · This paper scale is suitable for SS material (CNS) Α 4 ship $〇 X 297 public $ 1304061

該雜原子與χ或等取代基鍵結之情況當然亦被包含在本 發明中。 接下來敘述本發明化合物之製造方法。關於通式（1)或（11) 所示之本發明化合物之製造方法，各種方法曾被考量，雖 然可以使用通常的有機合成手段合成，但以例如藉由下文 所示之方法製造為代表。 [代表的製造方法] [製造方法1]The case where the hetero atom is bonded to an anthracene or the like is of course also included in the present invention. Next, a method for producing the compound of the present invention will be described. Regarding the production method of the compound of the present invention represented by the formula (1) or (11), various methods have been considered, and although it can be synthesized by a usual organic synthesis means, it is represented by, for example, the production by the method shown below. [Representative Manufacturing Method] [Manufacturing Method 1]

(a-01) (a，02) (I) 式中，U意指脫離基。其他各記號意味與上述定義相同之 意義。脫離基，例如可為卣素原子及三氟甲磺醯基等。反 應所使用^^溶媒雖無特殊限定，但期望為不易與原料物質 反應者，例如1-甲基吡咯啶酮、二甲基甲醯胺及氯苯等。 可以添加有機鹼或無機鹼以做為鹼。反應時間為10分鐘至 30小時。反應溫度為室溫至加熱回流溫度。 以下在代表性製造方法之各式申，Z，R則，R3(n , w , W11，R1，R2及γ具有與上述定義相同之意義；又…為氧原 子或硫原子；Rsa4具有與上文定義之R2相同之意義；為 可有取代基之Cl.δ烷基或可有取代基之Ci0芳基；化合物 (a-6)為化合物（a-61)或化合物（a-62) ; ·Κ^7()為可有取代基 烷基；為可有取代基之氮原子或氧原子；口為脫離 -62-(a-01) (a,02) (I) where U means the radical. The other symbols mean the same meaning as the above definition. The leaving group may be, for example, a halogen atom or a trifluoromethanesulfonyl group. The solvent used in the reaction is not particularly limited, but it is desirably such that it is difficult to react with a raw material such as 1-methylpyrrolidone, dimethylformamide or chlorobenzene. An organic base or an inorganic base may be added as a base. The reaction time is from 10 minutes to 30 hours. The reaction temperature is from room temperature to heating under reflux. Hereinafter, in the various formulas of the representative manufacturing method, Z, R, R3 (n, w, W11, R1, R2 and γ have the same meanings as defined above; again...is an oxygen atom or a sulfur atom; Rsa4 has and The meaning of R2 is the same; it is a Cl.δ alkyl group which may have a substituent or a Ci0 aryl group which may have a substituent; the compound (a-6) is a compound (a-61) or a compound (a-62); · Κ^7() is a substitutable alkyl group; a nitrogen atom or an oxygen atom which may have a substituent; the mouth is detached from -62-

裝 訂Binding

線 1304061 A7 B7 五、發明説明（57 ) 基；η及s各為0至6之整數；Rsa9G為蛸基或胺基；Rsa82為第 三丁氧羰基及芊基等胺基之保護基；Rsal，Rsa2，Rsa3， Rsa5° , Rsa6() , Rsa71及Rsa8G各獨立為從上述（3)記載之「可具 有環A之取代基」中選出之取代基。 [製造方法2-1] 下式表示之化合物（G2):Line 1304061 A7 B7 V. Inventive Note (57) Group; η and s are each an integer from 0 to 6; Rsa9G is a fluorenyl or an amine group; and Rsa82 is a protecting group for an amine group such as a third butoxycarbonyl group and a fluorenyl group; Rsal Rsa2, Rsa3, Rsa5°, Rsa6(), Rsa71 and Rsa8G are each independently a substituent selected from the "substituent having a ring A" described in the above (3). [Production Method 2-1] Compound (G2) represented by the following formula:

(各式中之記號具有與上述定義相同之意義）之代表性製造 方法：A representative manufacturing method (where the symbols in the formulas have the same meaning as defined above):

-63- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（58 ) (各式中之記號具有與上述定義相同之意義）。-63- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (58) (The symbols in each formula have the same meaning as defined above).

裝 (各式中之記號具有與上述定義相同之意義）。 〈步驟A-1〉彡步驟A-2〉 為從苯胺衍生物（a-1)製造喹啉酮衍生物、（a- 3)之環化反應 之步驟。使用Tetrahedron 53，1743 ( 1997)等所報告之一般 方法合成。 〈步驟A- 1&gt; 具體而言，具有期望取代基之苯胺衍生物（a-1)與原甲酸 三曱酯或原曱酸三乙酯等原曱酸酯衍生物及麥爾多拉母酸 在乙醇等醇類中反應，可以得到化合物（a- 2)。反應溫度為 室溫至加熱回流溫度，反應時間為1 〇分鐘至3 0小時。 〈步驟A-2&gt; -64 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 訂Loading (the symbols in each formula have the same meaning as defined above). <Step A-1> 彡Step A-2> A step of producing a quinolinone derivative and a cyclization reaction of (a-3) from the aniline derivative (a-1). It was synthesized using the general method reported by Tetrahedron 53, 1743 (1997). <Step A-1> Specifically, an aniline derivative (a-1) having a desired substituent and a orthophthalate derivative such as tridecyl orthoformate or triethyl orthoformate and a metoprolic acid The compound (a-2) can be obtained by reacting in an alcohol such as ethanol. The reaction temperature is from room temperature to heating under reflux, and the reaction time is from 1 Torr to 30 hours. <Step A-2> -64 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

1304061 、- A7 ______B7 五、發明説明（59 ) 繼而’藉由將化合物（a- 2)在苯醚及聯苯等混合溶媒或 Dawthenn A中加熱而得到化合物反應溫度為4〇°c至 加熱回泥溫度，以及反應時間為丨〇分鐘至3 〇小時。 &lt;步驟A-3&gt; 為氯化步驟。藉由將化合物（a-3)與氧氯化磷及亞硫醯氯 等氯化劑反應而得到化合物（a-4) ^反應溶媒可以使用氧氯 化鱗、亞硫醯氯、苯及甲苯等。反應溫度為室溫至加熱回 流溫度，以及反應時間為1〇分鐘至3〇小時。 二 〈步驟A-4&gt; ' 為使化合物（a- 4)與化合物（a- 42)反應，得到硝基體化合 物（a- 5)之步驟。反應溶媒可以使用^甲基吡咯啶酮、二甲 基甲醯胺、氯苯及2，6-二甲基吡啶。在該反應中，亦可以 添加鹼，具體而言，可以使用二異丙基乙胺及2,6•二甲基 吡啶等有機鹼或碳酸鉀等無機鹼。反應時間為1〇分鐘至3〇 _ 小時。反應;^度為室溫至加熱回流溫度β 〈步驟 Α-42&gt; ·、 為使化合物（a-4)與化合物（a-43)反應而得到胺基體化合 物（a-61)之步驟。反應溶媒可以使用丨-甲基吡咯啶酮及二 甲基亞颯等。在反應中可以使用·氫化鈉等鹼。反應時間為 10分鐘至30小時。反應溫度為室溫至加熱回流溫度。 〈步驟A-5&gt; 為使硝基體化合物（a-5)還原為胺基化合物（a_61)之步-r 驟。可以在一般被用於從硝基體還原為:胺基之反應所用之 條件下進行。具體而言，例如藉由鐵-氯化銨、鐵-鹽酸或1304061, - A7 ______B7 V. Description of the invention (59) Then, by heating the compound (a-2) in a mixed solvent such as phenyl ether and biphenyl or Dawthenn A, the reaction temperature of the compound is 4 〇 ° C to heating back. Mud temperature, and reaction time is 丨〇 minutes to 3 〇 hours. &lt;Step A-3&gt; is a chlorination step. The compound (a-4) can be obtained by reacting the compound (a-3) with a chlorinating agent such as phosphorus oxychloride or sulfinium chloride. ^The reaction solvent can be oxychlorinated scale, sulfinium chloride, benzene and toluene. Wait. The reaction temperature is from room temperature to the reflux temperature, and the reaction time is from 1 minute to 3 hours. (Step A-4&gt; ' For the reaction of the compound (a-4) with the compound (a-42), a step of obtaining a nitro compound (a-5). As the reaction solvent, methylpyrrolidone, dimethylformamide, chlorobenzene or 2,6-lutidine can be used. In the reaction, a base may be added. Specifically, an organic base such as diisopropylethylamine or 2,6•dimethylpyridine or an inorganic base such as potassium carbonate may be used. The reaction time is from 1 minute to 3 hours _ hours. The reaction is a room temperature to a heating reflux temperature β <Step Α-42>. A step of obtaining an amine matrix compound (a-61) by reacting the compound (a-4) with the compound (a-43). As the reaction solvent, hydrazine-methylpyrrolidone, dimethylammonium or the like can be used. A base such as sodium hydride can be used in the reaction. The reaction time is from 10 minutes to 30 hours. The reaction temperature is from room temperature to heating under reflux. <Step A-5&gt; In order to reduce the nitro compound (a-5) to the amine compound (a_61), step-r. It can be carried out under the conditions generally used for the reaction from the reduction of a nitro group to an amine group. Specifically, for example, by iron-ammonium chloride, iron-hydrochloric acid or

裝 訂Binding

線 -65- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 13〇4〇61 A7 B7 五 發明説明 鐵-乙酸等還原’以及藉由氫氧化免-氫氣而進行接觸還原 等》反應溶媒例如為轉、乙醇、四氫呋喃及二甲基甲醯 胺等》接觸還原在常壓或加壓下進行。反應時間為1〇分鐘 至30小時。反應溫度為室溫至加熱回流溫度。 &lt;步驟A-6&gt; 為將胺基體化合物（a-61)烷基化之步驟。使胺基體化合 物（a-61)與醛衍生物或酮衍生物反應，形成亞胺後，藉由 用氰基氫硼化鋼等還原劑還原，得到化合物（a_ 62)。 又，於鹼存在下，使胺基體化合物（a_61)與醯基氯衍生 物或酸酐反應’繼而藉由用氫化鋰鋁等還原劑還原，可以 得到化合物（a-62)。 &lt;步驟A-7&gt; 為使胺基衍生物（a-61)或化合物（a-62)與胺甲酸酯衍生物 (a-81)反應而得到脲衍生化合物（a_ 1〇)之步驟。反應溶媒可 以使用、曱苯、乙腈 '二曱基甲醯胺及二甲基亞石風 等。反應時間為10分鐘至30小時。反應在冰冷至加熱回流 溫度下進行。反應可以在氫化鈉，三乙胺及吡啶等有機鹼 化合物，以及碳酸鉀及碳酸鈉等無機鹼下進行。 〈步驟A-8〉 為使胺基衍生物（a- 61)或化合物（a- 62)與異氰酸酯衍生物 (a-82)反應而得到化合物（a-7)之步驟。反應溶媒可以使用 氯仿、甲苯、乙腈、二甲基甲醯胺及二甲基亞躐等β反應 時間為10分鐘至30小時，反應在冰冷至加熱回流溫度下進 行。反應可以在三乙胺及吡啶等有機鹼化合物以及碳酸鉀 -66- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（61 ) 及碳酸鈉等無機鹼下進行° &lt;步騾A-9&gt; 為使化合物（a- 7)與化合物（a- 83)在吡啶等鹼存在下反應 而得到脲衍生物（a-10)之步驟。反應溶媒可以使用二甲基 亞颯、二曱基甲醯胺及四氫呋喃等，反應時間為10分鐘至 3 0小時。反應溫度為0 C至加熱回流溫度。 &lt;步騾A- 10&gt; 為使彳匕合物物（a- 61)或化合物（a- 62)與氯甲酸苯酯等胺曱7 酸酯化試藥（a-84)反應而得到胺曱酸酯衍生物（a-9)之步 騾。在反應中，可以使用吡啶等鹼。反應溶媒可以使用二 甲基亞珉、二曱基甲醯胺及四氫呋喃等，反應時間為10分 鐘至30小時。反應溫度為〇°C至加熱回流溫度。 &lt;步驟A，ll&gt; 本步騾為藉由使胺基甲酸酯衍生物（a-9)與胺基衍生物（a-. 85)作用而得到躲衍生物化合物（a_ 1〇)之步驟乂在該反應 中，可以使用三乙胺等鹼。反應溶媒可以使用二甲基亞石風 及二曱基甲醯胺等溶媒，反應時間為10分鐘至3〇小時，以 及反應溫度為室溫至加熱回流溫度。 [製造方法2-2] 化合物（a-10)之另一製造方法·· -— _ -67- 本紙張尺國國冢標準(CNS) M規格(2ι〇χ29?公p 1304061 A7 B7 五、發明説明（62Line-65- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 13〇4〇61 A7 B7 Five inventions describe the reduction of iron-acetic acid and the like and the contact by hydrogen-free hydrogen The reaction solvent such as reduction or the like is, for example, a transfer, ethanol, tetrahydrofuran or dimethylformamide. The contact reduction is carried out under normal pressure or under pressure. The reaction time is from 1 minute to 30 hours. The reaction temperature is from room temperature to heating under reflux. &lt;Step A-6&gt; A step of alkylating the amine base compound (a-61). The amine matrix compound (a-61) is reacted with an aldehyde derivative or a ketone derivative to form an imine, which is then reduced with a reducing agent such as cyanoborohydride to obtain a compound (a-62). Further, the amine base compound (a-61) is reacted with a mercapto chloride derivative or an acid anhydride in the presence of a base, and then the compound (a-62) can be obtained by reduction with a reducing agent such as lithium aluminum hydride. &lt;Step A-7&gt; Step of obtaining a urea-derived compound (a-1) by reacting an amino derivative (a-61) or a compound (a-62) with a carbamate derivative (a-81) . The reaction solvent can be used, benzene, acetonitrile, 'dimercaptocarboxamide, dimethyl sulfite, and the like. The reaction time is from 10 minutes to 30 hours. The reaction is carried out under ice-cold to reflux temperature. The reaction can be carried out under an organic base such as sodium hydride, triethylamine or pyridine, or an inorganic base such as potassium carbonate or sodium carbonate. <Step A-8> A step of obtaining a compound (a-7) by reacting an amino derivative (a-61) or a compound (a-62) with an isocyanate derivative (a-82). The reaction solvent can be used for a reaction time of 10 minutes to 30 hours using chloroform, toluene, acetonitrile, dimethylformamide or dimethylhydrazine, and the reaction is carried out under ice-cooling to a reflux temperature. The reaction can be applied to organic alkali compounds such as triethylamine and pyridine and potassium carbonate-66- This paper scale is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1304061 A7 B7 5. Inventive Note (61) and Sodium Carbonate The reaction is carried out under an inorganic base. &lt;Step A-9&gt; A step of obtaining a urea derivative (a-10) by reacting the compound (a-7) with a compound (a-83) in the presence of a base such as pyridine. As the reaction solvent, dimethyl hydrazine, dimethyl carbamide, tetrahydrofuran or the like can be used, and the reaction time is from 10 minutes to 30 hours. The reaction temperature is from 0 C to the reflux temperature. &lt;Step A-10&gt; An amine is obtained by reacting a chelate compound (a-61) or a compound (a-62) with an amine oxime 7 acid ester reagent (a-84) such as phenyl chloroformate. The step of the phthalate derivative (a-9). In the reaction, a base such as pyridine can be used. As the reaction solvent, dimethyl hydrazine, dimethyl carbamide, tetrahydrofuran or the like can be used, and the reaction time is from 10 minutes to 30 hours. The reaction temperature is from 〇 ° C to the heating reflux temperature. &lt;Step A, ll&gt; This step is carried out by reacting a urethane derivative (a-9) with an amino derivative (a-.85) to obtain a dicing derivative compound (a-1). Step 乂 In the reaction, a base such as triethylamine can be used. As the reaction solvent, a solvent such as dimethylsulfite or dimercaptocaramine can be used, and the reaction time is from 10 minutes to 3 hours, and the reaction temperature is from room temperature to heating under reflux. [Manufacturing Method 2-2] Another Manufacturing Method of Compound (a-10)·· - _ -67- This paper is the National Standard (CNS) M Specification (2ι〇χ29? 公普 1304061 A7 B7 V. Description of the invention (62

(各式中之記號具有與上述定義相同之意義）。 〈步騾A-12〉 本步驟為使以脲構造為部份構造之酚衍生物（a-12)作用 於4-氯喹啉衍生物（a-4)，而用單步騾直接得到化合物（a-11) 之步驟。可以使用1-甲基吡咯啶酮、二曱基甲醯胺及氯苯 等做為反應溶媒。亦可以使用異丙基乙胺等有機鹼，或碳 酸鉀及氫化鈉等無機鹼做為鹼。反應時間為10分鐘至30小 時®反應溫度為室溫至加熱回流溫度。 [製造方法13] 化合物（a-5)及化合物（a-61)之另一製造.方法：(The symbols in the formulas have the same meaning as defined above). <Step A-12> In this step, a phenol derivative (a-12) having a urea structure as a partial structure is allowed to act on the 4-chloroquinoline derivative (a-4), and the compound is directly obtained by a single step ( Steps of a-11). 1-methylpyrrolidone, dimethylformamide, chlorobenzene or the like can be used as a reaction solvent. An organic base such as isopropylethylamine or an inorganic base such as potassium carbonate or sodium hydride can also be used as the base. The reaction time is from 10 minutes to 30 hours. The reaction temperature is from room temperature to heating under reflux. [Production Method 13] Another production of the compound (a-5) and the compound (a-61).

(2a*2)(2a*2)

-68- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（63 (各式中之記號具有與上述定義相同之意義）。 &lt;步騾2人-1&gt; 為使化合物（a-5)與吡啶衍生物（2ael)反應，而得到化合 物（2a-2)之步驟。在該反應中，可以使用碳酸鉀等鹼。反 應/谷媒可以使用二甲基甲醯胺等，反應時間為1〇分鐘至3〇 小時。反應溫度為室溫至加熱回流溫度。 &lt;步騾2Α_2&gt; 為使4：喏酮體（a-5)變換為硫替喹喏酮體（2a-3)之步驟。.二τ 藉由使做為反應試藥之硫化鈉及五硫化磷等硫試藥作用於 峻唸酮體（a- 5)而得到硫替喹喏酮體^反應溶媒可以使用二 甘醇一甲酸等。反應溫度為室溫至加熱回流溫度。反應時 間為10分鐘至30小時。 〈步驟2A-3&gt; 本步驟為使硫替喹喏酮體（2a-3)與化合物（2a-4)反應而得-到化合物5)之步驟。反應溶媒可以使用二曱基甲醯胺 等。反應溫度為室溫至加熱回流溫度^反應時間為1 〇分鐘 至30小時。可以使用吡啶等鹼。-68- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (63 (The symbols in each formula have the same meaning as defined above). &lt;Step 2 person-1&gt; A step of obtaining a compound (2a-2) by reacting the compound (a-5) with a pyridine derivative (2ael). In the reaction, a base such as potassium carbonate can be used. The reaction time is from 1 minute to 3 hours using dimethylformamide, etc. The reaction temperature is from room temperature to heating under reflux. &lt;Step 2骡_2&gt; To convert 4: fluorenone (a-5) to Step of thiotequinone ketone body (2a-3). TiO2 is obtained by using a sulfur reagent such as sodium sulfide or phosphorus pentasulfide as a reaction reagent for the ketone body (a-5). The reaction solvent may be diethylene glycol monocarboxylic acid, etc. The reaction temperature is from room temperature to heating under reflux. The reaction time is from 10 minutes to 30 hours. <Step 2A-3> This step is to make thiotequinoquinone. The step of reacting the ketone body (2a-3) with the compound (2a-4) to give the compound 5). As the reaction solvent, dimercaptomethylamine or the like can be used. The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 1 minute to 30 hours. A base such as pyridine can be used.

•69- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 A7 ________ B7 五、發明説明（64 )•69- The paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 ________ B7 V. Description of invention (64)

(各式中之記號具有與上述定義相同之意義）。 · &lt;步騾2A-4&gt; 本步笋為藉由化合物（a-4)與羥基吡啶衍生物（2a-6)反應^ 而得到化合物（2a- 7)之步驟。可以使用卜甲基吡咯啶酮、 二甲基甲醯胺及氯苯等做為反應溶媒《亦可以使用異丙基 乙胺等有機鹼，或碳酸鉀等無機鹼做為鹼 。反應時間為10 分鐘至30小時。反應溫度為室溫至加熱回流溫度。 &lt;步驟2A-5〉 為藉由化合物（2a- 7)與亞胺衍生物之兔偶合反應而得到_ 化合物（2a-J)之反應。在該反應中，可以用甲苯等做為溶 媒，用鈀衍生物例如（參（二亞芊基丙酮）二鈀（〇))以及膦例 如（2,2·-武（聯苯膦）-1，1’-聯蕃）做為觸媒，以及用第三丁氧 化鉀等做為鹼基。反應溫度為501至加熱回流溫度。反應 時間為約1小時至1 〇小時。 · &lt;步驟2A-6&gt; 本步騾為從化合物（2a- 8)得到胺基衍生化合物（2a_ 9)之步· 驟在遠反應中’使用乙鮮及水等’以及藉由鹽酸等酸作-用。反應溫度為0°C至約100°C。反應時間為10分鐘至約1〇 小時。(The symbols in the formulas have the same meaning as defined above). &lt;Step 2A-4&gt; This step is a step of obtaining a compound (2a-7) by reacting the compound (a-4) with a hydroxypyridine derivative (2a-6). As the reaction solvent, a methylpyrrolidone, dimethylformamide or chlorobenzene can be used. An organic base such as isopropylethylamine or an inorganic base such as potassium carbonate can also be used as the base. The reaction time is from 10 minutes to 30 hours. The reaction temperature is from room temperature to heating under reflux. &lt;Step 2A-5> The reaction of the compound (2a-J) is obtained by coupling a compound (2a-7) with a rabbit of an imine derivative. In the reaction, toluene or the like can be used as a solvent, and a palladium derivative such as (di(dimercaptoacetone) dipalladium (ruthenium)) and a phosphine such as (2,2·-wu (biphenylphosphine)-1) can be used. , 1'-Lianfan) as a catalyst, and the use of third potassium butoxide as a base. The reaction temperature was 501 to a heating reflux temperature. The reaction time is about 1 hour to 1 hour. &lt;Step 2A-6&gt; This step is a step of obtaining an amine-derived compound (2a-9) from the compound (2a-8), a step of using a fresh acid, water, etc. in a far reaction, and an acid such as hydrochloric acid. effect. The reaction temperature is from 0 ° C to about 100 ° C. The reaction time is from 10 minutes to about 1 hour.

裝 訂Binding

-70- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 —-- - '、· A7 ___ B7_ 五、發明説明（65 ) &lt;步驟2A-7&gt; 為將化合物（2a-9)脫氯而得到化合物（2a-10)之步驟。可 以使用藉由免/竣-氫氣之接觸還原。反應溶媒例如為甲 醇、乙醇及四氫呋喃等。接觸還原在常壓或加壓下進行。 可以使用二乙胺寺做為驗β反應時間為1〇分鐘至3〇小時。 反應溫度為室溫至加熱回流溫度。-70- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 —-- - ',· A7 ___ B7_ V. Invention description (65 ) &lt;Step 2A-7&gt; (2a-9) a step of dechlorination to give a compound (2a-10). It can be reduced by contact with hydrogen/hydrogen-free hydrogen. The reaction solvent is, for example, methanol, ethanol or tetrahydrofuran. Contact reduction is carried out under normal pressure or under pressure. The diethylamine temple can be used as a beta reaction for 1 minute to 3 hours. The reaction temperature is from room temperature to heating under reflux.

裝 (各式中之記號具有與上述定義相同之意義）^ &lt;步驟2Α-8&gt; 訂Loading (the symbols in each formula have the same meaning as defined above)^ &lt;Step 2Α-8&gt;

本步驟為將喹喏酮化合物（a- 3)變換為4-胺基烷氧基喹啉 體（2a-ll)&lt;反應。藉由化合物（a-3)與N-烷基酞醯亞胺衍 生物反應，然後用胼水合物等進行脫保護，可以得到目的 化合物（2a-11)。溶媒可以使用二甲基甲醯胺及四氫呋喃 等。反應溫度為室溫至加熱回流溫度，反應時間為丨〇分鐘 至3 0小時。可以使用碳酸鉀等做為鹼。 [製造方法2-4] 化合物（a- 4)之另一製造方法如下： -71 - 本纸張尺度適用中國國家標準(CMS) A4規格(210X 297公釐) 1304061 、- A7This step is a conversion of the quinophthalone compound (a-3) to a 4-aminoalkoxyquinoline (2a-ll) &lt; reaction. The object compound (2a-11) can be obtained by reacting the compound (a-3) with an N-alkyl sulfenylene derivative and then deprotecting with a hydrazine hydrate or the like. As the solvent, dimethylformamide, tetrahydrofuran or the like can be used. The reaction temperature is from room temperature to heating under reflux, and the reaction time is from 丨〇 minute to 30 hours. Potassium carbonate or the like can be used as the base. [Manufacturing Method 2-4] Another manufacturing method of the compound (a-4) is as follows: -71 - The paper size is applicable to the Chinese National Standard (CMS) A4 specification (210X 297 mm) 1304061, - A7

(3a~3) (各式中之記號具有與上述定義相同之意義）。 &lt;步驟3 A-1&gt; 為得到亞胺（3a-1)之步驟。藉由使乙氧基亞甲基丙二酸 一乙醋作用於苯胺衍生物化合物（a-1)，而得到化合物（3a_ ^ °該反應在無溶媒下進行，反應溫度以l〇〇°C為宜，反應 時間為30分^鐘至數小時。 &lt;步驟3A;2&gt; 本步驟為環化反應之步騾。將化合物（3a-1)在二苯瞇-聯 苯之混合溶媒中，藉由在約2〇(rc至約26(rc加熱進行環化 反應，而得到目的化合物（3a-2)。反應時間為3〇分鐘至Μ 小時。. 〈步驟3Α·3&gt; 本步驟為氯化步驟。藉由與&lt; 步驟3〉同樣的操作，可 以從化合物（3a-2)得到氯化化合物（3卜3)。 [製造方法3] ‘ ______ &lt;72-(3a~3) (The symbols in the formulas have the same meaning as defined above). &lt;Step 3 A-1&gt; To obtain an imine (3a-1). The compound is obtained by reacting ethoxymethylenemalonate-ethyl acetate with the aniline derivative compound (a-1) (3a_^ °, the reaction is carried out in the absence of a solvent, and the reaction temperature is 10 ° C Preferably, the reaction time is from 30 minutes to several hours. &lt;Step 3A; 2&gt; This step is a step of a cyclization reaction. The compound (3a-1) is in a mixed solvent of diphenyl hydrazine-biphenyl, The objective compound (3a-2) is obtained by a cyclization reaction at about 2 Torr (rc to about 26 (rc). The reaction time is 3 Torr to Μ hr.. <Step 3 Α·3&gt; This step is chlorine The chlorinated compound (3b3) can be obtained from the compound (3a-2) by the same operation as in <Step 3>. [Manufacturing method 3] '______ &lt;72-

本紙張尺度適用中國國家標準(CNS) A4規格 1304061 A7 B7 五、發明说明（67 下式代表之化合物（G3):This paper scale applies to China National Standard (CNS) A4 Specification 1304061 A7 B7 V. Description of Invention (67 Compound represented by the following formula (G3):

(各式中之記號具有與上述定義相同之意義）之製造方法如 下：The manufacturing method (the symbols in the formulas have the same meaning as defined above) is as follows:

(各式中之記號具有與上述定義相同之意▲)。 &lt;步驟B-l&gt;(The symbols in the formulas have the same meaning as defined above). &lt;Step B-l&gt;

使化合物（a-4)與吲哚衍生物（b_2)反應，而得到化合物 (b-1)之步驟。該反應在與上述〈步驟a-4&gt;同樣的條件下進 行。 〈步驟B-2&gt; 為從化合物（b-1)得到脲衍生物（b-3)之步驟。可以使用上 述異氰酸酯衍生物（a-82)及上述胺甲酸ί旨衍生物（a-81)。該 反應在與上述〈步驟A-7&gt;、〈步驟A-8〉及 &lt; 步驟A-9〉同樣 -73- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 線 1304061 A7 B7 五、發明説明（68 之條件下進行The step of reacting the compound (a-4) with the anthracene derivative (b_2) to obtain the compound (b-1). This reaction was carried out under the same conditions as in the above <Step a-4>. <Step B-2> is a step of obtaining a urea derivative (b-3) from the compound (b-1). The above isocyanate derivative (a-82) and the above-mentioned amine formic acid derivative (a-81) can be used. This reaction is the same as the above-mentioned <Step A-7>, <Step A-8>, and <Step A-9> -73- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). Line 1304061 A7 B7 V. Invention description (68 conditions)

[步驟S — 3][Step S — 3]

(各式中之記號具有與上述定義相同之意義）。 〈步驟B-3〉 為將取代基導入啕哚之3位之步驟。藉由將化合物（b-4) 與N-氯琥珀醯亞胺及N-溴琥珀醯亞胺等鹵化試藥，或者氧 氯化磷或亞硫醯氯與二甲基甲醯胺之混合試藥反應，而得 到化合物（b-5)。反應溶媒可以使用2-丙醇、四氫呋喃、乙 腈及二甲基甲酿胺等，反應溫度為0°C至加熱回流溫度，反 應時間為10分鐘至30小時。 [製造方法 下式代表之化合物（G4-1) :(The symbols in the formulas have the same meaning as defined above). <Step B-3> A step of introducing a substituent into the 3-position of hydrazine. By using the compound (b-4) with a halogenated reagent such as N-chlorosuccinimide and N-bromosinium iodide, or a mixture of phosphorus oxychloride or sulfoxide and dimethylformamide The drug is reacted to obtain the compound (b-5). As the reaction solvent, 2-propanol, tetrahydrofuran, acetonitrile, dimethylacetamide or the like can be used, and the reaction temperature is from 0 ° C to the reflux temperature, and the reaction time is from 10 minutes to 30 hours. [Manufacturing method Compound represented by the following formula (G4-1):

(各式中之記號具有與上述定義相同之意義）之製造方法如 下： 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（69 )The manufacturing method (the symbols in the formulas have the same meaning as defined above) is as follows: The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (69)

(各式中之記號具有與上述定義相同之意義）。 通式（G4-1)，依照 WO 97/02266，PCT/EP96/02728， Journal of Medicinal Chemistry, 1996, Vol. 39, No.12, 2285-2292記載之&gt; 法合成。 &lt;步騾C-l&gt; 、 為合成亞胺酸酯之反應。將氰基乙酸乙酯在二哼烷等溶 媒中藉用鹽酸處理而得到目的亞胺酸酯體化合物（c-2)。反 應溫度期望為約0°C至室溫，反應時間為數小時至數曰。 〈步驟C-2&gt; 為合成脒之反應。結由使化合物（c-2)在乙酵中與氨氣體 反應，而得到目的脒化合物（c- 3)。反應溫度為約0°C至室 溫，以及反應時間為數小時。 〈步驟C-3&gt; -75- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)(The symbols in the formulas have the same meaning as defined above). The formula (G4-1) is synthesized according to the method described in WO 97/02266, PCT/EP96/02728, Journal of Medicinal Chemistry, 1996, Vol. 39, No. 12, 2285-2292. &lt;Step C-l&gt;, a reaction for synthesizing an imidate. The ethyl cyanoacetate is treated with hydrochloric acid in a solvent such as dioxane to obtain the desired imidate compound (c-2). The reaction temperature is desirably from about 0 ° C to room temperature, and the reaction time is from several hours to several Torr. <Step C-2&gt; is a reaction for synthesizing hydrazine. The compound (c-2) is reacted with ammonia gas in the yeast to obtain the objective oxime compound (c-3). The reaction temperature is from about 0 ° C to room temperature, and the reaction time is several hours. <Step C-3> -75- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂Binding

13040611304061

為合成吡咯衍生物之反應。藉由將化合物（c-3)在乙酵中 與〇-_素衍生物（c-31)反應，而得到目的之吡咯衍生物（c_ 4)。反應溫度為室溫至加熱回流溫度，反應時間為數小時 至數曰。 &lt;步驟C-4&gt; 從吡咯環形成吡咯并嘧啶環之閉環反應。藉由將化合物 (c-4)與甲醯胺、曱酸反應，而得到目的化合物（c_5)。溶媒 可以使用二曱基曱醯胺等，反應溫度為約i 〇〇〇c至加熱回流〜· 溫度。反應時間為數小時至數曰。 &lt;步驟C-5&gt; 本步驟為氯化步驟。藉由與&lt; 步騾A-3&gt;同樣的操作，得 到目的之氯化化合物（c-6)。It is a reaction for synthesizing a pyrrole derivative. The desired pyrrole derivative (c-4) is obtained by reacting the compound (c-3) with the quinone derivative (c-31) in the yeast. The reaction temperature is from room temperature to heating under reflux, and the reaction time is from several hours to several hydrazines. &lt;Step C-4&gt; A ring closure reaction of a pyrrolopyrimidine ring from a pyrrole ring. The object compound (c-5) is obtained by reacting the compound (c-4) with formamide and decanoic acid. The solvent may be dimercaptoamine or the like, and the reaction temperature is about i 〇〇〇c to heating under reflux ~· temperature. The reaction time is from several hours to several hours. &lt;Step C-5&gt; This step is a chlorination step. The desired chlorinated compound (c-6) was obtained by the same operation as &lt; Step A-3&gt;.

(各式中之記號具有與上述定義相同之意義）。 &lt;步驟C-6&gt; 為將取代基導入吡咯衍生物（c-70)之S位之反應。將化合 物（c-70)於2,6-二甲基吡啶存在下，與化合物（c-71)在氮氣 -76^ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（71 ) 流化及遮光條件下反應，以得到目的化合物（c-8)。反應溶 媒可以使用.二氯甲烷等，反應溫度為約0°C至室溫度，以及 反應時間為1小時至30小時。 〈步騾07〉 藉由與（步騾C-4)同樣之操作得到化合物（c-9)。 〈步騾C-8&gt; 藉由與（步騾A-3)同樣之操作得到化合物（〇 10)。 [製造方法4-2] 下式代表之化合物（G4-2)(The symbols in the formulas have the same meaning as defined above). &lt;Step C-6&gt; A reaction for introducing a substituent into the S site of the pyrrole derivative (c-70). The compound (c-70) is used in the presence of 2,6-lutidine, and the compound (c-71) is applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) on a nitrogen-76^ paper scale. 1304061 A7 B7 V. INSTRUCTION DESCRIPTION (71) The reaction under fluidization and light-shielding conditions is carried out to obtain the objective compound (c-8). As the reaction solvent, dichloromethane or the like can be used, the reaction temperature is from about 0 ° C to the room temperature, and the reaction time is from 1 hour to 30 hours. <Step 07> The compound (c-9) was obtained by the same operation as (Step C-4). <Step C-8> A compound (〇 10) was obtained by the same operation as (Step A-3). [Production Method 4-2] Compound represented by the following formula (G4-2)

N〇2 (G4-2)Rsa2 (各式中之訖號具有與上述定義相同之意義）之製造方法如 下： ·、 FT1. 、COOH[步鄉2 c 一 13The manufacturing method of N〇2 (G4-2)Rsa2 (the nicknames in the formulas have the same meaning as defined above) is as follows: ·, FT1., COOH [step town 2 c a 13

COOH α R如 [步驟C一 2]COOH α R as [Step C-2]

IHCOOR [^¾ C-3] (2〇-3) (2C-1) __I ^l/^NHCOOR [#«2C-4] [^¾ C-5] ,-N02IHCOOR [^3⁄4 C-3] (2〇-3) (2C-1) __I ^l/^NHCOOR [#«2C-4] [^3⁄4 C-5] , -N02

TMS ^ - N NH? (2〇-β) 三甲矽l-TMS ^ - N NH? (2〇-β) Trimethyl 矽 l-

[步驟2CU[Step 2CU

〇2 M π (20-7) -77- 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐) 1304061 、 A7 _____ B7 五、發明説明（72 ) (各式中之記號具有與上述定義相同之意義）。 &lt;步騾2(：-1&gt; 為氯化反應。藉由化合物（2c-1)與亞硫醯氯反應而得到 目的化合物（2c-2)。反應溶媒，可以使用亞硫醯氯等，反 應溫度為加熱回流溫度，以及反應時間為數小時及數日。 &lt;步驟2C-2&gt; 為從羧酸形成胺基曱酸酯衍生物（2c-3)之轉位反應。藉 由羧酸衍生物（2c-2)於二苯基磷醯胺及三乙胺存在下，與 第三丁醇、芊醇及三甲矽烷醇等反應，而得到目的之胺基 甲酸酯衍生物（2c-3)。關於反應溶媒，可以使用第三丁 醇、苄醇、二甲基甲醯胺及曱苯等，反應溫度為室溫至加 熱回流溫度，以及反應時間為10分鐘至3〇小時β 〈步驟2C-3&gt; 本步驟為琪化反應。藉由鹼在p比啶之3位產生陰離子，使 琪作用而得到碘代化合物，然後進行脫胺基甲酸酯反應， 可以得到目的化合物（2c- 4)。關於碘化之、反應溶媒，可以 使用四氫吱喃及乙醚等，反應溫度為78艺至室溫，以及反 應時間為10分鐘至30小時。可以使用正丁基鋰等做為鹼。 亦適S添加Ν,Ν,Ν，，N，-四甲基伸乙二胺等鹼。脫胺基甲酸 酯反應之反應溶媒，可以使用水及醇類等，以及可以使用 氫溴酸水落液及鹽酸水溶液等做為酸，反應溫度為室溫至 加熱回流溫度，以及反應時間為丨分鐘至數小時。 〈步驟 2C-4&gt; -· 精由與（步驟Α·4)同樣之操作得到目的化合物（2c-5)。 _______-78- 本紙張尺度適用中國國家標準(CNS) A4規格(21〇 X 297公爱] --- 1304061 AT B7 73 五、發明説明（ 〈步驟2C-5&gt; 為碘化物(2c-5)與乙炔衍生物之偶合反應。藉由碘化 物’於肆（三苯膦）免等及琪化銅⑴等存在下，與（三〒基） ^炔等反應而得到目的化合物(2“)。反應溶媒可以：用 甲基甲I胺等’反應溫度為室溫至加熱回流溫度，以及 反應時間為1 〇分鐘至3 〇小時。 &lt;步驟2C-6&gt; 本步驟為環化反應。化合物（2e_6)在埃化銅⑴存在下， 藉由加熱而得到目的環化體化合物(2c_7)e反應溶媒可以 使用二甲基曱酿胺等，反應溫度為8{rc至加熱回流溫度， 以及反應時間為5分鐘至1 〇小時。 [製造方法4-3] 製造方法‘2中之化合物（2c_7)之另一製造方法如下·· (2C-91)〇2 M π (20-7) -77- This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1304061, A7 _____ B7 V. Invention description (72) (marks in each formula) Has the same meaning as defined above). &lt;Step 2 (:-1) is a chlorination reaction. The compound (2c-1) is reacted with sulfinium chloride to obtain the objective compound (2c-2). For the reaction solvent, sulfinium chloride or the like can be used. The reaction temperature is a heating reflux temperature, and the reaction time is several hours and several days. &lt;Step 2C-2&gt; is a transposition reaction for forming an amino phthalate derivative (2c-3) from a carboxylic acid. The compound (2c-2) is reacted with a third butanol, a decyl alcohol and a trimethyl decyl alcohol in the presence of diphenylphosphoniumamine and triethylamine to obtain a desired urethane derivative (2c-3). For the reaction solvent, third butanol, benzyl alcohol, dimethylformamide, toluene, etc. may be used, the reaction temperature is from room temperature to heating under reflux, and the reaction time is from 10 minutes to 3 hours. 2C-3&gt; This step is a cleavage reaction. An anion is produced by a base at a position 3 of p to a pyridine, and an iodine compound is obtained by a cleavage reaction, and then a carbamate reaction is carried out to obtain a target compound (2c- 4) For the iodination and reaction solvent, tetrahydrofuran and diethyl ether can be used, and the reaction temperature is 78 art. Room temperature, and the reaction time is 10 minutes to 30 hours. n-Butyl lithium or the like can be used as the base. It is also suitable to add a base such as hydrazine, hydrazine, hydrazine, N,-tetramethylethylenediamine. For the reaction solvent of the carbamate reaction, water, alcohol, or the like can be used, and hydrofluoric acid aqueous solution and aqueous hydrochloric acid solution can be used as the acid, the reaction temperature is from room temperature to heating and reflux temperature, and the reaction time is 丨 minute to <Step 2C-4> -· The objective compound (2c-5) is obtained by the same operation as (Step Α·4). _______-78- This paper scale applies to China National Standard (CNS) A4 specification (21 〇X 297 公爱] --- 1304061 AT B7 73 V. Description of the invention (<Step 2C-5> is the coupling reaction of iodide (2c-5) with acetylene derivative. By iodide' in bismuth (triphenyl) The desired compound (2") can be obtained by reacting with (trisyl) alkyne or the like in the presence of phosphine (1), etc. The reaction solvent can be: using methyl meamine or the like, the reaction temperature is room temperature to The reflux temperature is heated, and the reaction time is from 1 Torr to 3 Torr. &lt;Step 2C-6&gt; This step is The compound (2e_6) is obtained by heating in the presence of copper (1), to obtain the desired cyclized compound (2c_7). The reaction solvent can be dimethylamine or the like, and the reaction temperature is 8{rc to heating and refluxing. The temperature and the reaction time are from 5 minutes to 1 hour. [Production Method 4-3] Another production method of the compound (2c-7) in the production method '2 is as follows (2C-91)

(2C-92) (各式中之記號具有與上述定義相同之意義）。 〈步驟2C-7&gt; 本步驟為酮體（2c-8)轉變為硫代酮（2c-90)之轉變反應。 藉由與&lt;步驟2A-2&gt;同樣之操作而合成。、· 〈步驟2C-8&gt; -79- 本紙張尺度適用中國國家標準(CMS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（74 ) 藉由與&lt;步驟2A-3&gt;同樣之操作而合成。 [製造方法5-1] 下式表示之化合物（G5-1): R\(2C-92) (The symbols in the formulas have the same meaning as defined above). <Step 2C-7> This step is a conversion reaction in which a ketone body (2c-8) is converted into a thioketone (2c-90). It is synthesized by the same operation as &lt;Step 2A-2&gt;. <Step 2C-8> -79- This paper scale applies to Chinese National Standard (CMS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention Description (74) by &lt;Step 2A-3&gt; The same operation is combined. [Production Method 5-1] Compound (G5-1) represented by the following formula: R\

(G5-1) (各式中之記號具有與上述定義相同之意義）之代表性製造 方法如下： 裝 irThe representative manufacturing method of (G5-1) (the symbols in the formulas have the same meaning as defined above) is as follows:

(d-4) 妒5) -80-(d-4) 妒5) -80-

線 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061

、發明説明（ (各式中之記號具有與上述定義相同之意義）。 &lt;步驟D-l&gt; 藉由與&lt;步驟A-4&gt;同樣之操作而得到目的化合物（d-2)。 〈步驟D-2&gt; 本步驟為將氯化物轉變為胺基化合物之步驟。藉由孓氯 嘧哫何生物（d- 2)與氨反應而得到目的之胺基化合物（d- 3)。關於反應溶媒，可以使用乙醇及四氫呋喃等，反應溫 度為ot:至加熱回流溫度，以及反應時間為1〇分鐘至3〇小 時。 &lt;步驟D-3&gt; 裝 為使硝基化合物(d-3)轉變為胺基化合物(“)之還原反 應。藉由與（步驟A-5)同樣之操作而得到目的之胺基化合物 (d，4) 〇 &lt;步驟D-4&gt; 訂 藉由與（'步驟A-7)同樣之操作而得 5)。 付到目的之脲化合物（d- 線DESCRIPTION OF THE INVENTION (The symbols in the respective formulae have the same meanings as defined above.) &lt;Step D-1&gt; The objective compound (d-2) is obtained by the same operation as &lt;Step A-4&gt; Step D-2&gt; This step is a step of converting a chloride into an amine compound. The desired amino group compound (d-3) is obtained by reacting chloropyrimidine organism (d-2) with ammonia. As the solvent, ethanol, tetrahydrofuran or the like can be used, the reaction temperature is ot: to the reflux temperature, and the reaction time is from 1 minute to 3 hours. <Step D-3> is installed to convert the nitro compound (d-3) Is a reduction reaction of an amine compound ("). The same operation as (Step A-5) gives the desired amino compound (d, 4) 〇 &lt;Step D-4&gt; A-7) The same operation gives 5). The urea compound (d-line)

(d-i〇) -81 -本紙張尺度適用中國國家標準(CNS) A4規格(21〇 X 297公爱） l3〇4〇6l(d-i〇) -81 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇 X 297 public) l3〇4〇6l

(各式中之記號具有與上述定義相同之意義 &lt;步驟D- 6&gt;. 藉由與（步驟A-4)同樣之操作而得到目的化合物（心8)。 &lt;步驟D-7&gt; 為脫氯及硝基之還原反應之步騾。藉由氫氧化鈀-氫氣等 —般接觸還原條件可以得到目的化合物（心9)。反應溶媒例 浚可以使用甲醇、乙醇、四氫呋喃及二甲基曱醯胺等，接 觸遂原可以在常壓或加壓下進行。反應時間為1〇分鐘至％ 打時。反應溫度為室溫至加熱回流溫度。 &lt;步驟D-8&gt; 藉由與（步驟A-7)同樣之操作得到為目的之化合物（d 10)。 口 [製造方法5-2] 下式表示之化合物（G5-2):(The symbol in each formula has the same meaning as defined above. &lt;Step D-6&gt;. The objective compound (heart 8) is obtained by the same operation as (Step A-4). &lt;Step D-7&gt; Step of dechlorination and reduction of nitro group. The target compound (heart 9) can be obtained by contact-reduction conditions such as palladium hydroxide-hydrogen, etc. The reaction solvent can be exemplified by methanol, ethanol, tetrahydrofuran and dimethylhydrazine. The indole can be carried out under normal pressure or under pressure, and the reaction time is from 1 minute to 1%. The reaction temperature is from room temperature to heating and refluxing temperature. &lt;Step D-8&gt; A-7) Compound (d 10) which is obtained for the same operation. Port [Production Method 5-2] Compound (G5-2) represented by the following formula:

(各式中之記號具有與上述定義相同之意義）之代表性製造- 方法如下： ： -82- 本紙强:尺度適用中國國家標準(CNS) A4規格(210 X 297公爱) 1304061 A7 B7Representative manufacturing (the symbols in the various formulas have the same meaning as defined above) - The method is as follows: : -82- Ben paper strength: The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 1304061 A7 B7

五、發明説明（77 ) V^NHCOO^u (2d-l) [步騾2D-1] —— N NH2 [步驟 213-2] (2d-2)V. INSTRUCTIONS (77) V^NHCOO^u (2d-l) [Step 2D-1] - N NH2 [Step 213-2] (2d-2)

(各式中之S己號具有與上述定義相同之意義）。 &lt;步驟2D-1&gt; 為脫胺基甲酸酯反應❶藉由化合物（2 d-1)與氧作用而广 到目的之胺基衍生物（2d- 2)。可以使用水、二4燒、四^ 味喃、曱醇及乙醇等做為溶媒，反應溫度為室溫至加熱回 流溫度，以及反應時間為1 〇分鐘至3 0小時。可以用睡酸、 氫溴酸及三氟乙酸等做為酸。 〈步驟2D-2〉 使用化合物（2d-2)，以與製造方法5-1中之[步驟D- 6]〜[步驟D-8]同樣之方法進行操作，可以得到脉衍生物* (2d-3)。 [製造方法6] ，、 下式表示之化合物（G6-l)(G6-2)及（G6-3) ··(The S number in each formula has the same meaning as defined above). &lt;Step 2D-1&gt; For the decarboxylation reaction, an amine derivative (2d-2) which is broadly used by the action of the compound (2d-1) and oxygen is used. Water, di-4, tetrahydrofuran, decyl alcohol and ethanol can be used as the solvent, the reaction temperature is from room temperature to the reflux temperature, and the reaction time is from 1 Torr to 30 hours. Acids such as sleeping acid, hydrobromic acid, and trifluoroacetic acid can be used. <Step 2D-2> Using the compound (2d-2), the same procedure as in [Step D-6] to [Step D-8] in Production Method 5-1 can be carried out to obtain a pulse derivative* (2d) -3). [Production Method 6], Compounds (G6-1) (G6-2) and (G6-3)

裝 訂Binding

線line

A (G6^1) /Y—N02A (G6^1) /Y-N02

Cl I A (G6-3) xj31Cl I A (G6-3) xj31

A (G6-2) (各式中之記號具有與上述定義相同之意義）之另一途徑製 造方法如下： -83- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 ' A7 B7 五、發明説明（78 )Another way to manufacture A (G6-2) (the mark in each formula has the same meaning as defined above) is as follows: -83- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ' A7 B7 V. Description of invention (78)

(各式中之記號具有與上述定義相同之意義）。 &lt;步驟E- 1&gt; 為碘化物與丙烯酸乙酯之偶合反應。將化合物（e-Ι)，於 做為觸媒之乙酸鈀等以及3級胺（例如三丁胺等）存在下，與 丙稀酸乙I旨反應而得到目的化合物（e- 2)。反應溶媒，可以 使用二甲基甲醯胺等，反應溫度為100°C至加熱回流溫度， 以及反應時凋為5分鐘至30小時。 〈步騾 E-2&gt; ’、 為雙鍵之還原，繼而進行環化反應以及硝基之還原反 應。化合物（e-2)在鈀/碳-氫氣之條件下進行反應，以及進 行雙鍵之還原、環化反應及硝基之還原。反應溶媒，可以 使用曱醇、乙醇、四氫呋喃及二甲基甲醛等。接觸還原可 以在常壓或加壓下進行。反應時間為10分鐘至30小時。反 應溫度為室溫至加熱回流溫度。 〈步騾E-3&gt; ' 本步驟為藉由光照射將雙鍵異構化，繼而進行環化反 -84- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（79 應。反應溶媒，可以使用甲醇等，於2，-乙醯莕酮存在下藉 由光照射，.可以得到目的化合物（e- 4)。反應時間為1 〇分鐘 至3 0小時。 (2c-l) ΝΗ2 [步 (28-2) NHNOj[步软2£-2] •彳At (2Θ-3) [步驟2£-3】 (2β·4) ，Ν〇3_^ ^-COOHC _2㈣ (2e-5) :叫 #侧一丄 w κ (2β-8) (各式中之記號具有與上述定義相同之意義）。&lt;步驟2Ε-1&gt; 為硝基化之步驟。藉由使硫酸及發煙硝酸作用於化合物 (2e-l)而得到目的化合物（2e-2) β反應溶媒，可以使用硫酸 及發煙硝酸**·等，反應溫度為〇°C至室溫。反應時間為10分鐘 至3 0小時。 、&lt;步驟2E-2&gt; 為硝基之轉位反應《藉由使硫酸作用於化合物（2e-2)而 得到目的之化合物（2e- 3) ^反應溶媒，可以使用硫酸，反 應溫度為0°C至加熱回流溫度，以及反應時間為10分鐘至30 小時。&lt;步驟2Ε-3&gt; 將化合物（2e-3)用含有硝基之期望親磕劑，在卜甲基吡咯 啶酮、二甲基甲醯胺及氯苯等反應溶媒中，進行親核取代 -85- 本紙乐尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 裝 訂 線 1304061 A7 B7 五、發明説明（8〇 ) 反應’而得到目的之硝基體化合物（2e-4)。可以添加適宜 驗’例如二異丙基乙胺等有機鹼或碳酸鉀等無機鹼。反應 時間為10分鐘至30小時。反應溫度為室溫至加熱回流溫 度。 〈步驟2E-4&gt; 本步騾為將硝基還原為胺基之還原反應。以與&lt;A-5&gt;同 樣之方式操作，可以得到目的化合物（2 e - 5)。 〈步驟2E-5&gt; 本步驟為羧酸與二胺基體（2e-5)之縮合反應。藉由使羧 酸作用於二胺基化合物（2e- 5)，可以得到目的之化合物 (2e-6)。反應溶媒，可以使用硼磷酸等。反應溫度為室溫 至加熱回流溫度。反應時間為1 〇分鐘至3 0小時。可以使用 聚磷酸及五氧化磷作為脫水劑。(The symbols in the formulas have the same meaning as defined above). &lt;Step E-1&gt; is a coupling reaction of iodide and ethyl acrylate. The compound (e-Ι) is reacted with acrylic acid in the presence of a palladium acetate or the like as a catalyst and a tertiary amine (e.g., tributylamine) to obtain the objective compound (e-2). As the reaction solvent, dimethylformamide or the like can be used, and the reaction temperature is from 100 ° C to the reflux temperature, and the reaction is carried out for 5 minutes to 30 hours. <Step E-2> ', is a reduction of a double bond, followed by a cyclization reaction and a reduction reaction of a nitro group. The compound (e-2) is subjected to a reaction under palladium on carbon-hydrogen gas, and reduction of a double bond, cyclization reaction and reduction of a nitro group are carried out. As the reaction solvent, decyl alcohol, ethanol, tetrahydrofuran or dimethylformaldehyde can be used. Contact reduction can be carried out under normal pressure or under pressure. The reaction time is from 10 minutes to 30 hours. The reaction temperature is from room temperature to heating under reflux. <Step E-3> 'This step is to isomerize the double bond by light irradiation, and then carry out the cyclization anti-84- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Inventive Note (79) The reaction solvent can be obtained by irradiation with light in the presence of 2,-acetone, and the target compound (e-4) can be obtained. The reaction time is 1 〇 minutes. Up to 30 hours. (2c-l) ΝΗ 2 [Step (28-2) NHNOj [Step Soft 2 £-2] • 彳 At (2Θ-3) [Step 2 £-3] (2β·4) , Ν〇 3_^ ^-COOHC _2 (4) (2e-5) : ##一一丄w κ (2β-8) (The symbols in the formulas have the same meaning as defined above.) &lt;Step 2Ε-1&gt; is nitration The target compound (2e-2) β reaction solvent is obtained by allowing sulfuric acid and fuming nitric acid to act on the compound (2e-1), and sulfuric acid, fuming nitric acid, etc. can be used, and the reaction temperature is 〇°C. To the room temperature, the reaction time is from 10 minutes to 30 hours. &lt;Step 2E-2&gt; The transposition reaction of the nitro group "The compound of interest is obtained by allowing sulfuric acid to act on the compound (2e-2) (2e- 3) ^Reaction solvent, Sulfuric acid can be used, the reaction temperature is from 0 ° C to the reflux temperature, and the reaction time is from 10 minutes to 30 hours. &lt;Step 2Ε-3&gt; The compound (2e-3) is used as a desired affinity agent containing a nitro group. In the reaction solvent such as methylpyrrolidone, dimethylformamide and chlorobenzene, nucleophilic substitution is carried out. -85- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) Gutter 1304061 A7 B7 5. Description of the Invention (8〇) The reaction is carried out to obtain the desired nitro compound (2e-4). An organic base such as diisopropylethylamine or an inorganic base such as potassium carbonate may be added. The reaction time is 10 minutes. The reaction temperature is from room temperature to the reflux temperature. <Step 2E-4> This step is a reduction reaction for reducing a nitro group to an amine group. In the same manner as in <A-5>, it can be obtained. The objective compound (2 e - 5). <Step 2E-5&gt; This step is a condensation reaction of a carboxylic acid with a diamine matrix (2e-5). By reacting a carboxylic acid with a diamine compound (2e-5), The compound of interest (2e-6) can be obtained. For the reaction solvent, boron phosphorus can be used. The reaction temperature is from room temperature to reflux temperature, and the reaction time is from 1 Torr to 30 hours. Polyphosphoric acid and phosphorus pentoxide can be used as a dehydrating agent.

(各式中之記號具有與上述定義相同之意義）。 〈步驟 3E-1&gt; : 可以依照 Journal of sterocyclic chemistry，35 卷，1313 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) 1304061 A7 B7 五、發明説明（扪） (1998)記載之方法合成。藉由α -鹵素衍生物（3e-l)與丙二 腈反應，可以合成化合物（3e-2)。反應溶媒，可以使用二 甲基甲醯胺等，反應溫度為〇eC至加熱回流溫度，以及反應 時間為30分鐘至3〇小時。可以使用二乙胺作為鹼。 &lt;步驟3E-2&gt; 為構築呋喃并嘧啶環之步驟，藉由將化合物（3e-2)在甲 酿胺中及於添加無水乙酸下加熱至約2〇〇。〇而得到化合物 (3e-3)。反應時間為約數小時。 〈步騾3E-3〉 本步驟為溴化反應。藉由將化合物（3e-3)與二溴甲烷及 亞確酸異戊酯反應，而得到目的之溴代化合物（3e-4)。反 應落媒，可以使用二溴甲烷等，反應溫度為室溫至加熱回 流溫度，以及反應時間為30分鐘至3〇小時。 &lt;步驟3E-4&gt; 藉由與（步、驟A-4)同樣之操作得到化合物（3e-5)。(The symbols in the formulas have the same meaning as defined above). <Step 3E-1> : According to Journal of Sterocyclic chemistry, Volume 35, 1313 This paper scale applies Chinese National Standard (CNS) A4 specification (210x 297 mm) 1304061 A7 B7 V. Invention Description (扪) (1998) The method of synthesis. The compound (3e-2) can be synthesized by reacting an α-halogen derivative (3e-1) with malononitrile. As the reaction solvent, dimethylformamide or the like can be used, the reaction temperature is 〇eC to the heating reflux temperature, and the reaction time is 30 minutes to 3 hours. Diethylamine can be used as the base. &lt;Step 3E-2&gt; In order to construct a furanpyrimidine ring, the compound (3e-2) was heated to about 2 Torr by adding the anhydrous acetic acid in the melamine. The compound (3e-3) was obtained. The reaction time is about several hours. <Step 3E-3> This step is a bromination reaction. The desired bromo compound (3e-4) is obtained by reacting the compound (3e-3) with dibromomethane and isoamyl acid. For the reaction, it is possible to use dibromomethane or the like, the reaction temperature is from room temperature to the reflux temperature, and the reaction time is from 30 minutes to 3 hours. &lt;Step 3E-4&gt; The compound (3e-5) was obtained by the same operation as (Step, Step A-4).

同之意義-) (式中之記號具有與上述定義相 &lt;步驟3E_5&gt; … , 本纸張尺標準(CNi)-A4規格 1304061 A7 ^______B7 五、發明説明（82 ) 藉由與（步驟A-1)同樣之操作得到化合物（3e-7) β &lt;步騾3Ε-6&gt; 藉由與（步驟Α-2)同樣之操作得到化合物（3e_8)。 〈步驟3E-7&gt; 藉由與（步驟A-3)同樣之操作得到化合物（3e-9)。 式（4e-l)化合物：The same meaning -) (The symbol in the formula has the above definition &lt; Step 3E_5&gt; ..., the paper ruler standard (CNi)-A4 specification 1304061 A7 ^______B7 V. The invention description (82) by and (Step A -1) The same operation gives the compound (3e-7) β &lt;Step 3Ε-6&gt; The compound (3e_8) is obtained by the same operation as (Step Α-2). <Step 3E-7&gt; Step A-3) The same operation gives the compound (3e-9). Compound of the formula (4e-1):

(式中，Rmoo為可具有取代基之苯胺基或可具有取代基之 爷胺基等取代基）為在 Journal of Medicinal Chemistry，40, 3601 ( 1997)等中之合成方法記載之化合物。 式（4e-2)及式（4e-3)化合物：(In the formula, Rmoo is a substituent such as an anilino group which may have a substituent or a substituent which may have a substituent), and is a compound described in a synthesis method in Journal of Medicinal Chemistry, 40, 3601 (1997) and the like. Compounds of formula (4e-2) and formula (4e-3):

(式中，RsalGl為氟原子，可具有取代基之胺基，可具有取 代基之CN6烷氧基或可具有取代基之C2-7醯胺基等取代基） 為在 Journal of Medicinal Chemistry，39, 1823 ( 1996)等中之 合成方法記載之化合物。 [製造方法7] , 下式表示之化合物（Π): ----— ___ -88- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 B7 五、發明説明（ 83 )(wherein RsalG1 is a fluorine atom, an amine group which may have a substituent, a CN6 alkoxy group which may have a substituent or a C2-7 guanylamino group which may have a substituent), etc.) is in the Journal of Medicinal Chemistry, 39 , the compound described in the synthesis method of 1823 (1996). [Manufacturing method 7], the compound represented by the following formula (Π): ----- ___ -88- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 B7 V. Description of invention (83 )

(Π) (式中之記號具有與上述定義相同之意義）之代表性製造方 法如下： (1) 下式表示之化合物（a-01) ·· A (a-01) (式中足記號具有與上述定義相同之意義）可以利用一般已 知之習用有機反應而合成。又，關於化合物（a_〇1)，可以 採用上述製造方法4-1 , 4_2 , 5-1 , 5-2及6中記載之化合物 (c-6)、（cr-ίθ)、（2c-4)、（d-1}、（d-2)、（d.7)、（3e_4)、 (2e-4)、（3e-9)、（4e-l)、（4e-2)或（4e-3·)、。使用化合物（a、 〇i)，藉由（製造方法2-1)中之（步驟A-4)〜（步驟Α·η)記載 之反應條件，（製造方法2_2)中記載之反應條件，（製造方 法2- 3)中記載之反應條件以及（製造方法3)中記載之反應條 件，製造化合物（II)。 &quot; (2) Α/χ、丫/Ν〇2 (a-03) (a-04) _____ -89- 本紙張尺度適财g國家料(CNS) M規格(⑽x297公爱) l3〇4〇6iThe representative manufacturing method of (Π) (the symbol in the formula has the same meaning as defined above) is as follows: (1) The compound represented by the following formula (a-01) ·· A (a-01) The same meaning as defined above can be synthesized by a conventionally known conventional organic reaction. Further, as the compound (a_〇1), the compounds (c-6), (cr-ίθ), (2c-) described in the above production methods 4-1, 4_2, 5-1, 5-2 and 6 can be used. 4), (d-1}, (d-2), (d.7), (3e_4), (2e-4), (3e-9), (4e-l), (4e-2) or 4e-3·), using the compound (a, 〇i), the reaction conditions described in (Step A-4) to (Step Α·η) in (Production Method 2-1), (Production Method 2_2) The reaction conditions described in the reaction conditions described in (Production Method 2 - 3) and the reaction conditions described in (Production Method 3) are used to produce the compound (II). &quot; (2) Α/χ, 丫/Ν〇2 (a-03) (a-04) _____ -89- The paper size is suitable for the national material (CNS) M specification ((10)x297 public) l3〇4〇6i

五、發明説明（84 A7 B7 (式中之記號具有與上述定義相同之意義）。 將製造方法2-1中之[A-5]〜[A-11]之條件適當組合使用， 可以從化合物（a-03)或（a-〇4)製得衍生物（Π)。關於化合 物（a-03)或（a-〇4) ’具體而言，例如可以使用化合物（2c· 7)、（2c，92)、（e-4)、（3e-5)、（e-3)及（e-6)。 [製造方法8-1；!5. Description of the Invention (84 A7 B7 (The symbols in the formula have the same meanings as defined above). The conditions of [A-5] to [A-11] in the production method 2-1 can be appropriately combined and used, and the compound can be used. (a-03) or (a-〇4) to obtain a derivative (Π). Regarding the compound (a-03) or (a-〇4) 'specifically, for example, a compound (2c·7) can be used, 2c, 92), (e-4), (3e-5), (e-3), and (e-6). [Manufacturing method 8-1;

装 (式中之記號具有與上述定義相同之意義）之代表性合成法 如下：A representative synthesis of the (the symbol in the formula has the same meaning as defined above) is as follows:

訂Order

線 (式中之記號具有與上述定義相同之意義）。 &lt;步驟0-1&gt; -90 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 — A7 ___B7 j、發明説明（8δ ) 為還原胺化之步驟。藉由化合物（〇-1)與醛衍生物進行還 原性反應’ ·可以彳寸到目的之化合物（〇- 2)。反應溶媒，可以 使用乙酸、四氫呋喃、二氯乙烷、二氯甲烷及甲醇等，反 應溫度為0°C至加熱回流溫度，以及反應時間為3〇分鐘至3〇 小時。可以使用二乙醯氧基硼氫化鈉及硼氫化鈉等做為還 原劑。 - &lt;步騾0-2&gt; 本步驟為胺基甲酸酯化之步驟。藉由將化合物（〇_2)與氯、二^ 甲酸酯衍生物反應可以得到目的之化合物（心3)。反應溶媒 可以使用四氫咬喃及二氯甲貌等，反應溫度為〇它至加熱回 流溫度’以及反應時間為30分鐘至3〇小時。可以使用吡咬 及三乙胺等做為鹼。 &lt;步驟0-3&gt; 本步驟為使硝基還原為胺基之步驟。藉由與（步驟α_5)同一 樣之操作可以得到目的之化合物（4)。 〈步驟 0-4&gt; ·、 本步驟為分子内環化反應之步驟。使分子内存在之胺基 與胺基甲酸酯反應，可以得到目的之化合物（〇_ 5) ^反應溶 媒，可以使用四氫呋喃、二曱基甲醯胺、二甲基亞颯及乙 月月等，反應溫度為0 c至加熱回流溫度，以及反應時間為3〇 分鐘至30小時。可以使用氫化鈉、吡啶及三乙胺等做為_ 鹼。 [製造方法8-2] -· 化合物（〇-5)之另一製造方法如下： —-91- 本紙張尺度適¥ S S家標準(CNS) Α4規格(21G X 297公愛) 一 '~ -- 1304061Line (The symbol in the formula has the same meaning as defined above). &lt;Step 0-1&gt; -90 - The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 - A7 ___B7 j, invention description (8δ) is the step of reductive amination. By the compound (〇-1) and the aldehyde derivative, a reductive reaction can be carried out to the intended compound (〇-2). As the reaction solvent, acetic acid, tetrahydrofuran, dichloroethane, dichloromethane, methanol or the like can be used, and the reaction temperature is from 0 ° C to the reflux temperature, and the reaction time is from 3 minutes to 3 hours. Sodium diethyl hydride borohydride, sodium borohydride or the like can be used as a reducing agent. - &lt;Step 0-2&gt; This step is a step of urethane formation. The compound of interest (heart 3) can be obtained by reacting the compound (〇_2) with a chlorine or a bisformate derivative. The reaction solvent may be a tetrahydroanthracene or a dichloromethane or the like, and the reaction temperature is 〇 to a heating reflux temperature' and the reaction time is 30 minutes to 3 hours. It is possible to use a pyridine bite or triethylamine as a base. &lt;Step 0-3&gt; This step is a step of reducing a nitro group to an amine group. The objective compound (4) can be obtained by the same operation as (step α_5). <Step 0-4&gt; · This step is a step of intramolecular cyclization reaction. By reacting an amine group present in the molecule with a urethane to obtain a compound of interest (〇 _ 5) ^ reaction solvent, tetrahydrofuran, dimercaptocaramine, dimethyl azine, and erythritol may be used. The reaction temperature is from 0 c to the reflux temperature, and the reaction time is from 3 minutes to 30 hours. Sodium hydride, pyridine, triethylamine or the like can be used as the base. [Manufacturing method 8-2] -· The other manufacturing method of the compound (〇-5) is as follows: —91- The paper size is suitable for the SS standard (CNS) Α4 specification (21G X 297 public). - 1304061

(式中之記號具有與上述定義相同之意義）。 &lt;步驟0-5&gt; 2步驟為2硝基還原為胺基之步驟^由與（a_5)同樣之 操作，可以彳于到目的之二胺化合物（〇-6)。 二 &lt;步騾0-6〉 、本步驟為分子内環化反應之步驟。藉由將分子内之二個 胺基與光氣、三聚光氣、i•乙基_3·(3_:τ胺丙基）竣化二 亞胺鹽酸鹽、⑽似苯并三唑小基氧)(三(二甲胺基)） 鱗六氟磷酸鹽、1-乙基_3_(3_二甲胺丙基)碳化二亞胺鹽酸 鹽及1，1 -羰基二咪唑等縮合劑反應，可以得到目的之化合二 物（〇- 5)。〜反〜應溶媒’可以使用四氫咬喃 '二甲基甲醯胺、 一甲基亞職及乙腈等，反應溫度為至加熱回流溫度，以 及反應時間為30分鐘至30小時。可以添加適宜的鹼諸如氫 化鈉、吡啶或三乙胺等。 [製造方法9] 下式表示之化合物（Π)中，(The symbol in the formula has the same meaning as defined above). &lt;Step 0-5&gt; The second step is a step of reducing the 2 nitro group to an amine group. The same operation as (a_5) can be carried out to the desired diamine compound (〇-6). Second &lt;Step 0-6> This step is the step of intramolecular cyclization. By diluting two amine groups in the molecule with phosgene, trimerizing phosgene, i•ethyl_3·(3_:τ-aminopropyl), diimide diimide hydrochloride, (10) small benzotriazole Condensation of hexafluorophosphate (tris(dimethylamino)) hexafluorophosphate, 1-ethyl_3_(3-dimethylaminopropyl)carbodiimide hydrochloride and 1,1-carbonyldiimidazole The reaction of the agent gives the desired compound (〇-5). The anti-reagent solvent can be used as tetrahydromethane, dimethylformamide, monomethylamine or acetonitrile, and the reaction temperature is up to the reflux temperature, and the reaction time is 30 minutes to 30 hours. A suitable base such as sodium hydride, pyridine or triethylamine or the like can be added. [Production Method 9] In the compound (Π) represented by the following formula,

(II) -92 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（87 ) (式中之記號具有與上述定義相同之意義） 環A上之取.代基之變換反應可藉由適宜使用習知之氧化反 應、還原反應、酯形成反應、醯胺形成反應、保護基形成 反應、脫保護反應、加水分解反應、脫水反應、轉移反 應、親核反應、親核取代反應及芳香環親電子取代反應等 有機反應而進行。 — 具體而言，如下所述，可以進行環A上之取代基變換。 又，可將下述反應（1)組合而進行，（2)不僅用於最終產= 物，亦用於中間體，（3)不僅用於直接鍵結於環A上之取代 基之變換，亦可用於環A之取代基中未直接鍵結之部位之取 代基之變換。 [製造方法10](II) -92 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (87) (The symbol in the formula has the same meaning as defined above) Ring A The conversion reaction can be carried out by suitably using a conventional oxidation reaction, reduction reaction, ester formation reaction, guanamine formation reaction, protecting group formation reaction, deprotection reaction, hydrolysis reaction, dehydration reaction, transfer reaction, The organic reaction such as a nucleophilic reaction, a nucleophilic substitution reaction, and an aromatic ring-electron substitution reaction is carried out. - Specifically, the substituent transformation on ring A can be carried out as described below. Further, the following reaction (1) can be carried out in combination, (2) not only for the final product, but also for the intermediate, and (3) not only for the substitution of the substituent directly bonded to the ring A, It can also be used for the conversion of substituents in the substituents of the ring A which are not directly bonded. [Manufacturing Method 10]

(式中，〇1意指可具有取代基之氮原子或氧原子，此外各記 號具有與上述定義相同之意義）。 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 —* A7 _______B7 ____ 五、發明説明（88 ) &lt;步驟H-l&gt; 為將酯化.合物（h-1)還原為醇化合物（h-2)之還原反應。可 以使用硼氫化鋰及氫化鋰鋁等做為還原劑，反應溶媒，可 以使用乙醚及四氫呋喃等，反應溫度為〇。(：至加熱回流溫 度，以及反應時間為10分鐘至30小時。 〈步驟H-2〉 · 為將醇化合物（h-2)轉變為醛化合物（h-3)之氧化反應。氧 化劑，可以使用二氧化錳、氯鉻酸吡錠鹽（PCC)及重鉻酸&gt; 吡錠鹽（PDC)等，反應溶媒，可以使用氯仿、二氯甲烷及… 曱苯等，反應溫度為〇°C至加熱回流溫度，以及反應時間為 30分鐘至30小時。 〈步驟H-3&gt; 為還原性脫胺基反應。藉由使醛衍生物（h-3)與胺基衍生 物反應，然後於形成亞胺後，用氰基硼氰化鈉等還原，可 ^ 以得到化合i(h-4)。反應溶媒，可以使用甲醇及四氫呋喃 等，反應時間為10分鐘至30小時，反應溫·渡為〇°C至加熱回 流溫度。(In the formula, 〇1 means a nitrogen atom or an oxygen atom which may have a substituent, and each symbol has the same meaning as defined above). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 —* A7 _______B7 ____ V. Description of invention (88) &lt;Step H-l&gt; For esterification (h-1) Reduction to the reduction reaction of the alcohol compound (h-2). Lithium borohydride, lithium aluminum hydride or the like can be used as the reducing agent, and the reaction solvent can be diethyl ether or tetrahydrofuran, and the reaction temperature is hydrazine. (: to the heating reflux temperature, and the reaction time is 10 minutes to 30 hours. <Step H-2> · To oxidize the alcohol compound (h-2) to the aldehyde compound (h-3). The oxidizing agent can be used. Manganese dioxide, pyridinium chlorochromate (PCC), dichromic acid, pyridinium salt (PDC), etc., reaction solvent, chloroform, dichloromethane, and benzene can be used, and the reaction temperature is 〇 ° C to The reflux temperature is heated, and the reaction time is 30 minutes to 30 hours. <Step H-3> is a reductive deamination reaction by reacting an aldehyde derivative (h-3) with an amine derivative, and then forming a sub After the amine is reduced with sodium cyanoborohydride or the like, the compound i(h-4) can be obtained. The reaction solvent can be methanol or tetrahydrofuran, and the reaction time is 10 minutes to 30 hours, and the reaction temperature is 〇. °C to heating reflux temperature.

1304061 A7 ______ _ B7 五、發明説明（89 ) (式中’各έ己號具仴與上述定義相同之音義）。 &lt;步驟Η-4&gt; 本步驟為將醋化合物（h-5)轉變為醇化合物（h_6)之還原反 應。藉由與（步驟Η-D同樣之操作，可以合成目的之化合物 (h-6) ° &lt;步騾H-5&gt; . 為將醇化合物（h-6)轉變為醛化合物（h_7)之氧化反應。藉 由與（步驟H-2)同樣之操作，可以合成目的之化合物（h_ 士 7” &lt;步騾H-6&gt; 為還原性脫胺基反應。藉由與（步驟3)同樣之操作。可 以得到目的之化合物（h- 8)。1304061 A7 ______ _ B7 V. INSTRUCTIONS (89) (wherein each word has the same meaning as defined above). &lt;Step Η-4&gt; This step is a reduction reaction of converting the vinegar compound (h-5) into an alcohol compound (h-6). By the same operation as (Step Η-D, the compound of interest (h-6) ° &lt;Step H-5&gt; can be synthesized. To oxidize the alcohol compound (h-6) to the aldehyde compound (h-7) By the same operation as (Step H-2), the compound of interest (h_士7" &lt;Step H-6&gt; can be synthesized as a reductive deamination reaction by the same reaction as (Step 3). The desired compound (h-8) can be obtained.

(式中，各記號具有與上述定義相同之意義）。 &lt;步驟H-7&gt; 為將氰基還原為胺甲基之步驟。藉由通常之接觸還原反 應（以鈀-碳及氫氧化鈀-氫等做為觸媒），可以由化合物（h· 9)得到目的之化合物（h-10)。反應溶媒，可以使用四氫呋 喃、甲醇及乙醇等。反應時間為10分鐘至30小時，以及反 應溫度為〇°C至加熱回流溫度。可以使用三氟乙酸及鹽酸等 做為酸。 ^ [製造方法10-2] -9〇 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061(wherein each symbol has the same meaning as defined above). &lt;Step H-7&gt; A step for reducing a cyano group to an amine methyl group. The object compound (h-10) can be obtained from the compound (h·9) by a usual contact reduction reaction (palladium-carbon and palladium hydroxide-hydrogen as a catalyst). As the reaction solvent, tetrahydrofuran, methanol, ethanol or the like can be used. The reaction time is from 10 minutes to 30 hours, and the reaction temperature is from 〇 ° C to the heating reflux temperature. Trifluoroacetic acid, hydrochloric acid or the like can be used as the acid. ^ [Manufacturing Method 10-2] -9〇 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061

(式中，各記號具有與上述定義相同之意義）。 &lt;步驟2H-1&gt; 為進行化合物（2h-1)中之酯之加水分解而得到化合物（ 2)之步驟。反應中，可以使用氫氧化神、氫氧化制、竣酸 舞及碳酸納等鹼❶反應時間為10分鐘至3〇小時，以及反鹿 溫度為至加熱回流溫度。溶媒，可以使用水及四氫呋喃 等。 〈步驟2Η-2&gt; 本步驟為藉由羧酸與胺基衍生物之縮合反應而合成酿胺 衍生物（2h-3)。藉由化合物（2h-2)與胺衍生物於存在縮合 劑下反應，可以得到化合物（2h_ 3)。關於縮合劑，可以使 用1-乙基-3-(3-二甲胺丙基）碳化二亞胺鹽酸鹽，及（1Η· 1，2,3-苯并三唑-丨_基氧三（二甲胺基銹六氟磷酸鹽等。 反應時間為10分鐘至3〇小時，以及反應溫度為〇。〇至加熱回 - 流溫度。溶媒，可以使用二甲基甲醯胺及四氫呋喃等。 〈步驟 2H-3&gt; , 為藉由羧酸與醇之縮合反應而合成酯衍生物（2h-4)。藉 ______-96- 本紙張尺度適用中國國家標準(CMS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（91 ) 由化合物（2h- 2)與醇衍生物於存在縮合劑下反應，可以得 到化合物（2h-3)。關於縮合劑，可以使用卜乙基-3-(3-二甲 胺丙基）碳化二亞胺鹽酸鹽Q反應時間為丨〇分鐘至30小時， 以及反應溫度為0°C至加熱回流溫度。溶媒，可以使用二甲 基甲酿胺及四氫啥喃等。(wherein each symbol has the same meaning as defined above). &lt;Step 2H-1&gt; A step of obtaining a compound (2) by subjecting the ester in the compound (2h-1) to hydrolysis. In the reaction, an alkali hydrazine reaction time such as hydroxide, hydroxide, citric acid or sodium carbonate can be used for 10 minutes to 3 hours, and the anti-deer temperature is to a heating reflux temperature. As the solvent, water, tetrahydrofuran or the like can be used. <Step 2Η-2&gt; This step is a synthesis of a stilbene derivative (2h-3) by a condensation reaction of a carboxylic acid with an amine derivative. The compound (2h-3) can be obtained by reacting the compound (2h-2) with an amine derivative in the presence of a condensing agent. As the condensing agent, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride can be used, and (1Η·1,2,3-benzotriazole-oxime-oxy 3 (dimethylamino rust hexafluorophosphate, etc. The reaction time is from 10 minutes to 3 hours, and the reaction temperature is 〇. 〇 to the heating back-flow temperature. The solvent may be dimethylformamide or tetrahydrofuran. <Step 2H-3>, an ester derivative (2h-4) is synthesized by a condensation reaction of a carboxylic acid and an alcohol. By ______-96- This paper scale is applicable to the Chinese National Standard (CMS) A4 specification (210 X 297) 1304061 A7 B7 V. INSTRUCTION DESCRIPTION (91) The compound (2h-3) can be obtained by reacting the compound (2h-2) with an alcohol derivative in the presence of a condensing agent. For the condensing agent, it can be used. (3-dimethylaminopropyl)carbodiimide hydrochloride Q reaction time is from 丨〇 minutes to 30 hours, and the reaction temperature is from 0 ° C to heating reflux temperature. The solvent can be used with dimethyl ketoamine and Tetrahydrofuran and the like.

(式中’各記號具有與上述定義相同之意義）。 〈步驟2H-4&gt; 為進行化合物（2h-5)中之酯之加水分解反應，而得到化 合物（2h-6)之步驟。藉由與（步驟2H-1)同樣之操作，可以 從化合物（2h-5)得到化合物（2h-6)。 &lt; 步驟 2Η-'5&gt; 為藉羧酸衍生物（2h·6)與胺基衍生物之縮合反應而合 成酿胺衍生物（2h-7)。藉由與（步驟2H-2)同樣之操作，從 化合物（2h-6)得到化合物（2h-7)。(The symbols in the formula have the same meaning as defined above). <Step 2H-4&gt; A step of obtaining a compound (2h-6) for carrying out a hydrolysis reaction of the ester in the compound (2h-5). The compound (2h-6) can be obtained from the compound (2h-5) by the same operation as (Step 2H-1). &lt;Step 2Η-'5&gt; The arylamine derivative (2h-7) is synthesized by a condensation reaction of a carboxylic acid derivative (2h·6) with an amine derivative. The compound (2h-7) is obtained from the compound (2h-6) by the same operation as (Step 2H-2).

__ _ -97- 本紙張尺度適用中國國豕標準(CNS) A4規格(210X 297公董)__ _ -97- This paper size applies to China National Standard (CNS) A4 specification (210X 297 DON)

1304061 …_ A7 _ B7 _五、發明説明^~^7) ~&quot; (式中，各記號具有與上述定義相同之意義）。 &lt;步驟2Η-6&gt; 為藉由胺甲醯基化合物（2h_8)之脫水反應而得到腈衍生 物（2h-9)之步驟。反應溶媒，可以使用四氫呋喃及乙_ 等，脫水試藥，可以使用亞硫醯氯、三氟乙酸奸及二環己 基碳化一亞胺等。又，可以使用p比淀及三乙胺等做為驗。 反應溫度為〇 °C至加熱回流溫度，以及反應時間為3 〇分鐘至 30小時。 [製造方法10-3]1304061 ..._ A7 _ B7 _ V. Invention description ^~^7) ~&quot; (where the symbols have the same meaning as defined above). &lt;Step 2Η-6&gt; is a step of obtaining a nitrile derivative (2h-9) by a dehydration reaction of an amine formamidine compound (2h-8). As the reaction solvent, tetrahydrofuran, B- or the like can be used, and the dehydration reagent can be used, and sulfinium chloride, trifluoroacetic acid, and dicyclohexylcarbodiimide can be used. Further, it is possible to use p-precipitate and triethylamine as tests. The reaction temperature is from 〇 ° C to the reflux temperature, and the reaction time is from 3 Torr to 30 hr. [Manufacturing Method 10-3]

(式中，各記號具有與上述定義相同之意義 〈步驟3H-1&gt; 為將胺基醯化之步驟。藉由化合物（3h-丨）與醯基氯化物 或酸酐等反應，可以得到目的之化合物（3h-2)。反應溶 媒，可以使用四氫呋喃等，反應溫度為至加熱回流溫 度’以及反應時間為1 〇分鐘至3 〇小時。可以使用三乙胺等 做為鹼。 -98 - 本纸張尺度適用中國國家標準(CNS) Α4規^7〇 X 297公爱y 1304061 A7 B7(wherein each symbol has the same meaning as defined above. <Step 3H-1&gt; is a step of deuterating the amine group. By reacting the compound (3h-丨) with a mercapto chloride or an acid anhydride, the object can be obtained. Compound (3h-2). The reaction solvent may be tetrahydrofuran or the like, the reaction temperature is up to the reflux temperature of heating, and the reaction time is from 1 Torr to 3 Torr. Triethylamine or the like may be used as the base. -98 - Paper Zhang scale applies to China National Standard (CNS) Α 4 regulations ^ 7 〇 X 297 public y 1304061 A7 B7

五、發明説明（93 )V. Description of invention (93)

(式中，各記號具有與上述定義相同之意義） 〈步驟 3H-20〉 為醯化足步騾。藉由化合物（3h-3)與醯基氯化物或酸纤 等反應’可以得到目的化合物（3h-4)。反應溶媒，可以使 用四氫呋喃^及吡啶等，反應溫度為〇°C至加熱回流溫度，以 及反應時間為10分鐘至3 0小時。可以使甩三乙胺及π比咬等 做為鹼。 〈步驟 3H-21〉 為環化反應。反應溶媒，可以使用二甲基甲醯胺等，反 應溫度為100°C至加熱回流溫度，以及反應時間為分鐘至 30小時。可以使用碳酸鉀等做為鹼。 -99- 本紙裱尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7(In the formula, each mark has the same meaning as the above definition) <Step 3H-20> is a step of 醯化. The object compound (3h-4) can be obtained by reacting the compound (3h-3) with mercapto chloride or acid fiber or the like. As the reaction solvent, tetrahydrofuran, pyridine or the like can be used, and the reaction temperature is from 〇 ° C to the reflux temperature, and the reaction time is from 10 minutes to 30 hours. Triethylamine and π-bite can be used as a base. <Step 3H-21> is a cyclization reaction. As the reaction solvent, dimethylformamide or the like can be used, and the reaction temperature is from 100 ° C to the reflux temperature, and the reaction time is from minute to 30 hours. Potassium carbonate or the like can be used as the base. -99- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7

(3h-5) (3h-6) (式中，各記號具有與上述定義相同之意義）。 〈步驟3H-3&gt; 為磺醯胺化 &lt; 步騾。藉由將化合物（3h-5)與磺醯氯衍生 物反應可以得至,j目的之化合物（3h· 6)。反應溶媒，可以 使用四氫呋喃及二甲基甲醯胺等。反應溫度為〇它至加熱回 流溫度’以及反應時間為10分鐘至30小時。可以使用三乙 胺及吡啶等做為鹼。(3h-5) (3h-6) (wherein each symbol has the same meaning as defined above). <Step 3H-3> is sulfonamide &lt; step. The compound (3h·6) can be obtained by reacting the compound (3h-5) with a sulfonium chloride derivative. As the reaction solvent, tetrahydrofuran, dimethylformamide or the like can be used. The reaction temperature is 〇 it to the heating reflux temperature' and the reaction time is from 10 minutes to 30 hours. Triethylamine, pyridine or the like can be used as the base.

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線 (式中，各記號具有與上述定義相同之意義）。 &lt;步驟3H-4&gt; 為脫苄氧羰基化之步驟。藉由通常之.接觸還原反應（鈀-碳，氫氧化鈀-碳及氫氣等），可以從化合物（3h-7)得到化 -100- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（ 合物（3h- 8)。關於落媒，可以使用四氫吱喃、甲醇及乙醇 等。反應時間為1〇分鐘至30小時，以及反應溫度為〇°C至加 熱回流溫度。關於酸，可以使用三氟乙酸及鹽酸等。 [製造方法11]Line (wherein each symbol has the same meaning as defined above). &lt;Step 3H-4&gt; is a step of debenzyloxycarbonylation. By the usual contact reduction reaction (palladium-carbon, palladium hydroxide-carbon and hydrogen, etc.), it can be obtained from the compound (3h-7)-100- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210). X 297 mm) 1304061 A7 B7 V. Description of the invention (compound (3h-8). For the catalyst, tetrahydrofuran, methanol, ethanol, etc. may be used. The reaction time is from 1 minute to 30 hours, and the reaction temperature. It is 〇 ° C to the heating reflux temperature. As the acid, trifluoroacetic acid, hydrochloric acid, or the like can be used. [Production Method 11]

(式中，各記號具有與上述定義相同之意義）。 &lt;步騾1-1&gt; 為羧酸轉變為胺基衍生物（i-2)之轉位反應。藉由幾酸衍 生物（i-Ι)於二苯基磷醯胺及三乙胺存在下，與苄醇反應， 可以從化合物（i- 1)得到化合物（i- 2)。反應溶媒可以使用爷 醇、二甲基甲酿胺及甲苯等。反應溫度為室溫至加熱回流 溫度’以及/反應時間為1 〇分鐘至3 〇小時。 &lt;步驟1-2&gt; .(wherein each symbol has the same meaning as defined above). &lt;Step 1-1&gt; A transposition reaction in which a carboxylic acid is converted into an amine derivative (i-2). The compound (i-2) can be obtained from the compound (i-1) by reacting a few acid derivatives (i-oxime) with benzyl alcohol in the presence of diphenylphosphoniumamine and triethylamine. As the reaction solvent, melamine, dimethylamine, toluene or the like can be used. The reaction temperature is from room temperature to heating under reflux temperature' and / reaction time is from 1 Torr to 3 Torr. &lt;Step 1-2&gt;

N 藉由與（步驟A-4)、（步驟A-5)及（步驟A-7)之同樣操作， 可以從化合物（i-2)得到化合物（i_3)。N The compound (i-3) can be obtained from the compound (i-2) by the same operation as (Step A-4), (Step A-5) and (Step A-7).

-101 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 A7 B7 五、發明説明（96 ) (式中，各記號具有與上述定義相同之意義）。 &lt;步驟1-3&gt; . 為胺甲酿基轉變為胺基之轉位反應。藉由與溴水及氫氧 化鈉等驗反應，可以從化合物（i- 4)得到胺基體化合物（卜 5)。反應溶媒’可以使用水；反應溫度為室溫至加熱回流 溫度，以及反應時間為10分鐘至10小時。 [製造方法12-1]-101 - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Inventive Note (96) (wherein each symbol has the same meaning as defined above). &lt;Steps 1-3&gt; . The transposition reaction for converting an amine to an amine group. The amine matrix compound (Bu 5) can be obtained from the compound (i-4) by a reaction with bromine water and sodium hydroxide. Water can be used as the reaction solvent. The reaction temperature is from room temperature to heating under reflux, and the reaction time is from 10 minutes to 10 hours. [Manufacturing Method 12-1]

(式中，各記號具有與上述定義相同之意義）。 &lt;步騾M-l&gt; 為將甲瑞姜轉變為曱橫酿基之變換反應。化合物（1)藉 由與過酸反應，可以得到目的之化合物（甩-2)。關於過酸， 可以使用3 -氯過安息香酸等。反應溶媒，可以使用二氯甲 烷及氯仿等，反應時間為10分鐘至30小時，以及反應溫度 為°C至加熱回流溫度。 [製造方法12-2](wherein each symbol has the same meaning as defined above). &lt;Step M-l&gt; In order to convert Jiarui ginger into a transformation reaction. The compound (1) can be obtained by reacting with a peracid to obtain the intended compound (甩-2). As the peracid, 3-chloroperbenzoic acid or the like can be used. As the reaction solvent, methylene chloride, chloroform or the like can be used, and the reaction time is from 10 minutes to 30 hours, and the reaction temperature is from ° C to the heating reflux temperature. [Manufacturing Method 12-2]

-102--102-

本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐)This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

!304061 (式中’各1己號具有與上述定義相同之意義）。 &lt;步驟2M-1&gt; 為藉由親電子反應將取代基導入芳香環之步驟。藉由使 化合物（2m-1)與親電子試藥反應，可以得到化合物（2m-2)。親電子試藥之具體例，例如為viismeier試藥（從二甲基 甲醯胺或N-曱基甲醯替苯胺及氧氯化磷調製）、N-氯琥珀 酿亞胺、N-溴琥珀醯亞胺、醯基氯與路易士酸（例如氯化銘 及四氯化鈥等）之組合，及下式： / =吹M· \ 代表之試藥等，藉由彼等之作用，分別可以導入甲醯基、 氯 '溴、醯基、二甲胺甲基等。反應溶媒，可以使用二甲 基甲醯胺、乙腈、二氯甲烷及甲苯等，反應溫度為。C至加 熱回流溫度&lt;，以及反應時間為10分鐘至30小時。 [製造方法13] ·、 裝 訂!304061 (wherein each 1 has the same meaning as defined above). &lt;Step 2M-1&gt; A step of introducing a substituent into an aromatic ring by an electrophilic reaction. The compound (2m-2) can be obtained by reacting the compound (2m-1) with an electrophile reagent. Specific examples of electrophilic reagents, such as viismeier reagents (modulated from dimethylformamide or N-mercaptoacetamide and phosphorus oxychloride), N-chlorosuccinimide, N-brominated amber a combination of quinone imine, mercapto chloride and Lewis acid (such as chlorinated and ruthenium tetrachloride), and the following formula: / = blowing M · \ representative of the test, etc., by their role, respectively A methyl group, a chlorine 'bromine, a thiol group, a dimethylamine methyl group, etc. can be introduced. As the reaction solvent, dimethylformamide, acetonitrile, dichloromethane, toluene or the like can be used, and the reaction temperature is. C to the heating reflux temperature &lt;, and the reaction time is from 10 minutes to 30 hours. [Manufacturing Method 13] ·, Binding

[步驟Q - 1][Step Q - 1]

線 (式中’各記號具有與上述定義相同之意義）。 &lt;步驟Q-1〉 : 為化合物（q- 1)中之羥基保護基被脫保護之步驟&quot;该反應 -103- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（98 ) 係按照將被芊基保護之酚基脫保護所常用之方法來進行。 具體而言，例如可以使用三氟乙酸-硫代苯甲醚、氫氧化 鈀-氫氣及氧化鉑-氫氣等。反應溶媒，可以使用三氟乙酸 及二甲基甲醯胺等，反應時間為10分鐘至30小時，以及反 應溫度為室溫至加熱回流溫度。Lines (wherein the symbols have the same meaning as defined above). &lt;Step Q-1〉: The step of deprotecting the hydroxy protecting group in the compound (q-1)&quot; The reaction-103- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 gong) PCT) 1304061 A7 B7 V. INSTRUCTIONS (98) This is carried out in accordance with the usual methods for deprotecting phenolic groups that are protected by sulfhydryl groups. Specifically, for example, trifluoroacetic acid-thioanisole, palladium hydroxide-hydrogen, platinum oxide-hydrogen, or the like can be used. As the reaction solvent, trifluoroacetic acid, dimethylformamide or the like can be used, and the reaction time is from 10 minutes to 30 hours, and the reaction temperature is from room temperature to heating under reflux.

(式中，Rsa9()為胺基或硝基，其他各記號具有與上述定義相 同之意義）。 &lt;步騾Q-2&gt; 為化合物（q-3)中之羥基保護基被脫保謹之步驟。該反應 在與上述（吏驟Q-1)同樣之條件下進行。 [製造方法14] ·、 裝 訂(wherein, Rsa9() is an amino group or a nitro group, and the other symbols have the same meaning as defined above). &lt;Step Q-2&gt; is a step in which the hydroxy protecting group in the compound (q-3) is deprotected. This reaction was carried out under the same conditions as above (Step Q-1). [Manufacturing Method 14] ·, Binding

線 (式中，各記號具有與上述定義相同之意義）。 &lt;步驟R-l&gt; , 為使化合物（卜1)與卣代烷基化衍生物（卜2)等親電子試藥 -104- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（99 ) 反應，而得到化合物（r-3)之步驟。該反應可在以二甲基甲 醯胺、二甲基亞颯及四氫呋喃等為溶媒，反應時間為1 0分 鐘至30小時，以及反應溫度為。C至加熱回流溫度之條件下 進行。在該反應中亦可使用鹼，具體而言，例如碳酸鉀及 碳酸锶等。 用於反應之鹵代烷基衍生物（Rsa7LU),具體而言，例如 為（1)式R S-(CH2)s-C1所表示之鹵代燒硫基衍生物（式 中，s為1-6之整數，其他記號具有與上述定義相同之意一: 義），（2)式Br-(CH2)S-Cl所表示之鹵代燒基衍生物（式中，$ 為1-6之整數）；（3)下式表示之環氧丙烷衍生物：Line (wherein each symbol has the same meaning as defined above). &lt;Step R-l&gt;, for the electrophile test of the compound (Bu 1) and the deuterated alkylated derivative (B 2), etc. -104- This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Inventive Note (99) The reaction is carried out to obtain the compound (r-3). The reaction can be carried out using dimethylformamide, dimethyl hydrazine, tetrahydrofuran or the like as a solvent for a reaction time of 10 minutes to 30 hours, and a reaction temperature of . C is carried out under the conditions of heating to reflux temperature. A base may also be used in the reaction, and specifically, for example, potassium carbonate and cesium carbonate. The halogenated alkyl derivative (Rsa7LU) used for the reaction, specifically, for example, a halogenated sulfur-based derivative represented by the formula (1) R S-(CH 2 ) s-C1 (wherein s is 1-6 An integer, the other symbol has the same meaning as defined above: (2) a halogenated alkyl derivative represented by the formula Br-(CH2)S-Cl (wherein, $ is an integer of 1-6) (3) A propylene oxide derivative represented by the following formula:

(式中，U意指脫離基）；（4)下式表示之化合物：(wherein U means a leaving group); (4) a compound represented by the following formula:

(式中，U意指脫離基，RW2為第三丁氧羰基及字基等胺基 之保護基，以及s為1-6之整數）；或（5)被〇16燒氧基取代之 鹵代燒基衍生物。 -105- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 1304061 五、發明説明（(wherein U means a leaving group, RW2 is a protecting group for an amine group such as a third butoxycarbonyl group and a radical, and s is an integer of 1-6); or (5) a halogen substituted by an alkoxy group of fluorene 16 A substituted alkyl derivative. -105- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). 1304061 V. Description of invention (

A7 B7A7 B7

(式中’ Rsa73為氫原子或2、（三甲碎炫基）乙氧甲基，其他各 記號具有與上述定義相同之意義）。 &lt;步驟R-2&gt; 為作用於酚衍生物（P4),而導入取代基Rsa71之步騾。藉 由與（步騾R-1)同樣之操作，可以導入取代基RSaU。(wherein 'Rsa73 is a hydrogen atom or 2, (trimethylpyranyl) ethoxymethyl group, and the other symbols have the same meanings as defined above). &lt;Step R-2&gt; The step of introducing the substituent Rsa71 to act on the phenol derivative (P4). The substituent RSaU can be introduced by the same operation as (Step R-1).

(㈣ 人 ¢--7) (r-3) \ (式中，各記號具有與上述定義相同之意義 &lt;步驟R-3&gt; 為使羥基轉變為三氟甲磺酸酯之步驟。藉由化合物（r_ 6) 與三氟甲續酸對硝基苯§旨等三氟甲磺酸化試藥反應，可以 得到目的之化合物（r-7) ^反應溶媒，可以使用二曱基甲醯 胺等，反應溫度為or至加熱回流溫度，以及反應時間為10 分鐘至30小時。可以使用碳酸鉀等做為驗：。 〈步驟R-4&gt; -106- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） A7 B7((4) Human ¢--7) (r-3) \ (wherein each symbol has the same meaning as defined above. &lt;Step R-3&gt; The step of converting a hydroxy group into a triflate. The compound (r_6) is reacted with a trifluoromethanesulfonic acid p-nitrobenzene reagent to obtain a desired compound (r-7)^reaction solvent, and dimercaptocaramine can be used. The reaction temperature is from or to the reflux temperature, and the reaction time is from 10 minutes to 30 hours. Potassium carbonate or the like can be used as the test: <Step R-4> -106- The paper scale applies to the Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) A7 B7

1304061 五、發明説明（101 本步驟為使三氟甲磺酸酯基轉變為氰基之變換反應。藉 由化合物（r-7)與氰化鋅（Zn(CN)2)等氰化試藥反應，而得 到目的之化合物（r- 8)。可以使用肆（三苯膦）鈀等做為觸 媒。反應溶媒，可以使用二甲基甲醯胺等，反應溫度為室 溫至加熱回流溫度，以及反應時間為10分鐘至3〇小時。1304061 V. INSTRUCTIONS (101) This step is a shift reaction for converting a triflate group to a cyano group. The cyanide reagent such as the compound (r-7) and zinc cyanide (Zn(CN)2) is used. The reaction is carried out to obtain the intended compound (r-8). A ruthenium (triphenylphosphine) palladium or the like can be used as a catalyst. The reaction solvent can be dimethylformamide or the like, and the reaction temperature is from room temperature to heating under reflux temperature. , and the reaction time is 10 minutes to 3 hours.

(式中，各笔號具有與上述定義相同之意義）。 〈步驟R-5&gt; . % 為取代基Rsa71中有硫醚基之化合物（Γ〇)與弘氯過安息香 酸等氧化劑反應而得到化合物（2卜2)之步騾。反應溶媒， 可以使用二氯甲烷及氯仿等，反應時間為丨〇分鐘至Μ小 時，以及反應溫度為〇°C至室溫。 &lt;步騾R-6&gt; 為取代基Rsa71中有氯原子、溴原子、碘原子等鹵素原子 或甲磺醯氧基等脫離基，或者乙氧基等之化合物（γ·3)與親 核劑反應而得到化合物（2r-l)或化合物（2γ·4)之步驟。關於(wherein each pen number has the same meaning as defined above). <Step R-5> . % is a step in which a compound having a thioether group (Γ〇) in the substituent Rsa71 is reacted with an oxidizing agent such as chlorinated benzoic acid to obtain a compound (2, 2). As the reaction solvent, dichloromethane, chloroform or the like can be used, and the reaction time is from 丨〇 minute to Μ hour, and the reaction temperature is from 〇 ° C to room temperature. &lt;Step R-6&gt; The substituent Rsa71 has a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a leaving group such as a methylsulfonyloxy group, or a compound (γ·3) such as an ethoxy group and a nucleophilic group. The step of obtaining a compound (2r-1) or a compound (2γ·4) by a reaction. on

裝 訂Binding

線 __- 107 - 本紙張尺度適用中國ϋ家標準(CNS) Μ規格(210 X 297公爱) ~------------ 1304061 A7 '-* B7 五、發明説明（102) 親核劑，具體而言，例如為三咬或咪唑等含氮芳香族環衍 生物、嗎福啉及吡咯啶等胺衍生物、醇衍生物、酚衍生物 及硫醇衍生物等親核劑’。 關於反應溶媒，可以使用二甲基甲醯胺及四氫呋喃等， 反應時間為10分鐘至30小時’反應溫度為ot至加熱回流溫 度，以及可以使用破酸4甲及氫化鈉等做為鹼。 〈步騾R-7&gt;Line __- 107 - This paper size applies to China National Standard (CNS) Μ Specifications (210 X 297 public) ~------------ 1304061 A7 '-* B7 V. Description of invention ( 102) a nucleophile, specifically, a nitrogen-containing aromatic ring derivative such as a trident or imidazole, an amine derivative such as morphine or pyrrolidine, an alcohol derivative, a phenol derivative, or a thiol derivative. Nuclear agent'. As the reaction solvent, dimethylformamide, tetrahydrofuran or the like can be used, and the reaction time is from 10 minutes to 30 hours, the reaction temperature is from ot to the reflux temperature, and the acid-depleted tetramethyl and sodium hydride can be used as the base. <Step R-7>

(式中，Ra=sa82為第三丁氧羰基及芊基等胺基保護基，以及 其他各記號多有與上述定義相同之意義）。 對於有被保護基保護之胺基之化合物U-90)或化合物（卜 91)，可以進行胺基之脫保護反應，接著將被脫保護之胺基 烷基化。 (1)胺基之脫保護反應之步騾；關於脫保護之試藥，可以 使用三氟乙酸及鹽酸等。又保護基為芊基之情況，亦可以 使用藉由通常之接觸還原反應（氫氧化鈀-氫氣等）而脫保護 之反應。關於溶媒，可以使用三氟乙酸、甲醇及乙醇等。 反應時間為10分鐘至30小時，以及反應溫度為〇eC至加熱回 流溫度。 -108- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（103) (2)將脫保護之胺基烷化之步驟；藉由脫保護之胺基衍生 物與醛衍生物或酮衍生物反應，形成亞胺後，用氰基氫硼 化鋼等還原劑還原而得到化合物（2Γ_ 3)。關於反應溶媒， 可以使用甲醇及四氫呋喃等，反應時間為1〇分鐘至3〇小 時’以及反應溫度為0 °C至加熱回流溫度。 [製造方法15] 下式表示之化合物：(In the formula, Ra = sa82 is an amine group protecting group such as a third butoxycarbonyl group and a fluorenyl group, and the other symbols have the same meanings as defined above). For the compound U-90) or the compound (Bu 91) having an amine group protected by a protecting group, an amine group deprotection reaction can be carried out, followed by alkylation of the deprotected amine group. (1) The step of deprotection reaction of an amine group; for the reagent for deprotection, trifluoroacetic acid, hydrochloric acid or the like can be used. Further, in the case where the protecting group is a mercapto group, a reaction which is deprotected by a usual contact reduction reaction (palladium hydroxide-hydrogen or the like) can also be used. As the solvent, trifluoroacetic acid, methanol, ethanol or the like can be used. The reaction time is from 10 minutes to 30 hours, and the reaction temperature is from 〇eC to the heating reflux temperature. -108- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (103) (2) Step of alkylation of deprotected amine; by deprotection The amine derivative is reacted with an aldehyde derivative or a ketone derivative to form an imine, and then reduced with a reducing agent such as cyanoborohydride steel to obtain a compound (2Γ_3). As the reaction solvent, methanol, tetrahydrofuran or the like can be used, and the reaction time is from 1 to 3 hours and the reaction temperature is from 0 °C to the reflux temperature. [Production Method 15] A compound represented by the following formula:

(式中’各記號具有與上述定義相同之意義）之另一途徑合 成方法：Another way to synthesize (where the 'marks have the same meaning as defined above) is:

(各式中之記號具有與上述定義相同之意義 &lt;步驟P-l&gt; 化合物（P-丨），於氫化鈉等鹼存在下，可與醇衍生物（p-2) 反應’而得到化合物（p-3)。可以在1-甲:基吡咯啶酮或N，N-一甲基甲醒胺等溶媒中進行反應而合成。反應時間為10分(The symbols in the formulas have the same meanings as defined above. &lt;Step P-l&gt; The compound (P-oxime) can be reacted with the alcohol derivative (p-2) in the presence of a base such as sodium hydride to obtain a compound. (p-3), which can be synthesized by reacting in a solvent such as 1-methyl:pyrrolidone or N,N-methylmethamine, and the reaction time is 10 minutes.

1304061 A7 B7 五、發明説明（1〇4 ) 鐘至30小時，以及反應溫度為0°C至加熱回流溫度。 [製造方法1.6] 下式表示之化合物：1304061 A7 B7 V. Description of the invention (1〇4) Clock to 30 hours, and the reaction temperature is 0 ° C to the heating reflux temperature. [Production Method 1.6] A compound represented by the following formula:

Μ (式中，各記號具有與上述定義相同之意義）之另一途徑合 成方法： (Ρ-5) oY' (ρ-6) ατ Z-NHa -* (p-4) 、[步驟予一 2] (各式中之記號具有與上述定義相同之意義）。 為可以得到胺基甲酸酯衍生物之反應《藉由胺基衍生物 與氯甲酸苯酯反應而得到。反應溶媒，可以使用四氫呋喃 及二甲基甲醯胺等。反應溫度為〇°C至加熱回流溫度，以及 反應時間為30分鐘至30小時。 在上述反應中，可對胺基、羥基及羧基等反應性官能基 進行保護。 ： 關於胺基之保護基，通常只要為有機合成上已知可做為 -110- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 105 五、發明説明（ 胺基保護基疋基，任何基皆可，無特殊限制，具體而言例 如為甲酿基、乙醯基、氯乙醯基、二氯乙醯基、丙醯基、 冬乙醞基、苯氧乙醯基及噻吩乙醯基等經取代或未經取代 足低碳烷醯基；苄氧羰基、第三丁氧羰基及對·硝基苄氧羰 基等經取代或未經取代之低碳烷氧羰基；甲基、第三丁 基、2,2,2-三氯乙基、三苯甲基、對-曱氧芊基、對_硝基芊 基、二苯曱基及特戊醯氧甲基等經取代低碳烷基；三曱矽 烷基及第三丁基二甲矽烷基等經取代矽烷基；三甲矽烷曱 氧甲基、三甲矽烷乙氧曱基、第三丁基二甲矽烷甲氧曱基 及第二丁基二甲矽烷乙氧甲基等經取代矽烷基烷氧烷基； 亞苄基、亞水楊基、對-硝基亞苄基、間_氯亞芊基、3 5-二 (第三丁基）-4-經基亞亨基及3,5_二（第三丁基）亞；基等經 取代或未經取代之亞苄基等。 此等保護基之脫離，視所用保護基之種類，可藉由加水 分解及還原/等常用之方法進行。 關於經基之保護基，通常只要為有機合成上已知可做為 超基保護基之基’任何基皆可，無特殊限制，具體而言例 如為三甲矽烷基、第三丁基二甲矽烷基等低碳烷基矽烷 基；甲氧甲基、2-甲氧基乙氧曱基等低碳燒氧甲基；四氮 口比喃基；爷基、對-甲氧辛基、2，二甲氧宇基、鄰_硝基爷 基、對-硝基；基及三苯曱基等芳烷基；甲醯基及乙醯基等 酿基；第三丁氧談基、2-琪乙氧m基及2,2,2_三氯乙氧羰基 等低礙燒氧羰基；2.丙缔氧叛基、2•氣，2丙缔氧羧基、 甲氧羰基-2-丙埽氧羰基、2·甲基丙缔氧羰基、2•丁烯 -111 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公爱） 1304061另一 (wherein each symbol has the same meaning as defined above), another method of synthesis: (Ρ-5) oY' (ρ-6) ατ Z-NHa -* (p-4), [step to one 2] (The symbols in the formulas have the same meaning as defined above). The reaction for obtaining a urethane derivative is obtained by reacting an amine derivative with phenyl chloroformate. As the reaction solvent, tetrahydrofuran, dimethylformamide or the like can be used. The reaction temperature is from 〇 ° C to the reflux temperature, and the reaction time is from 30 minutes to 30 hours. In the above reaction, a reactive functional group such as an amine group, a hydroxyl group or a carboxyl group can be protected. : Regarding the protective group of the amine group, it is usually known as -110 on the organic synthesis. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 105 V. Description of the invention (Amino-protecting fluorenyl group, any group is optional, and is not particularly limited, and specifically, for example, a mercapto group, an ethyl fluorenyl group, a chloroethylene group, a dichloroethyl group, a propyl fluorenyl group, an ethylene thiol group, Substituted or unsubstituted phenylene fluorenyl groups such as phenoxyethyl thiol and thiophene ethenyl; substituted or unsubstituted benzyloxycarbonyl, tert-butoxycarbonyl and p-nitrobenzyloxycarbonyl groups Carboalkoxycarbonyl; methyl, tert-butyl, 2,2,2-trichloroethyl, trityl, p-nonyloxy, p-nitroguanidino, diphenylfluorenyl and tet a substituted lower alkyl group such as a fluorenylmethyl group; a substituted decyl group such as a tridecyl group and a tert-butyldimethyl dimethyl group; a trimethyl decane oxymethyl group, a trimethyl decane ethoxy group, a third butyl group a substituted decyl alkoxyalkyl group such as a decyl methoxy fluorenyl group and a second butyl dimethyl decane ethoxymethyl group; a benzylidene group, a salicylidene group, a p-nitrobenzylidene group a substituted or unsubstituted benzidine, such as a 3-chlorobutylidene group, a 3 5-di(t-butyl)-4-transylidene group, and a 3,5-di(t-butyl) subunit; The cleavage of these protecting groups, depending on the type of protecting group used, can be carried out by a common method such as hydrolysis, reduction, etc. The protecting group of the thiol group is usually known as an organic synthesis. The base of the protecting group may be any group, and is not particularly limited, and specifically, for example, a lower alkylalkyl group such as a trimethyldecyl group or a tert-butyldimethylalkyl group; a methoxymethyl group and a 2-methoxy group; a low-carbon aerobic methyl group such as an ethoxylated hydrazine group; a tetrazirthyl-pyryl group; a aryl group, a p-methoxyoctyl group, a 2, a dimethoxy group, an o-nitro group, a p-nitro group; And an aralkyl group such as a triphenyl fluorenyl group; a mercapto group such as a fluorenyl group and an acetamyl group; a third butyl oxy group, a 2- ethoxy ethoxy group, and a 2, 2, 2 - trichloroethoxycarbonyl group Oxygenated carbonyl; 2. propionyloxy, 2, gas, 2 propylene carboxy, methoxycarbonyl-2-propanyloxycarbonyl, 2 methacryloxycarbonyl, 2 • butene-111 paper The scale applies to the Chinese National Standard (CNS) A4 specification (210X297) Public love) 1304061

… AT B7 五、發明説明（106) 氧羰基及桂皮氧羰基等烯氧羰基；芊氧羰基、對-甲氧基爷 氧羰基、鄰-硝基芊氧羰基及對-硝基爷氧羰基等芳燒氧幾 基等。 此等保護基之脫離，視所用保護基之種類，可按照習用 方法進行加水分解及還原等。 關於羧基之保護基，通常只要為有機合成上已知可做為 羧基之保護基之基，任何基皆可，無特殊限制，具體而言 例如為甲基、乙基、異丙基及第三丁基等碳數為1〜4之直鍵 狀或分枝狀低碳烷基，例如2-碘乙基、2,2,2-三氯乙基等函 代低碳·虎基；甲氧甲基、乙氧曱基及異丁氧曱基等低竣燒 氧曱基；丁醯氧甲基及特戊醯氧甲基等低碳脂肪族醯氧甲 基；1-甲氧羰氧乙基及1-乙氧基羰氧乙基等丨·低後燒氧幾 氧乙基；苄基、對-甲氧芊基、鄰-硝基苄基及對-硝基字基 等芳烷基；二苯甲基及酞基等。 此等保H基之脫離，視所用保護基之種類，可按照習用 方法進行加水分解及還原等。 ·、 又，關於叛基之酯，若為有機合成上通常使用者將無特 殊限定，而且包含生理學上容許且在生理條件下可被加水 分解之酯基，具體而言，例如為碳數為丨至6之烷基；碳數 為6至12之芳基；芊基等碳數為7至20之芳烷基；碳數為7至 20之雜芳烷基；4-甲氧苄基；烷醯氧烷基例如乙醯氧甲 基、丙醯氧甲基或特戊醯氧甲基；烷氧羰氧烷基例如甲氧 羰氧曱基、乙氧羰氧甲基或2-甲氧羰氧乙基；以及（5_曱 基-2-酮基-1,3-二酮-4-基）-甲基等。 -112- 本紙張尺度適用中國國家標準(CNS) A4規格(21〇 X 297公釐) 1304061 A7 B7AT B7 V. DESCRIPTION OF THE INVENTION (106) Oxycarbonyl groups such as oxycarbonyl and cinnamyloxycarbonyl; anthraceneoxycarbonyl, p-methoxymethoxycarbonyl, o-nitrooxycarbonyl, p-nitrooxycarbonyl, etc. Aromatic oxygen group and the like. The detachment of these protecting groups can be carried out by hydrolysis and reduction according to the conventional methods depending on the type of protecting group used. The protecting group for a carboxyl group is usually a group which is known to be a protecting group of a carboxyl group in organic synthesis, and any group may be used without particular limitation, and specifically, for example, a methyl group, an ethyl group, an isopropyl group and a third group. a butyl group or the like having a direct bond or a branched lower alkyl group having a carbon number of 1 to 4, such as a 2-iodoethyl group, a 2,2,2-trichloroethyl group, or the like, a low carbon group; a methoxy group; Low-carbon oxyalkylene groups such as methyl, ethoxylated and isobutoxycarbonyl; low-carbon aliphatic oxiranyl methyl such as butyl oxymethyl and p-pentyloxymethyl; 1-methoxycarbonyloxy And 1-ethoxycarbonyloxyethyl isomers such as oxime, low post-pyroxy oxyethyl; benzyl, p-methoxyindenyl, o-nitrobenzyl and p-nitrophenyl Diphenylmethyl and fluorenyl. The detachment of these H-protecting bases can be carried out by hydrolysis and reduction according to the conventional methods depending on the type of the protecting group used. In addition, as for the ester of ruthenium, if it is organic synthesis, the user usually has no particular limitation, and includes an ester group which is physiologically acceptable and can be hydrolyzed under physiological conditions, specifically, for example, a carbon number. An alkyl group having a carbon number of 6 to 12; an aryl group having 6 to 12 carbon atoms; an aralkyl group having 7 to 20 carbon atoms such as a mercapto group; a heteroarylalkyl group having 7 to 20 carbon atoms; 4-methoxybenzyl group An alkoxyalkyl group such as acetoxymethyl, propyloxymethyl or pentyloxymethyl; an alkoxycarbonyloxyalkyl group such as methoxycarbonyloxycarbonyl, ethoxycarbonyloxymethyl or 2-methyl Oxycarbonyloxyethyl; and (5-mercapto-2-keto-1,3-dione-4-yl)-methyl and the like. -112- This paper size applies to Chinese National Standard (CNS) A4 specification (21〇 X 297 mm) 1304061 A7 B7

107 本發明所使用之溶媒，通常只要不會抑制反應且為有機 合成上使用者’任何溶媒皆可，無特殊限定，具體而言， 例如為甲醇、乙醇、丙醇及丁醇等低碳醇類；乙二醇及甘 油等多元醇類；丙酮、甲基乙基酮、二乙基酮及環己酮等 嗣類，乙趟、異丙謎、四氫吱喃、二p号燒、2·甲氧基乙 醇、1,2-二甲氧基乙烷等醚類；乙腈及丙腈等腈類；乙酸 曱酯、乙酸乙酯、乙酸異丙酯、乙酸丁酯及酸二乙酯等 酯類；二氯曱烷、氯仿、四氯化碳、丨，2_二氯乙烷、三氯 乙缔及四風1乙缔等齒代烴類；苯、曱苯、二甲苯、單氯 苯、硝基苯、茚、吡啶、喹啉、三曱基吡啶及酚等芳香族 類；戊烷、環己烷、己烷、庚烷、辛烷、異辛烷、輕質汽 油及石油瞇等烴類；乙醇胺、二乙胺、三乙胺、吡咯啶、 六氫吡啶、六氫吡畊、嗎福啉、苯胺、二甲基苯胺、苄胺 及甲苯胺等胺類；甲酿胺、N-甲基p比洛淀嗣、n，N-二曱基 咪峻酮、二甲基乙醯胺及N，N-二曱基甲醯胺等醯胺 類；六甲基磷酸三醯胺及六甲基亞磷酸三醯胺等磷酸醯胺 類；水以及其他通常使用之溶媒等中之一種或二種以上之 混合溶媒（混合比無特殊限定）。 關於鹼，通常只要為有機合成上已知可做為鹼者，任一 種皆可，無特殊限制，具體而言例如為碳酸鈉、碳酸氫 鈉、竣酸鉀、氫化鈉、氫化神、第三丁氧化奸、吡啶、二 甲胺吡啶、三甲胺、三乙胺、N，N-二異丙基乙胺、N-甲基 嗎福啉、N-甲基吡咯啶、N-甲基六氫吡啶、n，N-二甲基苯 胺、1，8-二氮雜雙環[5,4,0]十一烷-7-烯（DBU)、吡啶、4- -113- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061The solvent used in the present invention is generally not limited as long as it does not inhibit the reaction and is any solvent for the organic synthesis. Specifically, it is, for example, a lower alcohol such as methanol, ethanol, propanol or butanol. Classes; polyols such as ethylene glycol and glycerin; anthraquinones such as acetone, methyl ethyl ketone, diethyl ketone and cyclohexanone; acetamidine, isopropyl mystery, tetrahydrofuran, two p-burning, 2 · Ethers such as methoxyethanol and 1,2-dimethoxyethane; nitriles such as acetonitrile and propionitrile; decyl acetate, ethyl acetate, isopropyl acetate, butyl acetate and diethyl acetate Esters; dichloromethane, chloroform, carbon tetrachloride, hydrazine, 2_dichloroethane, trichloroethylene and tetracycline, acetylene, etc.; benzene, toluene, xylene, monochloro Aromatic such as benzene, nitrobenzene, hydrazine, pyridine, quinoline, tridecylpyridine and phenol; pentane, cyclohexane, hexane, heptane, octane, isooctane, light gasoline and petroleum hydrazine Hydrocarbons; amines such as ethanolamine, diethylamine, triethylamine, pyrrolidine, hexahydropyridine, hexahydropyrrol, morphine, aniline, dimethylaniline, benzylamine and toluidine Classes; amides such as amide, N-methyl p, lysine, n, N-dimercapto ketone, dimethyl acetamide, and N,N-dimercaptocaramine; A guanidinium phosphate such as trimethylamine phosphate or trimethylamine hexamethylphosphite; a mixed solvent of water or another commonly used solvent; or a mixture of two or more of them (the mixing ratio is not particularly limited). Regarding the base, it is generally known that it can be used as an alkali in organic synthesis, and any one may be used without particular limitation, and specifically, for example, sodium carbonate, sodium hydrogencarbonate, potassium citrate, sodium hydride, hydrogenated god, third Oxidation, pyridine, dimethylamine, trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylhexahydro Pyridine, n,N-dimethylaniline, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), pyridine, 4-113- National Standard (CNS) A4 Specification (210 X 297 mm) 1304061

二甲胺心、甲基峨咬、二甲基峨 氧化鈉、氫氧化鉀、氫氧化钿 . ^ L虱化鋰、丁基鋰、f醇鈉、甲醇鉀 及乙醇鈉等鈉或鉀之烷醇化物等。 關於自n右為通常酸自化物合成所使用之齒化劑， :可使一用任者，具體而言例如為光氣、二聚光氣（光氣二 水把）一_永光乳（光乳二聚體）、亞硫醯氯、亞硫醯溴、三氯 化磷、三溴化磷、氧氯化磷、五氯化磷、氯甲酸(三氯甲） I草醯氯、或者使此等_化劑作料㈣胺或倾酿胺 而得之比爾斯梅爾試藥等。 '於還原劑，若為通常有機合成使用者，即可，無特殊Dimethylamine, methyl niobium, dimethyl bismuth oxide, potassium hydroxide, cesium hydroxide. ^ L-deuterated lithium, butyl lithium, sodium f-folate, potassium methoxide and sodium ethoxide or other sodium or potassium alkane Alcohol compounds and the like. Regarding since n is the toothing agent used for the synthesis of the usual acid self-chemical compound, it can be used by any one, specifically, for example, phosgene, dimeric phosgene (phosgene and water), and yongguang (light) Milk dimer), sulfoxide, sulfoxide, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, chloroformic acid (trichloromethane) I grass, chlorine, or These chemistries are used to make a tetramine amine or a sorbent amine to obtain a Billsmer test. 'In the reducing agent, if it is a common organic synthesis user, it can be, no special

限疋，例如為 NaBH4、LiBH4、Zn(BH4)2、Me4NBHLimits, for example, NaBH4, LiBH4, Zn(BH4)2, Me4NBH

(〇Ac)3、NaBH3CN、Selectride、Super Hydride (LiB HEt3) &gt; LiA1H4 &gt; DIBAL ^ LiAIH (t.BuO)3 &gt; Red.al , binap f(外，尚有始、H釘及鎳等接觸氫化觸媒。 以上反應茗了後，如期望，可依照通常之處理方法，藉 由使用碎I膠或吸著樹脂之管柱層…去或從適當溶媒再a 晶而精製。 1 在本說明書中「藥理學上容許之鹽」未限於特定之種 類，例如可為鹽酸鹽、硫酸鹽、碳酸鹽、重碳酸鹽'氫溴 酸鹽及氫碘酸鹽等無機酸加合鹽；乙酸鹽、順丁烯二酸 鹽、乳酸鹽、酒石酸鹽及三氟乙酸鹽等有機羧酸加合;' 甲續酸鹽、羥曱磺酸鹽、羥乙磺酸鹽、苯磺酸鹽、甲苯確 紅鹽及牛績酸鹽等有機續酸加合鹽；三甲胺睡、二乙胺 鹽、吡啶鹽、普魯卡因鹽、甲基吡啶鹽、二s 114- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）(〇Ac)3, NaBH3CN, Selectride, Super Hydride (LiB HEt3) &gt; LiA1H4 &gt; DIBAL ^ LiAIH (t.BuO)3 &gt; Red.al , binap f (outside, there are still beginning, H nail and nickel, etc. Contact with Hydrogenation Catalyst After the above reaction has been carried out, if desired, it can be purified by using a crushed I gel or a column of sorbent resin, or by recrystallizing from a suitable solvent, according to the usual treatment method. The "pharmacologically acceptable salt" in the specification is not limited to a specific one, and may be, for example, a mineral acid addition salt such as a hydrochloride, a sulfate, a carbonate, a bicarbonate 'hydrobromide and a hydroiodide; Addition of organic carboxylic acids such as salt, maleate, lactate, tartrate and trifluoroacetate; 'carboate, oxonium sulfonate, isethionate, besylate, toluene Organic red acid addition salts such as red salt and bovine acid salt; trimethylamine sleep, diethylamine salt, pyridinium salt, procaine salt, methylpyridine salt, two s 114- paper scale applicable to Chinese national standards (CNS) A4 size (210 X 297 mm)

1304061 A7 B7 五、發明説明（109) N，N-二芊基伸乙二胺鹽、N-甲基葡萄糖胺鹽、二乙醇胺 鹽、三乙醇胺鹽、參（羥甲胺基）甲烷鹽及苯乙基芊胺鹽等 胺之加合鹽；精胺酸鹽、離胺酸鹽、絲胺酸鹽、甘胺酸 鹽、天冬胺酸鹽及榖胺酸鹽等胺基酸加合鹽。1304061 A7 B7 V. INSTRUCTIONS (109) N,N-Dimercaptoethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, ginseng (hydroxymethylamino)methane salt and phenylethyl An addition salt of an amine such as a guanamine salt; an amino acid addition salt such as a arginine, an amidate, a serine, a glycinate, an aspartate or a guanamine.

依照本發明，醫藥之投與量視症狀之程度、年齡、性 別、體重、投與形態及疾病之種類而異，通常成人每日投 與100微克至10公克，分1至數次投與。 依照本發明，醫藥之投與形態無特殊限定，可以藉由通 常使用之方法經口或非經口投與。 裝 可以使用製備製劑時通常使用之賦形劑、枯合劑、潤滑 劑、著色劑及矯味矯臭劑等，以及需要時可使用之安定 劑、乳化劑、吸收促進劑及界面活性劑等，以及添加一般 做為醫葯品製劑之原料之成分，按照習用方法來製備製 劑。 訂 線 關於此等減分，例如可以使用動植物油（大豆油、牛脂、 合成甘油酯等），烴（流動石堪、角鯊燒及·、固形石壤等），酯 油（肉苴蔻酸十八烷酯及肉莖蔻酸異丙酯等），高級醇類（黥 壌硬I曰醇及一十二统醇等），碎酮樹脂，碎酮油，界面活性 劑（脂肪酸聚氧伸乙酯、山梨醇酐之脂肪酸酯、脂肪酸甘油 酯、聚氧伸乙基山梨醇酐之脂肪酸酯、聚氧伸乙基硬化蓖 麻子油、聚環氧乙烷及聚環氧丙烷之嵌段共聚物等），水2 性高分子（羥乙基纖維素、聚丙烯酸、羧乙烯聚合物、聚2 一 、永乙缔p比洛症_及甲基纖維素争），酵類（乙醇及異 丙醇等），多元醇（甘油、丙二醇、聚二丙二醇及山梨醇 -115- 1304061 〜 〜- A7 B7 五、發明説明（110 ) 等），糖（葡萄糖及蔗糖等），無機粉體（無水矽酸、矽酸鋁 鎂及矽酸銲等），以及精製水等。可以使用供pH調製之無機 酸（鹽酸及磷酸等），無機酸之鹼金屬鹽等（磷酸鈉等），無 機鹼（氫氧化鈉等），有機酸（低碳脂肪酸、檸檬酸及乳酸 等），有機酸之鹼金屬鹽（檸檬酸鈉及乳酸鈉等），以及有機 鹼（精胺酸及乙醇胺等）。又，視需要可以添加防腐劑及抗 氧化劑等。 依照本發明之化合物，在試管中可以強力抑制：1)由血 管新生因子混合液誘導之血管内皮細胞之浸潤性管腔形 成，2)由單獨的血管新生因子特異性誘導之血管内皮細胞 之管腔形成，以及3)各種血管新生因子之受器激酶。再 者，在具有此等作用之化合物群之中，亦可以發現抑制癌 細胞增殖之化合物。内皮細胞浸潤及管腔形成為血管新生 中之重要步驟，具有其之抑制作用之化合物具有血管新生 抑制作用。&amp;不過，已知在身體中血管新生非藉由單獨的血 管新生因子來進行，而是藉由複數個血管新生因子之相加 及相乘作用來進行（參見（l)Koolwijk P，van Erck MGM，de Vree WJA, Vermeer MA, Weich HA, Hane maaijer R, van Hinsbergh VWM. Cooperative effect of TNF-alpha, bFGF and VEGF on the formation of tubular structures of human microvascular endot helial cells in a fibrin matrix. Role of urokinase activity. J. Cell Biol. 1996, 132, P1 177- 1 1 88 ； (2) Tallquist MD, Soriano P, Klinghoffer *RA. Growth factor signaling pathways in vascular development，Oncogene 1999, -116- 本紙張尺度適用中國國家#準(CNS) A4規格(210 x 297公釐） 1304061 A7 _______B7 五、發明説明（川） 18，P7917-7932.)。因此，對於由癌細胞等產生之複數個血 管新生因子所誘導之管腔形成有抑制作用之本發明化合 物，被期待在身體中顯示強力的血管新生抑制作用，在做 為血管新生抑制劑上極為有用。 依照本發明之化合物之生化學活性及做為醫藥之作用效According to the present invention, the dosage of the medicine varies depending on the degree of the symptoms, the age, the sex, the body weight, the form of administration, and the type of the disease. Usually, the adult is administered 100 micrograms to 10 grams per day, and is administered in one to several doses. According to the present invention, the administration form of the medicine is not particularly limited, and can be administered orally or parenterally by a usual method. As the preparation, an excipient, a dry agent, a lubricant, a coloring agent, a flavoring agent, and the like which are usually used in the preparation of a preparation, and a stabilizer, an emulsifier, an absorption enhancer, a surfactant, etc. which can be used as needed, and addition can be used. Generally, as a component of a raw material of a pharmaceutical preparation, a preparation is prepared according to a conventional method. For such reductions, for example, animal and vegetable oils (soybean oil, tallow, synthetic glycerides, etc.), hydrocarbons (flowing stone, shale, and solid stone) can be used. Octadecyl ester and isopropyl humate, etc., higher alcohols (黥壌 hard I sterol and twelfth alcohol, etc.), ketone resin, ketone oil, surfactant (fatty acid polyoxygen extension) Ethyl ester, fatty acid ester of sorbitan, fatty acid glyceride, fatty acid ester of polyoxyethylene ethyl sorbitan, polyoxyethylene ethyl hardened castor oil, polyethylene oxide and polypropylene oxide Segment copolymer, etc.), water 2 polymer (hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, poly 2, yong tong p bilo disease _ and methyl cellulose), yeast (ethanol And isopropanol, etc., polyol (glycerol, propylene glycol, polydipropylene glycol and sorbitol-115-1304061 ~ ~- A7 B7 V, invention description (110), etc.), sugar (glucose and sucrose, etc.), inorganic powder (anhydrous niobic acid, aluminum magnesium niobate and tannic acid welding, etc.), as well as refined water. It is possible to use a mineral acid (hydrochloric acid or phosphoric acid) for pH adjustment, an alkali metal salt of an inorganic acid (sodium phosphate or the like), an inorganic base (sodium hydroxide or the like), an organic acid (low carbon fatty acid, citric acid, lactic acid, etc.). , organic acid alkali metal salts (sodium citrate and sodium lactate, etc.), and organic bases (arginine and ethanolamine, etc.). Further, a preservative, an antioxidant, or the like may be added as needed. The compound according to the present invention can be strongly inhibited in a test tube: 1) invasive luminal formation of vascular endothelial cells induced by an angiogenic factor mixture, 2) tube of vascular endothelial cells specifically induced by angiogenic factors alone Cavity formation, and 3) receptor kinases of various angiogenic factors. Further, among the compound groups having such effects, compounds which inhibit the proliferation of cancer cells can also be found. Endothelial cell infiltration and lumen formation are important steps in angiogenesis, and compounds with their inhibitory effects have angiogenesis inhibitory effects. &amp; However, it is known that angiogenesis in the body is not carried out by a single angiogenic factor, but by the addition and multiplication of a plurality of angiogenic factors (see (l) Koolwijk P, van Erck MGM, de Vree WJA, Vermeer MA, Weich HA, Hane maaijer R, van Hinsbergh VWM. Cooperative effect of TNF-alpha, bFGF and VEGF on the formation of tubular structures of human microvascular endot helial cells in a fibrin matrix. Role of urokinase J. Cell Biol. 1996, 132, P1 177- 1 1 88 ; (2) Tallquist MD, Soriano P, Klinghoffer *RA. Growth factor signaling pathways in vascular development, Oncogene 1999, -116- This paper scale applies to China National #准(CNS) A4 specification (210 x 297 mm) 1304061 A7 _______B7 V. Invention description (Chuan) 18, P7917-7932.). Therefore, the compound of the present invention which inhibits lumen formation induced by a plurality of angiogenic factors produced by cancer cells or the like is expected to exhibit potent angiogenesis inhibitory action in the body, and is extremely effective as an angiogenesis inhibitor. it works. The biochemical activity of the compound according to the invention and its effect as a medicine

果（血管新生抑制活性及抗腫瘤活性等），可以藉由下述方 法評價。 ㈢ U 又’下述為藥理試驗例中所使用之簡寫之一覽表· &lt;簡寫一覽表&gt; DNA (去氧核糖核酸）， VEGFR2 (血管内皮增殖因子受器2), human placenta (人類胎盤），The fruit (angiogenesis inhibitory activity, antitumor activity, etc.) can be evaluated by the following method. (3) U </ br> The following is a list of abbreviations used in pharmacological test cases. &lt;Abbreviation list&gt; DNA (deoxyribonucleic acid), VEGFR2 (vascular endothelial growth factor receptor 2), human placenta (human placenta),

Hepes (N-[2-羥乙基]六氫吡畊-Ν，-[2·乙磺酸]，海派 衝液）， 、/Hepes (N-[2-hydroxyethyl]hexahydropyrazine-Ν,-[2·ethanesulfonic acid], Haipai), /

MgCl2(氯化屬），MgCl2 (chlorinated genus),

MnCl2(氯化錳）， ·、MnCl2 (manganese chloride), ·,

Na3V04(原釩（V)酸鈉）， ATP(腺核甞5、三磷酸）， EDTA (乙二胺四乙酸）， HTRF(均一時間-解析螢光）， FGFR1 (纖維母細胞增殖因子受器丨）， PDGFR冷（來自血小板之增殖因子受器万）， HGFR (肝細胞增殖因子受器）， _· EGFR (上皮增殖因子受器）， -117-Na3V04 (original vanadium (V) sodium), ATP (adenosine 5, triphosphate), EDTA (ethylenediaminetetraacetic acid), HTRF (uniform time-analytical fluorescence), FGFR1 (fibrocyte proliferation factor receptor)丨), PDGFR cold (proliferation factor receptor from platelets), HGFR (hepatocyte proliferation factor receptor), _· EGFR (epithelial growth factor receptor), -117-

1304061 〜 A7 B7 五、發明説明（112)1304061 ~ A7 B7 V. Description of invention (112)

Tris (參（羥甲基）胺基甲烷，Tris緩衝液），Tris (paraxyl (hydroxymethyl) aminomethane, Tris buffer),

NaCl (氯化.#〇， BSA (牛血清白蛋白）， HRP (辣根過氧化酶）， EGTA (Ν,Ν,Ν’，Ν’-四乙酸）， SDS (十二基硫酸鈉）， NP-40 (Nonidet P-40)， PCR (聚合酶鏈反應）， RT-PCR:反錄聚合酶鏈反應， RNA :核糖核酸， cDNA :互補之DNA， cRNA :互補之RNA， dNTP ··由 dATP、dCTP、dGTP 及 dTTP組成之混合物， UTP :尿甞5、三磷酸， CTP :胸甞三磷酸， dATP : 2’-去氧腺站5、三磷酸， 、 dCTP : 2、去氧胸甞5、三磷酸， dGTP : 2’-去氧鳥甞5、三磷酸， dUTP : 2、去氧尿站5’-三磷酸， GAPDH :甘油醛3-磷酸去氫酶， FBS :牛胎兒血清， PBS :磷酸鹽緩衝食鹽水， 溴化 MTT : (3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四唑 物；邊吐藍）， -118- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜 A7 B7 五、發明説明（113) DMSO :二曱基亞颯， PDGF :衍生自血小板之增殖因子， EGF :上皮增殖因子， FGF2 ··纖維母細胞增殖因子2， VEGF :血管内皮增殖因子， HGF :肝細胞增殖因子， TNF- α :腫瘤壞死因子-α， FCS :牛胎兒血清， EGM-2:内皮細胞增殖培養基-2 藥理試驗例1 :對於因血管新生因子混合物刺激造成之血管 内皮細胞之浸潤性管腔形成之抑制作用。 將人類臍帶靜脈内皮細胞（HUVEC)按照被報告之方法（新 生化學實驗講座”細胞培養技術”，ρ. 197-202)單離，在含 5%(：〇2之培育器（37°C)中用EGM-2培養基（從Clonetics公司 購入）培養至細胞匯集。在Transwell(從Coaster公司購入）培 養平皿之内部穴中加入0.4 ml牛纖維蛋白原（從Sigma公司購 入），以及用0.7單位/毫升之凝血酶（從Sigma公司購入）固 定。將HUVEC用胰蛋白酶及EDTA回收後，懸浮於内皮細 胞培養用無血清培養基（簡稱為SFM，從GIBCO BRL公司購 入）中，然後將該細胞懸浮液0.4 ml( 1 ·4 X 1CP個）播種在被 固定之纖維蛋白凝膠上，並在含5%C〇2之培育器中（37°C) 培養約4小時。4小時後，在Trans well之外室中加入包含血 管新生因子之混合物{ 10 ng/ ml EGF (從GIBCO BRL公司購 入），30 ng/ ml FGF2 (從 GIBCO BRL 公司購入），75 ng/ ml -119- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 :― ，·- A7 _______ _B7 ______ 五、發明説明（114) VEGF(從和光純藥購入），5〇 ng/ ml HGF(從R &amp; D公司購 入）’ 7·5 ng/ ml TNF- α (從Genzyme公司購入）[各血管新生 因子之濃度隨著所用HUVEC之批次多少有些改變]}以及經 稀釋之被檢物質之1.5 ml SFM溶液並於含5% C02之培育器 中（37C)培養。添加被檢物質後，於第2日及第4日交換成 新調製之包含血管新生因子混合物及被檢物質之丨.5 ml SFM溶液。從被檢物質添加開始日算起第6日，吸引除去内 壁之培養上清液後，加入溶解於PBS之3.3 mg/ ml MTT(從 Sigma公司購入）溶液〇 4 並在含5%C02之培育器中（37°C ) 培養約1小時。藉由顯微鏡觀察被MTT染色之纖維蛋白凝膠 内形成之管腔之數目及計分。亦即藉由將在被檢物質不存 在下之管腔數目記為「+ + +」，全然未形成管腔時之數目 1己為 「-」，以及使被檢物質作用時之管腔之數目記為 「+ + +,++, + ,+/_,以及_」5段，來評價被檢物質之抑 制作用之強波。 [表1][藥理試驗例1 :對於因血管新生因子混合物刺激造成 ^血管内皮細胞之浸潤性管腔形成之t制作用] 實施例編號 0.01 # Μ o.l uu 1.0 “Μ _25 -Η- +/. 53 __ 55 +44- +/- +/- ___72 +++ 胃 - __ 74 ++ - - __ -120- 本纸&amp;尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 〜— A7 B7 五、發明説明（115) 75 +++ +/- • 81 _ 100 +/- +/- 153 +/- 麟 一 172 + +/· +/- 189 +/- • 212 +/_ 245 +/- 崔 鑛 298 +/- 垂 316 +/- - 348 +/- • 觸 368 獨 一 • 374 +/- 編 404 • 鑛 415〜 +/- 猶 422 + 着 藥理試驗例2 :對於因血管新生因子刺激造成之血管内皮細 胞之三明治式管腔形成之抑制作用。 將人類臍帶靜脈内皮細胞（HUVEC)，依照與藥理試驗例1 同樣之方法單離，在含5%(：〇2之培育器（37°C)中用EGM-2 培養基（從Clonetics公司購入）培養至細胞匯集。將膠原： 5x RPMI 1640 :再構成用緩衝液（以上梃新田明膠公司購入） 之7 ·· 2 : 1之冰冷混合液注入24穴平皿之各穴中，每穴0.4 -121 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（116NaCl (chlorinated.#〇, BSA (bovine serum albumin), HRP (horseradish peroxidase), EGTA (Ν,Ν,Ν',Ν'-tetraacetic acid), SDS (sodium dodecyl sulfate), NP-40 (Nonidet P-40), PCR (polymerase chain reaction), RT-PCR: reverse transcription polymerase chain reaction, RNA: ribonucleic acid, cDNA: complementary DNA, cRNA: complementary RNA, dNTP ·· a mixture of dATP, dCTP, dGTP and dTTP, UTP: urinary tract 5, triphosphate, CTP: thymine triphosphate, dATP: 2'-deoxygland station 5, triphosphate, dCTP: 2, deoxythorax 5, triphosphate, dGTP: 2'-deoxyguanine 5, triphosphate, dUTP: 2, deoxyuridine 5'-triphosphate, GAPDH: glyceraldehyde 3-phosphate dehydrogenase, FBS: bovine fetal serum, PBS: phosphate buffered saline, brominated MTT: (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazole; side blue), -118-ben Paper scale applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ~ A7 B7 V. Description of invention (113) DMSO: Dimercaptopurine, PDGF: Proliferative factor derived from platelets, EGF: Epithelial proliferation Factor, FGF2 ··fiber Maternal cell proliferation factor 2, VEGF: vascular endothelial growth factor, HGF: hepatocyte proliferation factor, TNF-α: tumor necrosis factor-α, FCS: bovine fetal serum, EGM-2: endothelial cell proliferation medium-2 pharmacological test example 1 : Inhibition of invasive luminal formation by vascular endothelial cells stimulated by a mixture of angiogenic factors. Human umbilical vein endothelial cells (HUVEC) according to the reported method (New Chemistry Experiment Lecture) Cell Culture Technology, ρ. 197-202) Isolation, cultured into cells with EGM-2 medium (purchased from Clonetics) in a 5% (: 2) incubator (37 ° C). Plates were grown in Transwell (purchased from Coaster). 0.4 ml of bovine fibrinogen (purchased from Sigma) was added to the inner cavity, and 0.7 unit/ml of thrombin (purchased from Sigma) was added. The HUVEC was recovered by trypsin and EDTA, and suspended in endothelial cells. Using serum-free medium (referred to as SFM, purchased from GIBCO BRL), then seeding the cell suspension 0.4 ml (1 · 4 X 1CP) in the immobilized fibrin Glue, and cultured in the incubator containing 5% of the C〇2 (37 ° C) for about 4 hours. After 4 hours, a mixture containing angiogenic factors was added to the chamber outside Trans well {10 ng/ml EGF (purchased from GIBCO BRL), 30 ng/ml FGF2 (purchased from GIBCO BRL), 75 ng/ml - 119- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 :― ,·· A7 _______ _B7 ______ V. Description of invention (114) VEGF (purchased from Wako Pure Chemical), 5〇ng / ml HGF (purchased from R &amp; D) '7.5 ng/ml TNF-α (purchased from Genzyme) [concentration of each angiogenic factor varies somewhat with the batch of HUVEC used]} and diluted The 1.5 ml SFM solution of the test substance was cultured in a 5% CO 2 incubator (37C). After the test substance was added, it was exchanged on the 2nd day and the 4th day into a newly prepared 血管.5 ml SFM solution containing the angiogenic factor mixture and the test substance. On the 6th day from the start of the addition of the test substance, the culture supernatant of the inner wall was removed, and then a solution of 3.3 mg/ml MTT (purchased from Sigma) dissolved in PBS was added and incubated in 5% CO 2 . Incubate in the apparatus (37 ° C) for about 1 hour. The number and scoring of the lumens formed in the MTT-stained fibrin gel were observed by a microscope. That is, by counting the number of lumens in the absence of the test substance as "+ + +", the number 1 of the lumens is completely "-", and the lumen of the test substance is applied. The number is recorded as "+ + +, ++, +, +/_, and _" in five paragraphs to evaluate the strong wave of the inhibitory effect of the substance to be tested. [Table 1] [Pharmacological test example 1: Preparation for invasive lumen formation of vascular endothelial cells by stimulation of an angiogenic factor mixture] Example No. 0.01 # Μ ol uu 1.0 "Μ _25 -Η- +/ 53 __ 55 +44- +/- +/- ___72 +++ Stomach - __ 74 ++ - - __ -120- This paper &amp; scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304061 ~— A7 B7 V. Description of invention (115) 75 +++ +/- • 81 _ 100 +/- +/- 153 +/- Linyi 172 + +/· +/- 189 +/- • 212 + /_ 245 +/- Cui Mine 298 +/- Dip 316 +/- - 348 +/- • Touch 368 Unique • 374 +/- 404 • Mine 415~ +/- 422 + Pharmacological Test Example 2: Inhibition of sandwich lumen formation by vascular endothelial cells stimulated by angiogenic factors. Human umbilical vein endothelial cells (HUVEC) were isolated in the same manner as in pharmacological test example 1, in 5% (: 〇 2 incubator (37 ° C) was cultured in EGM-2 medium (purchased from Clonetics) to collect cells. Collagen: 5x RPMI 1640: Reconstituted with buffer (above 梃Tian Mingjiao purchased 7 ·· 2 : 1 ice-cold mixture into each hole of 24-hole plate, 0.4 -121 per hole - This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (116

ml，然後在含5% C〇2之培育器中（37 °C)靜置40分鐘以及凝 膠化。將HUVEC用胰蛋白酶及EDTA回收後，在各穴中藉 由加入為血管新生因子之2〇 ng/ ml FGF2 (從GIBCO BRL公 司購入）及10 ng/ ml EGF (從GIBCO BRL公司購入），或者 25 ng/ ml VEGF (從和光純藥購入）及1〇 ng/ ml EGF，或者 30 ng/ ml HGF (從R&amp;D公司購入）及1〇 ng/ ml EGF之内皮 細胞培養用無血清培養基（SFM，從Gibco公司購入）來懸浮 HUVEC，每穴加入該細胞懸浮液〇·4 ml (細胞數雖然隨著使 用之HUVEC之批號而不同，但通常使用丨〜；^ x 1〇5個細 胞）。在含5%C〇2之培育器中（37°C )培養一夜。第二日，將 上層之培養基吸引除去後，每一疊層膠原：5 x RPMI 1 640 :再構成用缓衝液（以上從新田明膠公司購入）之7 : 2 : 1之冰冷混合液0.4 ml，在含5%C〇2之培育器中（37°C)靜 置4小時並凝膠化。在上層中，加入包含上述各血管新生因 子以及經稀/釋之被檢物質之SFM溶液1·5 m卜並在含5%C〇2 之培同器中（37C)培養。在被檢物質添加·後第4日，吸引除 去各穴之培養上清液後，在各穴中加入溶於pBS之3.3 mg/ ml Μ丁丁（從Sigma公司講入）溶液〇·4 ml，並於5%C02培育器 中（37°C )培養約2小時。在各穴之膠原凝膠内所形成之管腔 藉由MTT染色，在電腦中取得該管腔照片（Mackint〇sh公司 製）’藉由圖像解析軟體「Mac Scope」（從三谷商事講入） 求得管腔之全長。求出在添加被檢物質之穴内所形成之管 腔之全長相對於在未添加被檢物質之穴:内所形成之管腔之 全長之％，從該比之值求出各被檢物質抑制5 〇 %管腔形成 -122- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂The ml was then allowed to stand in a 5% C〇2 incubator (37 ° C) for 40 minutes and gelatinized. After recovering HUVEC with trypsin and EDTA, 2 ng/ml FGF2 (purchased from GIBCO BRL) and 10 ng/ml EGF (purchased from GIBCO BRL), which are angiogenic factors, were added to each well, or 25 ng/ml VEGF (purchased from Wako Pure Chemical) and 1 ng/ml EGF, or 30 ng/ml HGF (purchased from R&amp;D) and 1 ng/ml EGF for serum-free medium for endothelial cell culture ( SFM, purchased from Gibco) to suspend HUVEC, and add 4 ml of the cell suspension per well (the number of cells varies depending on the batch number of HUVEC used, but usually 丨~;^ x 1〇5 cells) . Incubate overnight in a 5% C〇2 incubator (37 ° C). On the second day, after the upper layer of the culture medium was removed and removed, each laminated collagen: 5 x RPMI 1 640: reconstituted with a buffer solution (purchased from Xintian Gelatin Co., Ltd.) of 7:2:1 ice-cold mixture 0.4 ml, It was allowed to stand in a 5% C〇2 incubator (37 ° C) for 4 hours and gelled. In the upper layer, a SFM solution containing the above-mentioned respective angiogenic factors and the diluted/released test substance was added and incubated in a 5% C〇2 incubator (37C). On the 4th day after the addition of the test substance, the culture supernatant of each well was removed, and then a solution of 3.3 mg/ml Μ丁丁 (speaking from Sigma) dissolved in pBS was added to each well. It was incubated for about 2 hours in a 5% CO 2 incubator (37 ° C). The lumen formed in the collagen gel of each cavity was stained by MTT, and the lumen photograph (manufactured by Mackint〇sh Co., Ltd.) was obtained in a computer by image analysis software "Mac Scope" (speaking from Sangu Business) ) Find the full length of the lumen. The total length of the lumen formed in the cavity where the test substance is added is determined as % of the total length of the lumen formed in the cavity where the test substance is not added, and the ratio of each test substance is determined from the ratio 5 〇% lumen formation-122- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding

線 1304061 〜 A7 B7 五、發明説明（117 ) 所需之濃度（1C50)。 [表2][藥理試驗例2 :對於因VEGF刺激造成之血管内皮細 胞之三明治式管腔形成之抑制作用]。 實施例編號 IC5〇(nM) 實施例編號 ICsoCnM) 1 310 12 44 19 28 23 100 53 9.9 55 35 59 170 65 5.9 70 58 72 22 74 5.9 75 1.4 81 1.8 100 6.3 108 4.9 116 8.1 121 42 127 7.5 129 40 137 10 153 0.02 155 1.4 157 0.9 159 . 0.6 186 23 189 0.3 198 1.5 202 15 204 0.9 211 0·3 215 22 224 26 249 1·6 253 40 256 36 265 0.6 266 0.6 283 36 289 4.6 296 : 34 298 0.7 299 1.0 -123- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 s— A7 B7 五、發明説明（118) 300 7.5 304 0.3 308 5.2 314 4.2 316 1.0 320 2.5 325 1.0 326 1.0 327 56 346 25 368 5.4 372 44 374 3.0 381 4.7 382 4.6 386 10 404 2.8 405 28 408 39 415 3.8 419 10 422 4.8 433 5.6 436 22 440 1.4 441 3.6 442 12 444 5.5 445 6.2 446 4.0 450 4.5 454 3.7 455 ^ 7.8 463 26 490 26 492 *、 7.2 493 9.0 494 9.3 497 4.6 503 6.4 ’04 4.6 505 8.9 518 1.3 520 1.5 521 0.5 578 13 藥理試驗例3 :對於受器型酪胺酸激酶专性之抑制能力之測 定 -124- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜 、 A? _ B7 五、發明説明（119) 該測定係決定被驗物質抑制酷胺酸激酶活性之能力。編 碼VEGFR2之細胞質領域之DNA藉由全基因合成（Edwards M，International Biotechnology Lab 5(3)，19-25，1987)或 選殖而得到。接下來，其藉由在適當的表現系中被表現， 而得到有酪胺酸激酶活性之多肽。例如，已發現藉由在昆 蟲細胞中重組蛋白質之表現而得到之VEGFR2之細胞質領域 顯示固有的酪胺酸激酶活性。在VEGFR2之場合（Genbank登 錄編號 L04947)，將 Terman 等人（〇11(：〇861^，6(9)，1677-1683，1991)記載之DNA片段（為編碼細胞質領域之1.7 kb DNA片段且從離胺酸791開始及包含終止密碼子）從人類胎 盤cDNA庫（從Clonetics購入）單離，然後選殖入棒狀病毒轉 移酶載體（pBlueBacHis (從GIBCO BRL公司購入）。將該重 組構築物轉染昆蟲細胞（Spondoptea frugiperda 9 (Sf9))， 以調製重組棒狀病毒（重組棒狀病毒之調製及使用，可參考 標準教科/晝 Bac-To-Bac Baculovirus Expression system (GIBCO BRL公司））。供測定使用之其他酪胺酸激酶，從離 胺酸398開始之細胞質片段（FGFR1，Genbank登錄編號 X52833)，從離胺酸558開始之細胞質片段（PDGFR /3 ， Genbank登錄編號M21616)，或從離胺酸974開始之細胞質 片段（HGFR，Genbank登錄編號J02958)，可藉由同樣之方 法選殖及表現。EGFR從Sigma公司（製品編號E-2645)購 入。 為了 VEGFR2之酪胺酸激酶表現，將Sf9細胞用VEGFR2重 組病毒感染，然後於48小時後收集。將收集到之細胞用冰 125· 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 、 s - A7 B7 五、發明説明（120 ) 冷之磷酸緩衝化生理食鹽水（PBS)洗淨，每1·5 X 10s個細胞 用20 ml冰冷的溶裂緩衝液（5〇 mM Tds-HCl (pH 8·5)，5 mM 2-硫醇基乙醇，100 mM Κα，1 mM苯基甲基磺醯基氟 化物），1%(ν/ν) NP-40)再懸浮。將懸浮液於4°C及12000 rpm離心3 0分鐘’得到上清液。 將該上清液添加至用緩衝液A [20 mM Tris-HCl (pH 8·5)，5 mM 2-硫醇基乙醇，500 mM KC1，20 mM咪唾， 10%(v/v)甘油]平衡化之Ni-NTA瓊脂糖管柱（3 ml，從 QIAGEN公司購入）中。將該管拄用30 ml緩衝液A，繼而6 ml 緩衝液 B [20 mM Tris-HCl (pH 8.5)，5 mM 2-硫醇基乙 醇，1M KC1，10%(v/v)甘油]，再用緩衝液A6 ml洗淨。 洗淨後，用 6 ml緩衝液 C [ 20 mM Tris-HCl (pH 8·5)，5 mM 2-硫醇基乙醇，100 mM KC1，100 mM咪唑，10%(ν/ν)甘 油]溶出。將該溶出液加至透析膜（從Spectrum Laboratories 公司購入）扭，用透析緩衝液[20 mM Tris-HCl (pH 7·5)， 10%(ν/ν)甘油，1 mM二硫蘇糖醇，0·1 miM Na3V04 及 0·1 mM EGTA]透析。透析後，進行SDS電泳，在科麥西艷藍 (Coomassie Brilliant Blue)染色中，以 BSA(牛血清白蛋 白，從Sigma公司購入）作為標準物質，將在分子量約1〇〇 kDa檢出之重組體蛋白質（His6-VEGFR2，其為在N終端融 合6個組胺酸之VEGFR2之細胞質領域）進行蛋白定量後，保 存於-80°C直至使用為止。對於FGFR1之細胞質領域， PDGFR冷之細胞質領域或HGFR之細胞賢領域採用同樣之方 法，分別得到在N終端融合有6個組胺酸之重組蛋白質 一 -126- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 、 A7 B7 五、發明説明（121 ) (His6-FGFR1，His6· PDGFRiS 或His6-HGFR) β 酪胺酸激酶反應如下述進行。例如在VEGFR2之場合，在 96穴圓底平皿（NUNC公司，製品編號163320)之各穴中，添 加激酶反應液{200 mM Hepes (pH 7.4)，80 mM MgCl2，16 mM M11CI2，2 mM Na3V04} 10 // 1，與生物素結合之聚 (Glu4 : Tyrl)[生物素-聚（GT)，從CIS Diagnostic公司購入] 以及溶於二甲基亞颯之被驗物質（用0.1% BSA溶液稀釋100 倍者4#1 )並調成30//1。接下來，添加4 ATP(用蒸餾 水稀釋）並於30°C培育10分鐘後，添加500 mM EDTA (pH 8.0)10#卜 使用時間-解析螢光法（HTRF法）測定（Analytical Biochemistry，269，94- 104，1999)。亦即，將上述激酶反應 溶液移至96穴黑色半皿（Coaster公司，製品編號3694)中， 添加用銪化合物標記之抗磷醯酪胺酸抗體（Eu(K)-PY20， 從 CIS Diag1i〇stic公司購入）7·5 ng (用含20 mM Hepes (pH 7·0)，0.5 M KF 及 0.1%BSA 之溶液稀釋 2i、0 倍者，25#1)， 以及用XL665標記之抗生蛋白鏈菌素（XL665-SA，從CIS Diagnostic 公司購入）250ng [用含 20 mM Hepes (ρΗ7·0)， 0.5 M KF及〇.i%BSA之溶液稀釋62.5倍者，25#1]，放置於 室溫30分鐘後，用Discovery-HTRF顯微平皿分析器（公司製） 測定以激發波長337 nm照射時，於665 nm及620 nm之螢光 強度。生物素-聚（GT)之酪胺酸磷酸化率，以記載於CIS Diagnostic公司之HTRF標準實驗法之5 F%值表示。將於被 驗物質不存在下添加His6-VEGFR2之（5 F%值當做100%， -127- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜 --- A7 B7 五、發明説明（122) 以及將被驗物質及His6-VEGFR2不存在下之5 F%值當做 0%，然後求出被驗物質存在下之5 F%值之比率。從該比 率（％)算出抑制50% VEGFR2激酶活性所需之被驗物質濃度 (IC50)。 對於FGFR1，EGFR或HGFR激酶活性之抑制能力之測 定，分別使用 His6-FGFR1 15 ng，EGFR 23 ng *His6-HGFR 30 n g，以及使用上述酪胺酸激酶反應及HTRF法。 關於PDGFR冷激酶活性之抑制能力之測定，使用His6-PDGFR/3 50 ng進行上述酷胺酸激酶反應後，用下述方法檢 測出酪胺酸磷酸化生物素-聚（GT)。 亦即，將激酶反應液添加至96-穴抗生蛋白鏈菌素-包覆 之平皿（PIERCE公司，製品編號15129)中，並於室溫培育 30 分鐘。用洗淨液{20 mM Tris-HCl (ρΗ7·6)，137 mM NaCl，0.05% Tween-20，0.1% BSA} 1 50 # 1洗淨 3 次，添加 抗-磷醯基酪胺酸（PY20)-HRP結合物（Transduction Laboratories公司，製造編號P- 1 1625) 70·、# 1 {用含20 mM Tris-HCl (ρΗ7·6)，137 mM NaCl，0.05% Tween-20 及 1% BSA之溶液稀釋2000倍}，並於室溫培育1小時。培育後， 用洗淨液1 50 // 1洗淨3次，添加膜過氧化酶受質（夫納寇斯 公司，製造編號50-5077-03) 100 // 1並開始反應。於室溫放 置10分鐘後，添加1M磷酸100# 1以停止反應，藉由顯微平 孤讀數器（BIO KINETICS READER EL304，BI0-TEK INSTRUMENTS公司製）測定450 nm之吸:光度。將在未添加 被驗物質下，添加His6-PDGFR /3之場合之吸光度當做 -128- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（123) 100%，以及在未添加被驗物質及His6-PDGFR /3之場合之 吸光度當做0%，求出被驗物質存在下之吸光度率9從該吸 光度率算出抑制50%PDGFR冷激酶活性所需之被驗物質濃 度（IC50)。 [表3][藥理試1 会例：對於VEGFR2激酶之抑制作用] 實施例編號 IC5〇(nM) 實施例編號 IC5〇(nM) 1 51 10 4.9 14 2.7 15 8.7 21 4.3 30 22 31 17 33 6.9 34 3.4 25 5.5 36 14 37 22 43 18 54 15 55 29 65 15 99 - 8.6 100 9.6 111 21 116 ，、 4.2 121 8.7 143 70 159 25 173 356 178 12 182 71 183 29 184 59 187 14 208 9.2 252 31 253 23 259 16 260 11 262 9.5 265 &quot; 6.2 266 5.4 283 26Line 1304061 ~ A7 B7 V. Description of the invention (117) Required concentration (1C50). [Table 2] [Pharmacological test example 2: Inhibition of sandwich lumen formation of vascular endothelial cells by VEGF stimulation]. Example No. IC5〇(nM) Example No. ICsoCnM) 1 310 12 44 19 28 23 100 53 9.9 55 35 59 170 65 5.9 70 58 72 22 74 5.9 75 1.4 81 1.8 100 6.3 108 4.9 116 8.1 121 42 127 7.5 129 40 137 10 153 0.02 155 1.4 157 0.9 159 . 0.6 186 23 189 0.3 198 1.5 202 15 204 0.9 211 0·3 215 22 224 26 249 1·6 253 40 256 36 265 0.6 266 0.6 283 36 289 4.6 296 : 34 298 0.7 299 1.0 -123- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 s- A7 B7 V. Invention description (118) 300 7.5 304 0.3 308 5.2 314 4.2 316 1.0 320 2.5 325 1.0 326 1.0 327 56 346 25 368 5.4 372 44 374 3.0 381 4.7 382 4.6 386 10 404 2.8 405 28 408 39 415 3.8 419 10 422 4.8 433 5.6 436 22 440 1.4 441 3.6 442 12 444 5.5 445 6.2 446 4.0 450 4.5 454 3.7 455 ^ 7.8 463 26 490 26 492 *, 7.2 493 9.0 494 9.3 497 4.6 503 6.4 '04 4.6 505 8.9 518 1.3 520 1.5 521 0.5 578 13 Pharmacological Test Example 3: For the receptor type tyrosine kinase specificity Determination of inhibition capacity -124- The paper scale With China National Standard (CNS) A4 size (210 X 297 mm) 1304061 ~, A? _ B7 V. Description (119) invention of the measurement system determine the test substance to inhibit the kinase activity of the cool alanine. DNA encoding the cytoplasmic domain of VEGFR2 is obtained by whole gene synthesis (Edwards M, International Biotechnology Lab 5 (3), 19-25, 1987) or by colonization. Next, it is obtained by tyrosine kinase activity by being expressed in an appropriate expression system. For example, it has been found that the cytoplasmic domain of VEGFR2, which is obtained by the expression of recombinant proteins in insect cells, exhibits inherent tyrosine kinase activity. In the case of VEGFR2 (Genbank Accession No. L04947), the DNA fragment described by Terman et al. (〇11 (: 〇 861^, 6(9), 1677-1683, 1991) is a 1.7 kb DNA fragment encoding the cytoplasmic domain and Starting from the amino acid 791 and containing the stop codon), it was isolated from the human placenta cDNA library (purchased from Clonetics) and then cloned into a baculovirus transferase vector (pBlueBacHis (purchased from GIBCO BRL). The recombinant construct was transferred. Insect cells (Spondoptea frugiperda 9 (Sf9)) to prepare recombinant baculovirus (modulation and use of recombinant baculovirus, refer to the standard textbook / Bac-To-Bac Baculovirus Expression system (GIBCO BRL)). The cytoplasmic fragment (FGFR1, Genbank Accession No. X52833) starting from lysine 398, the cytoplasmic fragment starting from lysine 558 (PDGFR /3, Genbank Accession No. M21616), or from the other tyrosine kinases used for the assay, was determined. The cytoplasmic fragment (HGFR, Genbank Accession No. J02958) starting with Amino Acid 974 can be cloned and expressed by the same method. EGFR was purchased from Sigma (Product No. E-2645). The tyrosine kinase of VEGFR2 is expressed, Sf9 cells are infected with VEGFR2 recombinant virus, and then collected after 48 hours. The collected cells are iced 125. The paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1304061, s - A7 B7 V. INSTRUCTIONS (120) Cold phosphate buffered saline (PBS) washed with 1 ml of 10 s cells per hour with 20 ml of ice-cold lysis buffer (5 mM Tds) -HCl (pH 8·5), 5 mM 2-thiol ethanol, 100 mM Κα, 1 mM phenylmethylsulfonyl fluoride), 1% (ν/ν) NP-40) resuspended. The suspension was centrifuged at 4 ° C and 12000 rpm for 30 minutes to obtain a supernatant. The supernatant was added to buffer A [20 mM Tris-HCl (pH 8.5), 5 mM 2-thiol group. Ethanol, 500 mM KC1, 20 mM sodium saliva, 10% (v/v) glycerol] equilibrated Ni-NTA agarose column (3 ml, purchased from QIAGEN). The tube was diluted with 30 ml of buffer. A, then 6 ml buffer B [20 mM Tris-HCl (pH 8.5), 5 mM 2-thiol ethanol, 1 M KC1, 10% (v/v) glycerol], and washed with buffer A6 ml. After washing, dissolve with 6 ml of buffer C [20 mM Tris-HCl (pH 8·5), 5 mM 2-thiol-ethanol, 100 mM KC1, 100 mM imidazole, 10% (ν/ν) glycerol] . The eluate was applied to a dialysis membrane (purchased from Spectrum Laboratories, Inc.), and dialysis buffer [20 mM Tris-HCl (pH 7.5), 10% (v/v) glycerol, 1 mM dithiothreitol) was used. , 0·1 miM Na3V04 and 0·1 mM EGTA] dialyzed. After dialysis, SDS electrophoresis was carried out, and in the Coomassie Brilliant Blue staining, BSA (bovine serum albumin, purchased from Sigma) was used as a standard substance to recombine at a molecular weight of about 1 〇〇 kDa. The body protein (His6-VEGFR2, which is the cytoplasmic domain of VEGFR2 in which N histidine is fused with 6 histidines) was quantified and stored at -80 °C until use. For the cytoplasmic domain of FGFR1, the PDGFR cold cytoplasmic domain or the HGFR cell cultivar field uses the same method to obtain a recombinant protein with 6 histidines at the N-terminal. -126- This paper scale applies to the Chinese national standard (CNS) A4 size (210X297 mm) 1304061, A7 B7 V. Description of the invention (121) (His6-FGFR1, His6. PDGFRiS or His6-HGFR) The β tyrosine kinase reaction was carried out as follows. For example, in the case of VEGFR2, a kinase reaction solution {200 mM Hepes (pH 7.4), 80 mM MgCl2, 16 mM M11CI2, 2 mM Na3V04} is added to each well of a 96-well round bottom plate (NUNC Corporation, product number 163320). 10 // 1, biotin-bound poly(Glu4: Tyrl) [biotin-poly(GT), purchased from CIS Diagnostic] and test substance dissolved in dimethyl hydrazine (diluted with 0.1% BSA solution) 100 times 4#1) and adjusted to 30//1. Next, 4 ATP (diluted with distilled water) was added and incubated at 30 ° C for 10 minutes, and then 500 mM EDTA (pH 8.0) was added and measured by time-analytical fluorescence method (HTRF method) (Analytical Biochemistry, 269, 94-104, 1999). That is, the above kinase reaction solution was transferred to a 96-well black half dish (Coaster, Inc., product number 3694), and an anti-phosphotyrosine antibody (Eu(K)-PY20, labeled with a ruthenium compound was added, from CIS Diag1i〇 Stic company purchased 7·5 ng (diluted 2i, 0 times, 25#1) with 20 mM Hepes (pH 7.0·0), 0.5 M KF and 0.1% BSA, and anti-protein chain labeled with XL665 Phytocetin (XL665-SA, purchased from CIS Diagnostic) 250 ng [62.5 times diluted with a solution containing 20 mM Hepes (ρΗ7·0), 0.5 M KF and 〇.i% BSA, 25#1], placed in the chamber After 30 minutes of heating, the fluorescence intensity at 665 nm and 620 nm when irradiated at an excitation wavelength of 337 nm was measured using a Discovery-HTRF microplate analyzer (manufactured by the company). The biotin-poly(GT) tyrosine phosphorylation rate is expressed as 5 F% of the HTRF standard assay described by CIS Diagnostic. His6-VEGFR2 will be added in the absence of the substance to be tested (5 F% value as 100%, -127- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304061 ~ --- A7 B7 V. Inventive Note (122) and the ratio of the 5 F% in the absence of the test substance and His6-VEGFR2 as 0%, and then the ratio of the 5 F% value in the presence of the test substance is obtained. From the ratio (%) The concentration of the test substance required to inhibit 50% of VEGFR2 kinase activity (IC50). For the inhibition of FGFR1, EGFR or HGFR kinase activity, His6-FGFR1 15 ng, EGFR 23 ng *His6-HGFR 30 ng were used, respectively. And using the above tyrosine kinase reaction and HTRF method. For the determination of the inhibitory ability of PDGFR cold kinase activity, after the above valine kinase reaction was carried out using His6-PDGFR/3 50 ng, tyrosine was detected by the following method Phosphorylated biotin-poly(GT). That is, the kinase reaction solution was added to a 96-well streptavidin-coated plate (PIERCE, product number 15129) and incubated at room temperature for 30 minutes. Wash solution {20 mM Tris-HCl (ρΗ7·6), 137 mM NaCl, 0.05% Tween -20, 0.1% BSA} 1 50 # 1 Wash 3 times, add anti-phosphonium tyrosine (PY20)-HRP conjugate (Transduction Laboratories, Inc., manufacturing number P-1 1625) 70·, #1 { Dilute 2000 times with a solution containing 20 mM Tris-HCl (ρΗ7·6), 137 mM NaCl, 0.05% Tween-20 and 1% BSA}, and incubate for 1 hour at room temperature. After incubation, use a washing solution 1 50 / / 1 Wash 3 times, add membrane peroxidase receptor (Fna Nagas, manufacturing number 50-5077-03) 100 / 1 and start the reaction. After standing at room temperature for 10 minutes, add 1M phosphoric acid 100 #1 to stop the reaction, the absorbance at 450 nm was measured by a microscopic flat-isolator (BIO KINETICS READER EL304, manufactured by BI0-TEK INSTRUMENTS). His6-PDGFR /3 was added without adding the test substance. Absorbance of the occasion as -128- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (123) 100%, and without adding test substance and His6 The absorbance at the time of -PDGFR /3 is 0%, and the absorbance rate in the presence of the test substance is determined. 9 The inhibition of 50% of PDGFR cold kinase is calculated from the absorbance. The concentration of the test substance required for the activity (IC50). [Table 3] [Pharmacological Test 1 Example: Inhibition of VEGFR2 Kinase] Example No. IC5〇(nM) Example No. IC5〇(nM) 1 51 10 4.9 14 2.7 15 8.7 21 4.3 30 22 31 17 33 6.9 34 3.4 25 5.5 36 14 37 22 43 18 54 15 55 29 65 15 99 - 8.6 100 9.6 111 21 116 , , 4.2 121 8.7 143 70 159 25 173 356 178 12 182 71 183 29 184 59 187 14 208 9.2 252 31 253 23 259 16 260 11 262 9.5 265 &quot; 6.2 266 5.4 283 26

裝 訂Binding

線 -129- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（124) 314 5.3 316 6.4 346 4.6 348 4.6 350 43 353 2.2 356 1.4 364 8.1 365 5.4 368 3.0 374 8.4 375 16 381 2.6 382 9.0 387 4.1 394 .15 398 3.5 404 6.5 410 2.2 413 3.2 435 22 437 9.9 441 2.8 449 2.2 463 5.9 465 13 556 14 藥理試驗例$ :對於癌細胞及正常細胞之細胞增殖之抑制作 用 -、Line-129- This paper size applies to China National Standard (CNS) A4 size (210 X 297 mm) 1304061 A7 B7 V. Invention description (124) 314 5.3 316 6.4 346 4.6 348 4.6 350 43 353 2.2 356 1.4 364 8.1 365 5.4 368 3.0 374 8.4 375 16 381 2.6 382 9.0 387 4.1 394 .15 398 3.5 404 6.5 410 2.2 413 3.2 435 22 437 9.9 441 2.8 449 2.2 463 5.9 465 13 556 14 Pharmacological test case $: for cancer cells and normal cells Inhibition of cell proliferation -

將癌細胞（例如人類胰臟細胞KP- 4)或正常細胞（例如大鼠 小腸上皮細胞IEC-18)每3〜4日用含10%FBS之RPMI 1640培 養基（從曰水製藥購入）繼代培養，並使用增殖期之細胞。 使用胰蛋白酶-EDTA回收細胞後，計測細胞數（在KP-4之場 合，調成為2 X 103個/穴；在IEC18之場合，調成為8 X 102 個/穴），將用含10%FBS之RPMI 1640培養基稀釋之0.1 ml 細胞懸浮液播種在細胞培養用之96穴平:皿中。在含5% C〇2 之培育器中（37°C)培養一夜後，添加用含10%FBS之RPMI -130- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）Cancer cells (such as human pancreatic cells KP-4) or normal cells (such as rat intestinal epithelial cells IEC-18) are subcultured every 3 to 4 days with RPMI 1640 medium (purchased from Surabaya Pharmaceuticals) containing 10% FBS. Culture and use cells of proliferative phase. After recovering the cells using trypsin-EDTA, measure the number of cells (in the case of KP-4, adjust to 2 X 103 cells/hole; in the case of IEC18, adjust to 8 X 102 cells/hole), and use 10% FBS. 0.1 ml of the cell suspension diluted in RPMI 1640 medium was seeded in 96 wells: dish for cell culture. After culturing overnight in a 5% C〇2 incubator (37 °C), add RPMI-130- 10% FBS with the Chinese National Standard (CNS) A4 size (210 X 297 mm).

訂Order

線 1304061 〜 A7 B7 五、發明説明（125) 1640培養基稀釋之被驗物質溶液0.1 m卜然後再於含5%C02 之培育器中（37°C)培養一夜。在被驗物質添加後第三日， 加入溶解於PBS之3 ·3 mg/ ml MTT(從Sigma公司購入）之溶 液0.05 ml，並在含5%C02之培育器中（37°C)培養約2小時。 吸引除去培養上清液，將在各穴中生成之甲賸用DMSO溶 解後，在測定波長為540 nm及對照波長為660 nm下，用平 盟讀數器-MTP-32 (曰冕電氣公司）測定各穴之吸光度。求 出添加被檢物質時穴之吸光度相對於未添加被檢物質時穴 之吸光度之％，從該比值求出抑制50%細胞增殖所需被檢 物質之濃度（IC5〇)。 藥理實驗例5 ：對於L6(大鼠肌肉母細胞）之PDGF依存性增 殖之作用 將L6(大鼠肌肉母細胞）每3〜4日用含10% FBS之D-MEM 培養基（從日水製藥購入）繼代培養，並使用增殖期之細 胞。使用漱音白酶-EDTA回收細胞，用不含10%FBS之D-MEM培養基洗淨1次後，計測細胞數。在〜包覆I型膠原之組 織培養用96穴平皿中，將用不含10% FBS之D-MEM培養基 稀釋之0.1 ml細胞懸浮液以5 xlO3個/穴之方式播種，並在 含5% C〇2之培育器中（37 °C)培養。第二天加入用不含 10%FBS之D-ΜΈΜ培養基稀釋之被驗物質溶液0.05 m卜且 在約同時加入40 nM之PDGF溶液0.05 ml(終濃度10 nM) 後，然後再在含5%C02之培育器中（37°C)培養一夜。在添 加被驗物質後第三日，在各穴中加入WST- 1溶液（從和光純 藥公司購入）0.01 ml，並在含5%C02之培育器中（37°C)培養 -131 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜 s - A7 B7 五、發明説明（126) 約3小時及使之發色。在測定波長為41 5 nm及對照波長為 660 iim下，·用平皿讀數器-MTP-32 (曰冕電氣公司）測定各 穴之吸光度。求出添加被檢物質時穴之吸光度相對於未添 加被檢物質時穴之吸光度之％，從該比值求出抑制50%細 胞增殖所需被檢物質之濃度（IC5〇)。Line 1304061 ~ A7 B7 V. Description of the invention (125) The test substance solution diluted in 1640 medium was 0.1 m and then cultured overnight in a 5% CO 2 incubator (37 ° C). On the third day after the test substance was added, 0.05 ml of a solution of 3·3 mg/ml MTT (purchased from Sigma) dissolved in PBS was added, and cultured in a 5% CO 2 incubator (37 ° C). 2 hours. The culture supernatant was removed by suction, and the dimethyl sulphate formed in each well was dissolved in DMSO. At a measurement wavelength of 540 nm and a control wavelength of 660 nm, the Pingmeng reader-MTP-32 (曰冕电公司) was used. The absorbance of each well was measured. The absorbance of the cavity at the time of adding the test substance was determined as % of the absorbance of the cavity when the test substance was not added, and the concentration of the test substance required to suppress cell proliferation by 50% (IC5 〇) was determined from the ratio. Pharmacological Experiment 5: Effect on PDGF-dependent proliferation of L6 (rat muscle mother cells) L6 (rat muscle mother cells) was treated with D-MEM medium containing 10% FBS every 3 to 4 days (from Rishui Pharmaceutical Co., Ltd.) Purchase) subculture, and use proliferating cells. The cells were recovered using 漱-white enzyme-EDTA, and washed once with D-MEM medium containing no 10% FBS, and the number of cells was measured. In a 96-well plate coated with type I collagen, 0.1 ml of the cell suspension diluted with D-MEM medium containing no 10% FBS was seeded at 5 x 10 3 /hole, and contained 5%. Incubate in a C〇2 incubator (37 °C). On the next day, add 0.05 m of the test substance solution diluted with D-ΜΈΜ medium without 10% FBS, and add about 50 μM of PDGF solution 0.05 ml (final concentration 10 nM) at about the same time, and then in 5%. Incubate overnight in a C02 incubator (37 ° C). On the third day after the addition of the test substance, 0.01 ml of WST-1 solution (purchased from Wako Pure Chemical Industries Co., Ltd.) was added to each well, and cultured in a 5% CO 2 incubator (37 ° C) -131 - this The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ~ s - A7 B7 V. Invention Description (126) Approx. 3 hours and make it color. At a measurement wavelength of 41 5 nm and a control wavelength of 660 μm, the absorbance of each well was measured using a plate reader-MTP-32 (曰冕电公司). The absorbance of the hole at the time of adding the test substance was determined as % of the absorbance at the time when the test substance was not added, and the concentration of the test substance required to suppress proliferation of 50% of the cells (IC5 〇) was determined from the ratio.

藥理試驗例6 ： DNA微量陣列/藉定量PCR解析mRNA表現 1.從樣品萃取全部RNA 將細胞在5% C02條件下或低氧（1%)下於37°C培養。例如 在HUVEC之場合，使用EGM-2培養基（從Clonetics購入）在 5%(：02及37°(：之條件下培養。使被檢物質作用後，於一定 時間後依照隨附之操作法，用TRIZ0L試藥（從GIBCO BRL 公司購入）進行細胞溶解。具體而言如下述。對於10 cm2之 培養面積，添加1 ml之TRIZ0L試藥，進行數次之吸放及回 收。將該樣品離心後，將得到之上清液放置於室溫5分鐘 後，以相對/於每1 ml TRIZ0L試藥添加0.2 ml之比率添加氣 仿（從純正化學公司購入）。將該溶液激·、烈震盪1 5秒，攪 捽，於室溫放置2〜3分鐘後進行離心（12，000 X g，10分鐘， 4°C )。將離心後之水層移至新的試管中，以相對於每1 mi TRIZ0L·試藥添加0.5 mi之比率添加異丙醇（從和光純藥購 入）’於室溫放置10分鐘後進行離心（12,000 X g，10分鐘， 4°C )。將得到之沉澱用75%乙醇（從和光純藥購入）洗淨後 風乾’以供在以下操作作為全部RNA。 2 · RNA之定量 ， RNA可以藉由北方氏吸潰解析、DNA微量陣列、RT-PCR _________-132-______ 本紙張尺度適用中國國豕標準(CNS) A4規格（21〇x 297公釐） 1304061 、 s A7 B7 五、發明説明（127 ) 及定量PCR等技術定量。以DNA微量陣列及定量PCR為較 佳。以下將分別予以說明，但本發明不受此限。 1)藉由 DNA微量陣列之定量（Schena M. et al, Science, 270 ( 5235)，467-70，1995 以及 Lockhart，D. J. et al.，Nature Biotechnology, 14 (13)，1675- 1680, 1996)如下述進行。 ①cDNA合成及生物素標識 以最初得到之RNA為模板，用Superscript Choice System (從GIBCO BRL公司購入）及T7-d(T)24引子合成雙股 cDNA，繼而以該cDNA為模板，合成生物素化cRNA。 具體而言，首先在10#g之RNA中加入5#g之T7-d(T)2jl 子，1 X第一股緩衝液，10 mM DTT，500 # Μ之dNTP混合 物，20單元1之Superscript II反錄酶，於42 °C反應1小 時，以合成單股cDNA。繼而添加1 X第二股缓衝液，200# Μ 之 dNTP混合物，67 U/ ml DNA連結酶，270 U/ ml DNA 聚合酶I及1&quot;3U/ ml RNaseH，於16°C反應2小時，以合成雙 股cDNA。再者，添加67 U/ ml T4 DNA衮合酶並於16°C反 應5分鐘後，加入10// 1 0·5Μ EDTA (從Sigma公司購入）並 停止反應。 將得到之cDNA用酚/氯仿（從Ambion公司購入）精製，使 用RNA轉錄體標記套組（從Enzo Diagnostics購入），依照隨 附之操作法，藉由生物素化UTP以及CTP進行標記化反應。 將反應生成物用Rneasy管柱（從QIAGEN公司購入）精製後， 在200 mM Tris乙酸鹽pH 8.1，150 mM乙酸鎂及50 mM乙 酸鉀中，於94°C加熱35分鐘，以將cRNA片段化。 -133- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜 A7 _ B7 五、發明説明（128 ) ②對DNA微量陣列（GeneChip)之雜合及測定 將片段化之cRNA，在例如100 mM MES，1 Μ鈉鹽，20 mM EDTA及 0·01% Tween 20 中，於 45°C，與 GeneChip (從 Affymetrix公司購入）Hu6800/人類癌症G110陣列或同等製 品雜合16小時。雜合後，GeneChip依照Affymetrix流控技術 站所附之規程EukGE- WS2或所用陣列最適合之規程洗淨及 染色。在染色方面，使用抗生蛋白鏈菌素-藻紅蛋白（從 Molecular Probe公司購入）及生物素化抗-抗生蛋白鏈菌素 山羊抗體（從Vector公司購入）。將染色後之基因片用HP氬-離子雷射共焦顯微鏡（從Hewlett Packard公司購入）掃描， 以及測定螢光強度。在該螢光之場合，測定使用488 nm之 激發及570 nm之射出進行。 定量數據解析用GeneChip軟體（從Affymetrix公司購入）或 Genespring (從Silicon Genetics公司購入）進行。為進行 RNA之定量求出各個探針家族每一「完美配對雜合信號-錯配信號」之平均差值，在該值為5以上且二條件間RNA之 定量值乖離之場合（較佳乖離1.8倍以上），將該基因之表現 判斷為有意義地「增加」或「減少」。 2)如下述藉由定量性PCR進行定量 定量性PCR，藉由使用SYBR Green (從Applied Biosystems公司購入）及ABI Prism 7700序列檢測系統（從 Perkin-Elmer Applied Biosystems公司購入）或與其同等之製 品，如下述進行。 - 操作用反錄反應及PCR反應2段進行。為最初階段之反錄 -134- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂Pharmacological Test Example 6: DNA microarray / quantitative PCR analysis of mRNA expression 1. Extraction of whole RNA from sample The cells were cultured at 37 ° C under 5% CO 2 conditions or under hypoxia (1%). For example, in the case of HUVEC, EGM-2 medium (purchased from Clonetics) is used at 5% (: 02 and 37 ° (: conditions). After the test substance is applied, after a certain period of time, according to the attached operation method, Cell lysis was carried out using a TRIZ0L reagent (purchased from GIBCO BRL). Specifically, as follows: For a culture area of 10 cm2, 1 ml of TRIZ0L reagent was added, and several times of absorption and recovery were performed. After the supernatant was placed at room temperature for 5 minutes, the gas was added (purchased from Pure Chemical Company) at a ratio of 0.2 ml per 1 ml of TRIZ0L reagent. The solution was shaken and shaken 1 5 seconds, stir well, place at room temperature for 2 to 3 minutes and then centrifuge (12,000 X g, 10 minutes, 4 ° C). Move the water layer after centrifugation to a new tube, relative to each 1 The mi TRIZ0L· reagent was added at a ratio of 0.5 mi to add isopropanol (purchased from Wako Pure Chemical Industries). After standing at room temperature for 10 minutes, centrifugation (12,000 X g, 10 minutes, 4 ° C) was carried out. % ethanol (purchased from Wako Pure Drugs) washed and air dried for the following operations All RNA. 2 · RNA quantification, RNA can be analyzed by Northern blotting, DNA microarray, RT-PCR _________-132-______ This paper scale applies to China National Standard (CNS) A4 specification (21〇x 297厘) 1304061, s A7 B7 V. Inventive Note (127) and quantitative PCR, etc. DNA microarray and quantitative PCR are preferred, respectively, which will be described below, but the invention is not limited thereto. Quantification of DNA microarrays (Schena M. et al, Science, 270 (5235), 467-70, 1995 and Lockhart, DJ et al., Nature Biotechnology, 14 (13), 1675-1680, 1996) were performed as follows. 1 cDNA Synthesis and Biotin Labeling Using the originally obtained RNA as a template, a double-stranded cDNA was synthesized using Superscript Choice System (purchased from GIBCO BRL) and T7-d(T)24 primers, and then the cDNA was used as a template to synthesize biotinylation. Specifically, first, add 5#g of T7-d(T)2jl, 1 X first buffer, 10 mM DTT, 500 # Μ dNTP mixture, 20 unit 1 in 10#g RNA. The Superscript II anti-recording enzyme was reacted at 42 ° C for 1 hour to synthesize a single-stranded cDNA. Then add 1 X second buffer, 200# Μ dNTP mixture, 67 U / ml DNA ligase, 270 U / ml DNA polymerase I and 1 &quot; 3U / ml RNaseH, react at 16 ° C for 2 hours, Synthesis of double-stranded cDNA. Further, after adding 67 U/ml of T4 DNA chelating enzyme and reacting at 16 ° C for 5 minutes, 10//1 0·5 Μ EDTA (purchased from Sigma) was added and the reaction was stopped. The obtained cDNA was purified with phenol/chloroform (purchased from Ambion), and an RNA transcript labeling kit (purchased from Enzo Diagnostics) was used to carry out a labeling reaction by biotinylated UTP and CTP according to the attached procedure. The reaction product was purified by Rneasy column (purchased from QIAGEN), and heated at 94 ° C for 35 minutes in 200 mM Tris acetate pH 8.1, 150 mM magnesium acetate and 50 mM potassium acetate to fragment the cRNA. . -133- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ~ A7 _ B7 V. Description of invention (128) 2 Hybridization and determination of DNA microarray (GeneChip) CRNA, in, for example, 100 mM MES, 1 Μ sodium salt, 20 mM EDTA and 0. 01% Tween 20, at 45 ° C, with GeneChip (purchased from Affymetrix) Hu6800 / human cancer G110 array or equivalent 16 hours. After hybridization, GeneChip is washed and stained according to the protocol EukGE-WS2 attached to the Affymetrix Flow Control Technology Station or the most suitable protocol for the array used. For staining, streptavidin-phycoerythrin (purchased from Molecular Probe) and biotinylated anti-streptavidin goat antibody (purchased from Vector) were used. The stained gene tablets were scanned with an HP argon-ion laser confocal microscope (purchased from Hewlett Packard Co., Ltd.), and the fluorescence intensity was measured. In the case of this fluorescence, the measurement was carried out using excitation at 488 nm and injection at 570 nm. Quantitative data analysis was performed using GeneChip software (purchased from Affymetrix) or Genespring (purchased from Silicon Genetics). For the quantification of RNA, the average difference between each "perfect paired heterozygous signal-mismatch signal" of each probe family is determined. When the value is 5 or more and the quantitative value of the RNA between the two conditions is deviated (preferably 1.8 times or more), the performance of the gene is judged to be "increased" or "decreased" meaningfully. 2) Quantitative quantitative PCR by quantitative PCR as follows, using SYBR Green (purchased from Applied Biosystems) and ABI Prism 7700 Sequence Detection System (purchased from Perkin-Elmer Applied Biosystems) or equivalent products, Perform as follows. - The operation is carried out in two stages of the reverse recording reaction and the PCR reaction. For the initial stage of the reverse recording -134- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) binding

線 1304061 〜 、- A7 B7____ 五、發明説明（129) 反應，藉由於得到之RNA中添加dNTP ·寡d(丁）μ引子· RNase抑制劑· Multiscribe 反錄酶（從 Perkin-Elmer Applied Biosystems公司購入）及於25°C保溫10分鐘後，於48°C加熱 30分鐘而進行。藉由在95°C加熱5分鐘停止反應β 將得到之cDNA供給第2段PCR反應。PCR反應，例如在4 ng cDNA，1 X SYBR PCR缓衝液，3 mM MgCl2，dATP、 dCTP及dGTP 各200 # Μ , 400/z M dUTP，200 nM 引子對， 0.01U/ β 1 AmpErase UNG ? 0.025 U/ ii 1 Ampli Taq Gold DNA聚合酶（從 Perkin-Elmer Applied Biosystems公司講入） 之反應系中進行。反應條件為50°C/2分鐘，951/10分鐘’ 繼而進行95°C/20秒-55°C/20秒-72°C/30秒40個循環。引子 及探針，用引子表現（Primer Expression，從Perkin-ElmerLine 1304061 ~, - A7 B7____ V. Inventive Note (129) Reaction by adding dNTP to the obtained RNA · Oligo d (butyl) μ primer · RNase inhibitor · Multiscribe anti-recording enzyme (purchased from Perkin-Elmer Applied Biosystems) After incubation at 25 ° C for 10 minutes, it was heated at 48 ° C for 30 minutes. The reaction was stopped by heating at 95 ° C for 5 minutes to supply the obtained cDNA to the second-stage PCR reaction. PCR reaction, for example, in 4 ng cDNA, 1 X SYBR PCR buffer, 3 mM MgCl2, dATP, dCTP and dGTP each 200 # Μ , 400 / z M dUTP , 200 nM primer pair , 0.01 U / β 1 AmpErase UNG ? 0.025 U/ii 1 Ampli Taq Gold DNA polymerase (speaking from Perkin-Elmer Applied Biosystems) was carried out in the reaction system. The reaction conditions were 50 ° C / 2 min, 951 / 10 min' followed by 40 cycles of 95 ° C / 20 sec - 55 ° C / 20 sec - 72 ° C / 30 sec. Primers and probes, expressed by primers (Primer Expression, from Perkin-Elmer

Applied Biosystems公司購入）或與其同等之軟體設計。關 於複數個被檢物質之比較，定量值藉由在各檢體中之轉錄 量變動較少-之管家基因（較佳藉由GAPDH之mRNA濃度）進 行補正。 、 藥理試驗例7 ••使用小鼠皮下空氣囊法評價活體内血管新生 謗導活性 ①VEGF(血管内皮增殖因子）表現載體之構築 以人類胎盤cDNA庫（從東洋紡購入）作為模板，以VEGF 之序歹4 編號 5,CCGGATCCATGAACTTTCTGCTG3,及 5· GTGAATTCTGTATCGATGGTT3·作為引子進行 PCR。在 PCR反應終了後，將y終端磷酸化，進·行1.2%瓊脂糖凝膠 電泳而分離出約600 bp DNA帶。藉由自體連結聚合後，將 -135- _ 本紙張尺度適用中國國家榡準(CNS) A4規格(210X297公釐） 1304061 、 … A7 B7 五、發明説明（130) cDNA用EcoRI及Bam HI切斷，然後插入pUC19載體之EcoRI 及BamHI部位。之後轉形入大腸菌JM83中，並從轉形之純 系中回收質體。用Hind III及EcoRI從質體切出VEGFcDNA 片段後，插入包含neo耐性基因之表現載體。 ② VEGF高表現株之製作 將人類胰臟癌細胞株KP-1(3 X 106細胞）在含10%FCS之 RPMI 1640培養基中培養一夜後，將VEGF表現載體3/zg用 Effctene轉染試劑套組（從QIAGEN購入）導入KP-1細胞中。 在包含Geneticin 600 # g/ ml之含 10%FCS之RPMI 1640培養 基中培養，選擇高表現藥劑耐性細胞，稱為VEGF高表現 KP-1 細胞（KP-1/VEGF)。 ③ 培養上清液中VEGF量之測定 將KP-1/VEGF調整成5 X 105細胞/ ml，將各0.5 ml注入24 穴平孤之穴内，以及於37 °C下培養24小時。回收培養上清 液，使用VEGF測定套組（從免疫生物研究所購入）定量 VEGF，以及確認高表現。 .、 ④使用小鼠皮下空氣囊法評價活體内血管新生誘導活性 將微孔環（從日本Milipore公司購入）用0.45 # m之 Durapore濾膜（從日本Milipore公司購入）密封及製作小室。 在該小室内，從注入口注入懸浮於〇· 17 ml膠原凝膠之3 X 10ό個人類胰臟癌KP-1/VEGF細胞並封入。繼而在麻醉下， 在6週齡之C57BL/6N雌鼠之背部皮下注入約10 ml之空氣並 製作空氣囊，然後將先前之小室移植A：·其中。於移植终了 後約6小時，經口投與懸浮於〇 5%甲基纖維素之被驗物質 _______-136-____ 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐） 1304061 '、_ 、… A7 ____B7 五、發明説明（131 ) (0.1 ml/10 g體重），之後1日1次，連續投與4日。 於^植小室後4日，從移植有小室之小鼠尾部靜脈注射〇.2 ml 以 ”Cr (Amersham Pharmacia)標記之小鼠紅血球（2 5 χ 106 cpm/ ml)。一定時間後，切除接在小室之部分之皮膚， 凍結後，只正確地切離接於小室之部份，然後用了記數器 測定放射活性。從上述血液量減去移植只封入膠原凝膠之 小室之場合之血液量，以所得之值作為血管新生量β又， 該實驗係以對照組（溶媒投與群）丨群1〇隻及化合物投與群i 群5隻之方式進行。 致星試驗例8 :使用皮下移植模型，對KP-1/VEGF細胞評價 抗腫瘤活性 將以1 X 107/ ml之濃度懸浮於PBS&lt;VEGF高表現胰臟癌 細胞（KP-1/VEGF)，以〇·ι ml之容量移植於6週齡 Balb/c(nu/nu)雌鼠之右脇腹皮下部。從腫瘤體積成為約1〇〇 mm3之時，嗷驗物質以一週5日之時間表經口投與2星期。 被驗物質，以成為〇·} ml/10 g體重之投輿量之方式，懸浮 於0.5%曱基纖維素中。腫瘤尺寸，用游尺測定，丨星期2 次。又，腫瘤體積，用游尺測定腫瘤之長徑及短徑，以及 用1/2 X (長徑X短徑x短徑）計算。又，該實驗係以對照組 (落媒投與群）1群1 〇隻及被驗物質投與群〗群5隻之方式進 行。 JLg試驗例9 :使用胰臟同所移植模型評價腫瘤增殖、癌性 腹水貯留及生存期間 ： 將6〜7週齡6&amp;11)/(：(1111/1111)雌鼠在麻醉下切開腹部，露出騰 -137- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱） 1304061 A7 _____ _ B7 五、發明説明（132) 臟。將以7 X 1〇7/ ml之濃度懸浮於PBS之VEGF高表現胰臟 癌細胞（KP-1/VEGF)，以〇.1 ml之容量直接移植於胰臟頭 部。從移植後4星期，被驗物質以一週5日之時間表經口投 與1〇星期。被驗物質，以成為〇·1 ml/1〇 g體重之投與量之 方式’懸浮於0.5%甲基纖維素中。其間，測定體重，1星期 2次’從外觀察有無腹水之貯留並記錄之。在生存期間，累 计到實驗終了時死亡小鼠之數目。又，對於死後可以剖檢 之個體測定腫瘤重量。又，實驗在1群8至1〇隻之範圍内進 行。 產業上之利用可能性 依照本發明，具有下列作用··（1)對於由上皮細胞增殖因 子（簡稱EGF)/VEGF/纖維母細胞增殖因子（簡稱肝 細胞增殖因子（簡稱為HGF)/腫瘤壞死因子α (簡稱為TNF-α )構成之血管新生因子混合液誘導之血管内皮細胞浸潤性 官腔形成有^強力抑制作用，（2)對於單獨的血管新生因子 (例如VEGF、FGF及HGF等各種因子）特龚性誘導之血管内 皮細胞之管腔形成具強力抑制作用，以及（3)對於各種血管 新生因子之受器激酶有強力抑制作用，而可以提供在作^ 醫藥上具高度有用性之新穎化合物。 再者，從具有上述（1)至（3)之作用之化合物群中，亦可 以提供具有腫瘤細胞之增殖抑制作用之化合物群。 又，已知在身體中之血管新生，非藉由單獨的血管新生 因子，而是藉由複數個血管新生因子之·相加·相乘作用而 進行（（l)Koolwijk Ρ，van Erck MGM，de Vree WJA，Vemeer -138- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 -Applied Biosystems purchased or equivalent software design. Regarding the comparison of a plurality of test substances, the quantitative value is corrected by the housekeeping gene (preferably by the mRNA concentration of GAPDH) which has less variation in the transcription amount in each sample. Pharmacological test example 7 • Evaluation of angiogenesis in vivo using the subcutaneous air sac of mice 1 VEGF (vascular endothelial growth factor) expression vector construction The human placental cDNA library (purchased from Toyobo) was used as a template, in the order of VEGF歹4 No. 5, CCGGATCCATGAACTTTCTGCTG3, and 5· GTGAATTCTGTATCGATGGTT3· were used as primers for PCR. After the end of the PCR reaction, the y-terminus was phosphorylated and subjected to 1.2% agarose gel electrophoresis to isolate a DNA band of about 600 bp. After self-linking polymerization, the -135- _ paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1304061, ... A7 B7 V. Inventive Note (130) cDNA is cut with EcoRI and Bam HI Broken, then inserted into the EcoRI and BamHI sites of the pUC19 vector. Thereafter, it was transformed into Escherichia coli JM83, and the plastid was recovered from the transformed pure line. After cleavage of the VEGF cDNA fragment from the plastid by Hind III and EcoRI, a expression vector containing the neo tolerance gene was inserted. 2 Preparation of VEGF high-performance strains Human pancreatic cancer cell line KP-1 (3×106 cells) was cultured overnight in RPMI 1640 medium containing 10% FCS, and VEGF expression vector 3/zg was transfected with Effctene reagent kit. The group (purchased from QIAGEN) was introduced into KP-1 cells. The cells were cultured in a RPMI 1640 medium containing 10% FCS containing Geneticin 600 #g/ml, and high-performance drug-resistant cells, which are called VEGF high-performance KP-1 cells (KP-1/VEGF), were selected. 3 Determination of the amount of VEGF in the culture supernatant KP-1/VEGF was adjusted to 5 X 105 cells/ml, 0.5 ml each was injected into a 24-hole Pinggu, and cultured at 37 °C for 24 hours. The culture supernatant was recovered, and VEGF was quantified using a VEGF assay kit (purchased from the Institute of Immunobiology), and high performance was confirmed. 4. Evaluation of in vivo angiogenesis-inducing activity using a mouse subcutaneous air bag method A microporous ring (purchased from Milipore, Japan) was sealed and fabricated into a chamber with a 0.45 # m Durapore filter (purchased from Milipore, Japan). In the chamber, 3 X 10 ό individual pancreatic cancer KP-1/VEGF cells suspended in 〇·17 ml of collagen gel were injected from the injection port and sealed. Then, under anesthesia, about 10 ml of air was injected subcutaneously into the back of a 6-week-old C57BL/6N female and an air sac was made, and then the previous chamber was transplanted A:·. About 6 hours after the end of transplantation, the test substance suspended in 5% 5% methylcellulose was orally administered _______-136-____ This paper scale is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1304061 ', _, ... A7 ____B7 V. Description of invention (131) (0.1 ml/10 g body weight), followed by one day, and continued for 4 days. On the 4th day after the planting of the chamber, 2 ml of mouse red blood cells (25 χ 106 cpm/ml) labeled with "Cr (Amersham Pharmacia) were injected intravenously from the tail of the mice transplanted with the chamber. After a certain time, the resection was performed. In the skin of a part of the chamber, after freezing, only the part that is connected to the chamber is correctly cut, and then the radioactivity is measured by a counter. The blood of the case where the collagen gel is sealed only is subtracted from the above blood volume. The amount was obtained by using the obtained value as the angiogenesis amount β. The experiment was carried out in the same manner as the control group (solvent-administered group), the group 1 and the compound-administered group i group. Subcutaneous transplantation model, anti-tumor activity against KP-1/VEGF cells will be suspended in PBS&lt;VEGF high-performance pancreatic cancer cells (KP-1/VEGF) at a concentration of 1×107/ml, with a capacity of ι·ι ml The transplanted to the right flank of the right flank of a 6-week-old Balb/c (nu/nu) female. When the tumor volume became about 1 mm3, the test substance was orally administered for 2 weeks on a 5 day schedule. The substance to be tested is suspended in 0.5% 曱 base fiber in the form of 舆·} ml/10 g body weight. Suzhong. Tumor size, measured with a ruler, twice a week. Also, tumor volume, the long and short diameter of the tumor was measured with a ruler, and calculated by 1/2 X (long diameter X short diameter x short diameter) In addition, the experiment was carried out in the control group (reagent delivery group) 1 group 1 〇 and the test substance administration group group 5 group. JLg test example 9: Evaluation of tumor using pancreas and transplanted model Proliferation, cancerous ascites storage and survival period: 6~7 weeks old 6&amp;11)/(:(1111/1111) female rats were cut open under anesthesia to reveal Teng-137- This paper scale is applicable to Chinese national standard (CNS) A4 size (210 X 297 public) 1304061 A7 _____ _ B7 V. Inventive Note (132) Dirty. VEGF high-performance pancreatic cancer cells (KP-1) suspended in PBS at a concentration of 7 X 1〇7/ml /VEGF), directly transplanted into the head of the pancreas with a volume of 1 ml. From 4 weeks after transplantation, the test substance was orally administered for 1 week on a 5 day schedule. The substance to be tested became 〇 · The dosage of 1 ml/1 〇g body weight is suspended in 0.5% methylcellulose. During this period, the body weight is measured, twice a week, and the ascites is observed from the outside. It was stored and recorded. During the survival period, the number of dead mice at the end of the experiment was accumulated. Further, the tumor weight was determined for the individual who could be examined after death. Further, the experiment was carried out within a range of 8 to 1 1 of 1 group. Industrial Applicability According to the present invention, it has the following effects: (1) For epithelial cell proliferation factor (abbreviated as EGF) / VEGF / fibroblast growth factor (abbreviated as hepatocyte proliferation factor (HGF) / tumor necrosis) Factor α (abbreviated as TNF-α) constitutes a potent inhibitory effect on the infiltration of vascular endothelial cells induced by angiogenic factor mixture, and (2) for angiogenic factors alone (eg VEGF, FGF and HGF) TB-induced vascular endothelial cell luminal formation has a strong inhibitory effect, and (3) has a strong inhibitory effect on various angiogenic factors, and can provide novelty that is highly useful in medicine. Compound. Further, from the group of compounds having the above-described effects (1) to (3), a compound group having a growth inhibitory action of tumor cells can also be provided. Further, it is known that angiogenesis in the body is performed by a single angiogenic factor, but by the addition and multiplication of a plurality of angiogenic factors ((l) Koolwijk Ρ, van Erck MGM, De Vree WJA,Vemeer -138- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 -

AT B7 五、發明説明（133) MA, Weich HA, Hane maaijer R，van Hinsbergh VWM. Cooperative effect of TNF-alpha, bFGF and VEGF on the formation of tubular structures of human microvascular endothelial cells in a fibrin matrix, Role of urokinase activity. J. Cell Biol. 1996, 132, P1 177- 1 188 ； (2) Tallquist MD, Soriano P, Klinghoffer RA. Growth factor signaling pathways in vascular development. Oncogene 1999, 18, P7917-7932)。 因此，對於癌細胞產生之複數個血管新生因子誘導之管 腔形成具有抑制作用之本發明化合物，可以期待在身體中 顯示強力的血管新生抑制作用，為極有用的血管新生抑制 劑。又，本發明化合物，可以作為血管新生抑制作用能發 揮效用之疾病之預防及治療劑，血管新生抑制劑，抗腫瘤 劑，血管腫瘤治療劑，癌轉移抑制劑，網膜血管新生症治 療劑或糖尿/病性網膜症治療劑，炎症性疾病治療劑，包含 變形性關節炎、風濕性關節炎、乾癬或延遲性過敏反應之 炎症性疾病之治療劑，粥腫性動脈硬化症治療劑，以及依 憑血管新生抑制作用之抗腫瘤劑。 (實施例） 藉由以下之實施例詳細及具體地說明本發明，但本發明 不限於此等實施例。 [製造例] 製造例1 : 2-(3-氣丙某）-1,2,3-三唑（製造例1-八） -139- 本纸張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 1304061 ' ，A7 __B7 五、發明説明(^^ &quot; 1- (3-氯丙基）-1，2,3-_三唑i告你丨 將氫化鈉（1.55 g’ 30.8301 mmol，60%(在油中））懸浮於 己烷後放置’在除去上清液者中添加二甲基甲醯胺（25 ml) 並使之懸浮’於冰冷卻下在其中滴入1H-1，2,3 -三峻（1.5 ml，25.8867 mmol)。於室溫攪摔5分鐘，使其完全溶解 後，加入1-溴-3-氯丙烷（2.82 m卜28.4754 mmol)並於室溫 擾拌8小時。於冰冷卻下加入水，用乙醚及乙酸乙酯接續萃 取，用飽和食鹽水洗淨，用無水硫酸鎂乾燥及減壓餾去溶 媒後，用NH矽凝膠管柱層析（己烷-乙酸乙酯）分離異構體 及精製，分別得到為無色油狀物之低極性2-(3-氯丙基）· 1，2,3·三唑（0.429 g，2.9466 mmol，11.3 8% )以及高極性ΙΟ-氯丙基）-1 ，2,3-三唑 （0.910 g ， 6.2504 mmol ， 24.15% ) 。 2- (3_氯丙基）-1，2,3-三唑（製造例1-八） lH-NMR光譜（CDCl3)5(ppm): 2.42 (2H，tt，J=6.4 Ηζ，6·4 Hz), 3·54 (2H，W=6.4 Hz), 4·64 (2H，t，J=6.4 Hz), 7·61 (2H，s) 〇 1-(3-氯丙基）-1，2,3-三唑（製造例卜B) ·、 W-NMR 光譜（CDCl3)(5(ppm): 2·41 (2H，m)，3·52 (2H，d， J=6.0 Hz), 4.60 (2H, d, J=6.4 Hz), 7.61 (1H, d, J=0.8 Hz), 7·72 (1H，d，J=0.8 Hz)。 製造例2 1 ·氪-3 - (4- p比咬基）丙燒 將 3-( 4-吡啶基）-1-丙醇（2.68 g，19.3724 mmol)溶於二氯 甲烷（100 ml)中，加入三苯膦（5.6 g，21:.3096 mmol)，繼而 於冰冷下，慢慢加入N-氯琥珀醯亞胺（2·6 g，19.3724 -140 -_ 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 發明説明（135) mmol) ’並將其以原樣攪掉整夜。減壓餾去溶媒後，將殘 餘物溶於乙酸乙酯中，及用1N鹽酸萃取。將其用飽和碳酸 氣納水溶液中和後，用乙酸乙酯萃取，用飽和食鹽水洗 淨’用供水硫酸鎂乾燥及減壓餾去溶媒後，得到為黃褐色 油狀物之標題化合物（2 375 g，15 26〇5 mm&quot; , 78·77%)。 其於未精製下用於接下來之反應。 H-NMR 光瑨（CDCl3)5(ppm)·· 2·11 (2H, m)，2·80 (2H，t， J=7.6 Hz), 3.54 (2H, t, J=6.4 Hz), 7.14 (2H, dd, J=1.6 Hz, 4.4 Hz)，8.52 (2H, dd, J=1.6 Hz，4.4 Hz)。 製造合·Π 生-胺某-3 -氣齡 將3-氟-4-硝基酚（5.0 g , 31.83 mmol)溶於乙酸乙酯（5〇 ml)及四氫呋喃（75 ml)，加入鈀/碳（2〇 g),在氫蒙氣及室 溫下揽拌8.5小時。濾去觸媒，用乙醇洗淨後，減壓餾去溶 媒’將得到/之結晶加至己烷：乙醇=! : i中以洗淨。遽取 結晶，用乙醚洗淨及吸引乾燥，得到為凌黃色結晶之標題 化合物（1·62 g，12.74 mmol，40.61%)。 1H-NMR光譜（DMSO-d6)5(ppm): 4.35 (1H，br s)，6.32 (ΙΗ dd，J=2.4 Hz，8.4 Hz), 6.39-6.45 (1H，m)，6·57 (1H，dd， J=8.4 Hz，10.4 Hz)。 ’ 製造例4 2,4-二氟苯基）- Ν’ - (2-氣-4-與笨某）3尿 將4-胺基-3 -氟硝基酚（500 mg，3.9335 mmol)溶於四氫吱 喃（15 ml)中’滴入2，4- 一氟異讯酸g旨（0.56 ml，47199 -141 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 五、發明説明（AT B7 V. Inventions (133) MA, Weich HA, Hane maaijer R, van Hinsbergh VWM. Cooperative effect of TNF-alpha, bFGF and VEGF on the formation of tubular structures of human microvascular endothelial cells in a fibrin matrix, Role of Urokinase activity. J. Cell Biol. 1996, 132, P1 177- 1 188; (2) Tallquist MD, Soriano P, Klinghoffer RA. Growth factor signaling pathways in vascular development. Oncogene 1999, 18, P7917-7932). Therefore, the compound of the present invention having an inhibitory effect on the formation of a plurality of angiogenic factors induced by cancer cells can be expected to exhibit potent angiogenesis inhibitory action in the body, and is an extremely useful angiogenesis inhibitor. Further, the compound of the present invention can be used as a prophylactic and therapeutic agent for diseases in which angiogenesis inhibitory effects can be exerted, an angiogenesis inhibitor, an antitumor agent, a vascular tumor therapeutic agent, a cancer metastasis suppressor, a retinal angiogenesis therapeutic agent or diabetes / disease retinopathy therapeutic agent, inflammatory disease therapeutic agent, therapeutic agent including inflammatory disease of deformed arthritis, rheumatoid arthritis, dryness or delayed allergic reaction, therapeutic agent for atherosclerotic arteriosclerosis, and relieving An anti-tumor agent that inhibits angiogenesis. (Examples) The present invention will be specifically and specifically described by the following examples, but the present invention is not limited to the examples. [Production Example] Production Example 1: 2-(3-Acetophenone)-1,2,3-triazole (Production Example 1-eight) -139- This paper scale is applicable to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) 1304061 ', A7 __B7 V. Description of the invention (^^ &quot; 1- (3-chloropropyl)-1,2,3-_triazole i tells you that sodium hydride (1.55 g' 30.8301 mmol, 60% (in oil)) After suspension in hexane, place 'In the supernatant, add dimethylformamide (25 ml) and suspend it. Under ice cooling, drop 1H into it. -1,2,3 - Sanjun (1.5 ml, 25.8867 mmol). After stirring for 5 minutes at room temperature, after completely dissolving, add 1-bromo-3-chloropropane (2.82 m b 28.4754 mmol) and room The mixture was stirred for 8 hours, and water was added thereto under ice-cooling. The mixture was extracted with diethyl ether and ethyl acetate and washed with brine, dried over anhydrous magnesium sulfate and evaporated to remove solvent. The isomers were separated (hexane-ethyl acetate) and purified to give the crude, 2-(3-chloropropyl)·1,2,3·triazole (0.429 g, 2.9466 mmol) as a colorless oil. , 11.3 8%) and high polarity ΙΟ-chloropropyl)-1,2,3- Oxazole (0.910 g, 6.2504 mmol, 24.15%). 2-(3-chloropropyl)-1,2,3-triazole (manufacturing example 1-eight) lH-NMR spectrum (CDCl3) 5 (ppm): 2.42 (2H, tt, J = 6.4 Ηζ, 6· 4 Hz), 3·54 (2H, W=6.4 Hz), 4·64 (2H, t, J=6.4 Hz), 7·61 (2H, s) 〇1-(3-chloropropyl)-1 , 2,3-triazole (manufacturing example B) ·, W-NMR spectrum (CDCl3) (5 (ppm): 2·41 (2H, m), 3·52 (2H, d, J = 6.0 Hz) , 4.60 (2H, d, J = 6.4 Hz), 7.61 (1H, d, J = 0.8 Hz), 7·72 (1H, d, J = 0.8 Hz). Manufacturing Example 2 1 ·氪-3 - (4 -p-biti-propyl)-propanol 3-(4-pyridyl)-1-propanol (2.68 g, 19.3724 mmol) was dissolved in dichloromethane (100 ml) and triphenylphosphine (5.6 g, 21: .3096 mmol), and then slowly add N-chloroammonium iodide (2·6 g, 19.3724 -140 -_) on paper temperature. This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm). 1304061 A7 Description of the invention (135) mmol) 'The mixture was stirred overnight. The residue was dissolved in ethyl acetate and extracted with 1N hydrochloric acid. After neutralizing the aqueous solution, it is extracted with ethyl acetate and washed with saturated brine. The title compound (2 375 g, 15 26 〇 5 mm &quot;, 78·77%) was obtained as a tan oil. The product was used in the next reaction. H-NMR 瑨 (CDCl3) 5 (ppm) · · 2·11 (2H, m), 2·80 (2H, t, J = 7.6 Hz), 3.54 (2H, t, J = 6.4 Hz), 7.14 (2H, dd, J=1.6 Hz, 4.4 Hz), 8.52 (2H, dd, J=1.6 Hz, 4.4 Hz). Manufactured Π·Π-amine-3 - gas age 3-fluoro-4- Nitrophenol (5.0 g, 31.83 mmol) was dissolved in ethyl acetate (5 mL) and tetrahydrofuran (75 ml). Palladium/carbon (2 g) was added and the mixture was stirred at room temperature for 8.5 hours. The catalyst was filtered off, washed with ethanol, and the solvent was distilled off under reduced pressure. The crystals obtained were added to hexane: ethanol =: : i to be washed. The crystals were taken, washed with diethyl ether and dried with suction to obtain The title compound (1·62 g, 12.74 mmol, 40.61%). 1H-NMR spectrum (DMSO-d6) 5 (ppm): 4.35 (1H, br s), 6.32 (ΙΗ dd, J = 2.4 Hz, 8.4 Hz), 6.39-6.45 (1H, m), 6·57 (1H , dd, J = 8.4 Hz, 10.4 Hz). 'Manufacturing Example 4 2,4-Difluorophenyl)- Ν' - (2-Ga-4- and Benz) 3 Urine 4-Amino-3-fluoronitrophenol (500 mg, 3.9335 mmol) dissolved 'Instillation of 2,4-fluorois acid in tetrahydrofuran (15 ml) (0.56 ml, 47199-141 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) ) 1304061 V. Description of invention (

A7 B7A7 B7

mmol)，並於氮蒙氣下加熱回流1小時。放冷後減塾館去溶 媒，將得到之結晶加至己烷：乙醇=丨··丨中以洗淨。濾取 結晶，用己烷：乙醇=1 : 1洗淨及吸引乾燥，得到為淡紫 色結晶之標題化合物（960 mg，3·4〇ΐ6 mm〇b 86 48% )。 iH-NMR 光譜（DMSO-d6)5(ppm): 6.54 (1H，m)，6.60 (1H， ddd, J=2.4 Hz, 2.4 Hz, 8.8 Hz), 7.00 (1H, m), 7.27 (1H, ddd, J=2.8 Hz, 9.0 Hz, 11.6 Hz), 7.69 (1H, m), 8.07 (1H, ddd, J=6.0 Hz, 9.0 Hz, 9.0 Hz), 8.53 (1H, s), 8.72 (1H, s)3 9.56 (1H，s)。 ，， 製造例5 7·宇氧基-6-银基-4- (4·瑞基苯氧基）〃杳说 在W0 98/ 13350記載之7-苄氧基-心氯-6·氰基喹啉（2.6〇 g，8.83 mmol)中，加入4-硝基酚（2·46 g , 17 7 mm〇1)及二 甲基叶1：淀（2·06 ml ’ 17.7 mmol)，並於 i55- 158 °C 攪:掉 2 小 時。使反應〜系統回到室溫後，溶解於四氫呋喃中，加入飽 和碳酸氫鈉水溶液並擾拌1 0分鐘，減恩濃縮，遽取析出之 固體，加至矽凝膠層析管柱中（富士希利希亞NH型，溶出 液：己烷：乙酸乙酯50 : 50—只有乙酸乙酯），濃縮包含目 的物之溶出液’然後將所得固體用乙駿洗淨。減壓乾燥， 得到標題化合物（1.84 g，4.63 mmol，52.6%)。 1 H-NMR光譜（DMSO-d6) 5 (ppm): 5.48 (2H，s)，0.89 (1H d J=6.1 Hz), 7.30-7.60 (8H, m), 7.78 (1H, s), 8.36-8.41 (2H, m), 8.80 (1H, s), 8.85 (1H, d, J=6.1 Hz) ^ 製造例6 142- 一· -----* 本紙張尺度適用中國國家標準(CMS) A4規格(210x 297公釐) 1304061 A7 B7 五、發明説明（137) 胺基本乳基卞氧基）-6-氣基?奎琳 在製造例.5所得之7-苄氧基-6-氰基-4- (4-硝基苯氧基）喹 啉中，加入鐵粉（0.6 g)，氯化銨（1.4 g)，乙醇（100 ml)及 水（30 ml)中，並於90°C攪拌2.5小時。使反應系統回到室溫 後，經矽藻土過濾，將濾液分液，將有機層用水及飽和食 鹽水依次洗淨及用硫酸鈉乾燥後，減壓濃縮乾固，得到包 含目的物之粗製物1 ·3 1 g。該粗製物以原樣用於下一反應 (製造例7)。 iH-NMR 光譜（CDCl3)5(ppm)·· 3·75 (2H，b〇，5·35 (2H，s)， 6.46 (1Η, d, J=5.2 Hz), 6.75-6.78 (2H, m), 6.94-6.97 (2H, m), 7.35 (1H, d, J=7.6 Hz), 7.42 (2H, t, J=6.8 Hz), 7.50-7.55 (3H, m)，8.63 (1H，d，J=5.2 Hz)，8·72 (1H，s) 〇 製造例7 K爷氧基6-氨基-4-(3-最·-4-硝某茇氣某、g争毗 將WO 98413350記載之7-芊氧基-4-氯-6-氰基喹啉（8·82 g，30·0 mmol)懸浮於1-曱基吡咯啶酮（3ΰ ml)中，加入3-氟-4-硝基酚（5.18 g，33.0 mmol)及Ν,Ν-二異丙基乙胺（3.88 g，30.0 mmol)，然後於ll〇°C加熱攪拌4小時Μ吏反應系統 回到室溫後加入水，以使固體析出。濾取得到之固體，用 水’甲醇及乙酸乙酯洗淨後，於60°C乾燥，得到為無色結 晶之標題化合物（4·98 g，12.0 mmol , 40% )。 iH-NMR 光譜（CDCl3)5(ppm): 5·37 (2H，s)，6·73 (1H，d， J=5.2 Hz), 7.07-7.13 (2H, m), 7.33-7.45-(3H, m), 7.50-7.56 (2H, m), 7.60 (1H, s), 8.21-8.27 (1H, m), 8.55 (1H s), 8.83 一 -143- 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） 1304061 二 、- A7 _— B7_____ 五、發明説明（138) (1H，d, J=5.2 Hz) 〇 製造例8 7二y氧基基-4-(3-氟-4-胺基苽氣基被· 將製造例7得到之7-苄氧基-6-氰基-4- (3-氟-4-硝基苯氧 基）喹啉（5·3〇 g，12.8 mmol)，鐵（3.57 g，64.0 mmol)及氯 化銨（6·85 g，128 mmol)懸浮於乙醇（120 ml)-水（30 ml)之 混合溶媒中，並於100。(：加熱攪摔3小時。反應終了後，反 應混合物經矽藻土過濾，用乙酸乙酯（5〇〇 ml)-N，N-二甲基 曱醯胺DMF(50 ml)之混合溶媒沖洗。將有機層用水及飽和 食鹽水洗淨，用硫酸鎂乾燥後濃縮。將得到之固體從乙酸 乙醋-己烷之混合溶媒中再結晶後乾燥，得到為淡褐色結晶 之才衣題化合物（2.53 g，6.56 mmol，51%)。 1H-NMR光譜（CDCl3)5(ppm)·· 3.80 (2H，br s)，5·35 (2H，s)， 6·48 (1Η，d，J=5.3 Ηζ)，6.78-6.90 (3Η，m)，7.32-7.44 (3Η，m)， 7.51 (1H, 7.52-7.56 (2H, m), 8.66 (1H, d, J=5.3 Hz), 8.69 (1H，S)。 ·、 製造例9 氰基-7-(2·甲氧基乙氧基）-4-( 4-硝某茉氳某V杏啉 將4-氯-6-氰基- 7-(2-甲氧乙氧基）喹啉（3 g)與4-硝基酚 (3.17 g)及2,6-二甲基0比咬（2 ·7 ml)之混合物在油浴中於155 C加熱攪掉1 · 5小時。反應終了後，添加乙酸乙酯，使固體 析出並濾取之。將固體用1N氫氧化鈉水溶液沖洗，水洗後 乾燥，得到標題化合物1.8 g。 二 lH-NMR (DMSO-d6) (5 (ppm): 3.36 (3H, s), 3.76-3.79 (2H, m), -144- 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 、 …- A7 B7 五、發明説明（I39 ) 4.41-4.44 (2H, m), 6.85 (1H, d, J=5.2 Hz), 7.54 (2H, d, J=9.2 Hz), 7.68 (1H, s), 8.37 (2H, d, J=9.2 Hz), 8.74 (1H, s), 8.83 (1H，d，J=5.2 Hz)。(mmol), and heated to reflux under nitrogen for 1 hour. After cooling, reduce the solvent to the solvent, and add the crystals to hexane: ethanol = 丨·· 丨 to wash. The crystals were filtered, washed with EtOAc EtOAc (EtOAc) iH-NMR spectrum (DMSO-d6) 5 (ppm): 6.54 (1H, m), 6.60 (1H, ddd, J = 2.4 Hz, 2.4 Hz, 8.8 Hz), 7.00 (1H, m), 7.27 (1H, Ddd, J=2.8 Hz, 9.0 Hz, 11.6 Hz), 7.69 (1H, m), 8.07 (1H, ddd, J=6.0 Hz, 9.0 Hz, 9.0 Hz), 8.53 (1H, s), 8.72 (1H, s) 3 9.56 (1H, s). , Production Example 5 7-Oxyl-6-silveryl-4-(4-renylphenoxy)anthracene 7-benzyloxy-cardochlor-6-cyano group described in WO 98/13350 4-quinolol (2.6 g, 17 7 mm 〇1) and dimethyl leaf 1: lake (2·06 ml ' 17.7 mmol) were added to quinoline (2.6 g, 8.83 mmol). I55- 158 °C Stir: 2 hours off. After the reaction system was returned to room temperature, it was dissolved in tetrahydrofuran, saturated aqueous sodium hydrogencarbonate solution was added and spoiled for 10 minutes, concentrated and concentrated, and the precipitated solid was taken and added to the column of the gel column (Fuji Helicia NH type, eluate: hexane: ethyl acetate 50: 50 - ethyl acetate only, concentrate the eluate containing the desired product' and then wash the resulting solid with acetyl chloride. The title compound (1.84 g, 4.63 mmol, 52. 1 H-NMR spectrum (DMSO-d6) 5 (ppm): 5.48 (2H, s), 0.89 (1H d J = 6.1 Hz), 7.30-7.60 (8H, m), 7.78 (1H, s), 8.36- 8.41 (2H, m), 8.80 (1H, s), 8.85 (1H, d, J=6.1 Hz) ^ Manufacturing Example 6 142- I· -----* This paper scale applies to the Chinese National Standard (CMS) A4 Specification (210x 297 mm) 1304061 A7 B7 V. INSTRUCTION DESCRIPTION (137) Amine basic aryl methoxy)-6- carbyl quinine The 7-benzyloxy-6-cyano group obtained in the production example 5. -4- (4-nitrophenoxy)quinoline, adding iron powder (0.6 g), ammonium chloride (1.4 g), ethanol (100 ml) and water (30 ml) at 90 ° C Stir for 2.5 hours. After the reaction system was returned to room temperature, the mixture was filtered through celite, and the filtrate was separated. The organic layer was washed with water and saturated brine and dried over sodium sulfate. 1 · 3 1 g. This crude material was used as it is in the next reaction (Production Example 7). iH-NMR spectrum (CDCl3) 5 (ppm)··3·75 (2H, b〇, 5·35 (2H, s), 6.46 (1Η, d, J=5.2 Hz), 6.75-6.78 (2H, m ), 6.94-6.97 (2H, m), 7.35 (1H, d, J=7.6 Hz), 7.42 (2H, t, J=6.8 Hz), 7.50-7.55 (3H, m), 8.63 (1H,d, J=5.2 Hz),8·72 (1H,s) 〇Manufacturing Example 7 K-oxy 6-amino-4-(3-most·-4-nitrogen oxime, g contiguously described in WO 98413350 7-Methoxy-4-chloro-6-cyanoquinoline (8·82 g, 30·0 mmol) was suspended in 1-decylpyrrolidone (3 ΰ ml), and 3-fluoro-4-nitrate was added. Phenol (5.18 g, 33.0 mmol) and hydrazine, hydrazine-diisopropylethylamine (3.88 g, 30.0 mmol), then heated and stirred at ll ° ° C for 4 hours. The reaction system was returned to room temperature and water was added. The title compound (4.98 g, 12.0 mmol, 40%) was obtained as colorless crystals. NMR spectrum (CDCl3) 5 (ppm): 5·37 (2H, s), 6.73 (1H, d, J = 5.2 Hz), 7.07-7.13 (2H, m), 7.33-7.45-(3H, m ), 7.50-7.56 (2H, m), 7.60 (1H, s), 8.21-8.27 (1H, m), 8.55 (1H s), 8.83 one-143- paper Applicable to China National Standard (CNS) A4 specification (21〇x 297 mm) 1304061 II.- A7 _- B7_____ V. Description of invention (138) (1H,d, J=5.2 Hz) 〇Manufacturing example 8 7 y Alkyl-4-(3-fluoro-4-aminoindole group) 7-Benzyloxy-6-cyano-4-(3-fluoro-4-nitrophenoxy) obtained in Production Example 7. Quinoline (5·3〇g, 12.8 mmol), iron (3.57 g, 64.0 mmol) and ammonium chloride (6·85 g, 128 mmol) suspended in ethanol (120 ml)-water (30 ml) In a mixed solvent, and at 100 ° (: heating and stirring for 3 hours. After the reaction is finished, the reaction mixture is filtered through celite, using ethyl acetate (5 〇〇ml)-N,N-dimethyl decylamine DMF (50 ml) was mixed with a solvent, and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated. The obtained solid was recrystallized from a mixed solvent of ethyl acetate-hexane and dried to give the title compound (2.53 g, 6.56 mmol, 51%). 1H-NMR spectrum (CDCl3) 5 (ppm)·· 3.80 (2H, br s), 5·35 (2H, s), 6·48 (1Η, d, J=5.3 Ηζ), 6.78-6.90 (3Η, m), 7.32-7.44 (3Η, m), 7.51 (1H, 7.52-7.56 (2H, m), 8.66 (1H, d, J=5.3 Hz), 8.69 (1H, S) ·, Manufacturing Example 9 Cyanide -7-(2.methoxyethoxy)-4-(4-nitrogen, a certain apricot, 4-chloro-6-cyano-7-(2-methoxyethoxy)quine A mixture of porphyrin (3 g) and 4-nitrophenol (3.17 g) and 2,6-dimethyl 0 to bite (2. 7 ml) was stirred in an oil bath at 155 C for 1.5 hours. After the end, ethyl acetate was added, and the solid was separated and filtered, and the solid was washed with 1N aqueous sodium hydroxide, washed with water, and dried to give the title compound 1.8 g. 2H-NMR (DMSO-d6) (5 (ppm) : 3.36 (3H, s), 3.76-3.79 (2H, m), -144- This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 , ...- A7 B7 V. Description of invention (I39) 4.41-4.44 (2H, m), 6.85 (1H, d, J=5.2 Hz), 7.54 (2H, d, J=9.2 Hz), 7.68 (1H, s), 8.37 (2H, d, J =9.2 Hz), 8.74 (1H, s), 8.83 (1H, d, J = 5.2 Hz).

Jji 例 i卫· ../ zu(4 -胺基笨氣基6-¾基- 7-(2-甲氣基乙氣基）岭说 將6-氰基-7-( 2-甲氧基乙氧基）-4-(4-硝基苯氧基）u奎啉 (1.8 g)，鐵（1.8 g)及氯化銨（3·6 g)懸浮於乙醇（30 ml)-水 (7 ml)之混合溶媒中，並於80°C加熱攪拌2小時。反應終了 後，反應混合物經矽藻土過濾，用乙酸乙酯洗出。將有機 層用飽和食鹽水洗淨，用硫酸鎂乾燥及濃縮。將得到之固 體用乙醚洗淨及乾燥，得到1 ·2 g標題化合物。 ^-NMR (DMSO-d6) 5 (ppm): 3.36 (3H, s), 3.75-3.78 (2H, m), 4.38-4.41 (2H, m), 5.19 (2H, brd), 6.45 (1H, d, J=5.2 Hz), 6.65 (2H, d, J=8.8 Hz), 6.93 (2H, d, J=8.8 Hz), 7.59 (1H, s), 8.68 (1H, dr、J=5.2 Hz), 8.71 (1H，s)。 製造例1 1 、 6-氨某-4-(3-氩-4-硝某茉氳基7-(2-甲氩某乙氣某V杳啉 將4-氯-6-氰基-7-(2-甲氧基乙氧基）喹啉（1.7 g)及3-氟-4-硝基酚（2.0 g)懸浮於氯苯（20 ml)中並加熱回流6小時。 反應終了後餾去溶媒，加入醋酸乙酯，然後析出固體。濾 取得到之固體，用乙謎洗後，用1N氫氧化鈉水溶液洗淨， 再用水洗及乾燥，得到1.55 g標題化合物。 ^-NMR (DMSO-d6)&lt;5(ppm): 3.38 (3H, s*), 3.78-3.81 (2H, m)5 4.44-4.47 (2H, m), 7.02 (1H, d, J=5.2 Hz), 7.33-7.37 (1H, m), -145- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 ------ B7Jji Example i. . . / zu (4-amino-based stupid group 6-3⁄4yl-7-(2-methyl-glycolyl)-based 6-cyano-7-(2-methoxy Ethoxy)-4-(4-nitrophenoxy)uquinoline (1.8 g), iron (1.8 g) and ammonium chloride (3.6 g) suspended in ethanol (30 ml)-water (7 In a mixed solvent of ml), the mixture was heated and stirred at 80 ° C for 2 hours. After the reaction was completed, the reaction mixture was filtered over EtOAc (EtOAc)EtOAc. The resulting solid was washed with diethyl ether and dried to give 1 g of the title compound. NMR (DMSO-d6) 5 (ppm): 3.36 (3H, s), 3.75-3.78 (2H, m) , 4.38-4.41 (2H, m), 5.19 (2H, brd), 6.45 (1H, d, J=5.2 Hz), 6.65 (2H, d, J=8.8 Hz), 6.93 (2H, d, J=8.8 Hz), 7.59 (1H, s), 8.68 (1H, dr, J=5.2 Hz), 8.71 (1H, s). Manufacturing Example 1 1 , 6-Ammonia-4-(3-argon-4-nitrate) Molybdenyl 7-(2-methyl argon, a certain V porphyrin, 4-chloro-6-cyano-7-(2-methoxyethoxy)quinoline (1.7 g) and 3-fluoro- 4-Nitrophenol (2.0 g) was suspended in chlorobenzene (20 ml) and heated to reflux for 6 hours. After the reaction was completed, the solvent was distilled off and vinegar was added. Ethyl ester, then solid was precipitated. The solid obtained was filtered, washed with EtOAc, EtOAc EtOAc (EtOAc) 5 (ppm): 3.38 (3H, s*), 3.78-3.81 (2H, m)5 4.44-4.47 (2H, m), 7.02 (1H, d, J=5.2 Hz), 7.33-7.37 (1H, m ), -145- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 ------ B7

7.69 (1H, dd, J=2.8 Hz, J=12 Hz), 7.72 (1H, s), 8.33 (1H, t5 j=8.8 Hz)，8·75 (1H，s), 8·88 (1H, d，J=5.2 Hz)。jjji &lt;H 12 土4-胺基：3--氣氧.基）-6-氰基-K2-甲氣某j氣某争毗 以與製造例10同樣之方式，從製造例11得到之硝基體 (1.5 5 g)得到1.23 g標題化合物。 ^-NMR (DMSO-d6) δ (ppm): 3.3 8 (3H, s), 3.78-3.81 (2H, m), 4.42-4.44 (2H, m), 5.25-5.27 (2H, brd), 6.54 (1H, d, J=5 2 Hz), 6.87-6.89 (2H, m), 7.10-7.14 (1H, m), 7.62 (1H, s), 8.72 (1H，d，J=5.2 Hz), 8·74 (1H，s)。 ¥造例13 蜃某-7-甲氣基硝基茉氫某&amp; 將與製造例7同樣之方式得到之4-氯-6-氰基-7-甲氧基44(0.35 g) ’ 4-硝基紛（0.36 g)與 2,6-二甲基p 比淀（〇·25 ml) 之混合物在〃使用油浴下，在170°C加熱攪拌。反應終了後， 在反應混合物中加入水及乙酸乙S旨以萃取。將有機戶用飽 和碳酸氫鈉水溶液及飽和食鹽水洗淨，用疏^酸鎂^乾燥及濃 縮，將得到之殘餘物加至NH矽凝膠管柱（富士希利希亞化 學公司）中’用溶媒（乙酸乙酯-己烷===12)溶出及濃縮，得 到0.2 g標題化合物。 ^-NMR (DMSO-d6) &lt;5 (ppm): 4.06 (3H, s), 6.87 (1H, d, J=5.6 Hz), 7.54 (2H, d, J=8.8 Hz), 7.65 (lH, s), 8.36 (2H, d, J=8.8 Hz), 8.75 (1H，s)，8.84 (1H，d, J=5r.6 Hz)。 製造例14 -146- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）7.69 (1H, dd, J=2.8 Hz, J=12 Hz), 7.72 (1H, s), 8.33 (1H, t5 j=8.8 Hz), 8·75 (1H, s), 8·88 (1H, d, J = 5.2 Hz). Jjji &lt;H 12 soil 4-amino group: 3--oxygen. group)-6-cyano-K2-methyl gas A certain gas was obtained in the same manner as in Production Example 10, and was obtained from Production Example 11. The nitro group (1.55 g) gave 1.23 g of the title compound. ^-NMR (DMSO-d6) δ (ppm): 3.3 8 (3H, s), 3.78-3.81 (2H, m), 4.42-4.44 (2H, m), 5.25-5.27 (2H, brd), 6.54 ( 1H, d, J=5 2 Hz), 6.87-6.89 (2H, m), 7.10-7.14 (1H, m), 7.62 (1H, s), 8.72 (1H,d,J=5.2 Hz), 8· 74 (1H, s). Manufacture Example 13 蜃-7-Methane-nitro-nitrogen hydrogen &amp; 4-chloro-6-cyano-7-methoxy 44 (0.35 g) '4 obtained in the same manner as in Production Example 7. A mixture of -nitrogen (0.36 g) and 2,6-dimethyl p-precipitate (〇·25 ml) was heated and stirred at 170 ° C under an oil bath. After the end of the reaction, water and acetic acid B were added to the reaction mixture for extraction. The organic household was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried and concentrated with magnesium sulfate, and the residue was applied to the NH(s) gel column (Fuji Hilithia Chemical Co.) It was dissolved and concentrated with a solvent (ethyl acetate-hexane ===12) to give 0.2 g of the title compound. ^-NMR (DMSO-d6) &lt;5 (ppm): 4.06 (3H, s), 6.87 (1H, d, J = 5.6 Hz), 7.54 (2H, d, J = 8.8 Hz), 7.65 (lH, s), 8.36 (2H, d, J = 8.8 Hz), 8.75 (1H, s), 8.84 (1H, d, J = 5r.6 Hz). Manufacturing Example 14 -146- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂Binding

線 1304061 、-· A7 B7五、發明説明（141) 4“4-胺基笨氣基V 6-氨基-7-甲氣基4啉 以與製造例1〇同樣之方法，從6-氰基-7-甲氧基-4-(4-硝 基苯氧基）喹啉（0.2 g)得到0.17 g標題化合物。 ^-NMR (DMSO-d6) (5 (ppm): 4.06 (3H, s), 5.15-5.20 (2H, τη), 6.46 (1H, d, J=5.6 Hz), 6.66 (2H, d, J=8,8 Hz), 6.93 (2H, d, J=8.8 Hz), 7.56 (1H, s), 8.69 (1H, d, 1=5.6 Hz), 8.71 (1H, s)。 製造例1 5 6-氨基-4-(3-氣-4-硝基笨氣基）-7-甲氣基4啉 以與製造例13同樣之方法，從與製造例7同樣之方法得到 之4-氯-6-氰基-7-甲氧基哇啉（0.5 g)，得到0.33 g標題化合 物。 !H-NMR (DMSO-d6) δ (pprn): 4.07 (3H, s), 7.00 (1H, d, J=5.2 Hz), 7.30-7.34 (1H, m), 7.65 (1H, dd, J=2.8 Hz, J=12 Hz)3 7.66 (1Ή, s), 8.30 (1H, t, J=8.8 Hz), 8.72 (1H, s), 8.87 (1H, d, J=5.2 Hz)。 、 製造例1 6 4“ 4-胺基-3-氟笨氣基6-氰基-7-甲氣基4·啉 以與製造例1 0同樣之方法，從6-氰基-4- ( 3-氟-4-硝基苯 氧基）-7-曱氧基喹啉（0.32 g)得到0.24 g標題化合物。 lH-NMR (DMSO-d6) 5 (ppm): 4.06 (3H, s), 5.26 (2H, br s), 6.54 (1H, d, J=5.2 Hz), 6.85-6.91 (2H, m), 7.11 (1H, dd, J=2.0 Hz，11.2 Hz), 7.59 (1H，s)，8.72:(1H，d，J=5.2 Hz)， 8.73 (1H，s)。 -147- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（142) 製造例1 7 K 4“ 6-氨基-7“ 2-甲氣基乙氣基V4-嗥啉基）氣笨基）胺甲 酸笨酯 將製造例10得到之4-(4-胺基苯氧基）-6-氰基-7-(2-甲氧 基乙乳基）p奎琳（3.354 g，10·0 mmol)在氮蒙氣下溶解於二 甲基曱醯胺（35 ml)後，依次加入吡啶（2.43 ml，30.0 mmol) 及氣曱酸苯醋（1 ·38 ml，11 ·0 mmol)，然後於室溫攪掉3小 時。在反應液中加入水（40 ml)及濾取析出之結晶。將濾液 用乙酸乙酯萃取，然後將有機層用水及飽和食鹽水洗淨， 及用無水硫酸鈉乾燥。濾除乾燥劑及減壓濃縮，將得到之 結晶與先前之結晶合併懸浮於己垸/乙酸乙g旨（5 : 1)中，授 捽一夜後，濾取結晶及減壓乾燥，得到為淡褐色結晶之標 題化合物（4.334 g，9.52 mmol，95·2%)。 1H-NMR 光譜（CDCl3)(5(ppm): 3.53 (3Η，s)，3.91 (2Η，t， J—4.4 Hz), ^.38 (2H, t, J=4.4 Hz), 6.49 (1H, d, J=5.2 Hz) 7.07 (1H, br), 7.17-7.32 (5H, m), 7.40-7-.45 (2H, m)3 7.44 (1H, s), 7.59 (2H, d, J=8.8 Hz), 8.67 (1H, d, J=5.6 Hz), 8.7〇 (lH，s)。 ’ · 製造例1 8 氰基甲氧基乙氣某）_,杳啉某）氧 胺甲酸茉酯 將製造例12得到之4-(4-胺基-3-氟苯氧基）· 6-氰基-7·(2_ 甲氧基乙氧基）喹啉（2500 mg)溶解於二··甲基甲醯胺2〇毫升 及批啶1.7毫升中，以及在氮蒙氣下冷卻至。在其中加 -148-Line 1304061, -· A7 B7 V. Inventive Note (141) 4 "4-Amine-based gas-based V 6-amino-7-methyl alkyl 4 phenium in the same manner as in Production Example 1 from 6-cyano group -7-Methoxy-4-(4-nitrophenoxy)quinoline (0.2 g) gave 0.17 g of the title compound. NMR (DMSO-d6) (5 (ppm): 4.06 (3H, s) , 5.15-5.20 (2H, τη), 6.46 (1H, d, J=5.6 Hz), 6.66 (2H, d, J=8,8 Hz), 6.93 (2H, d, J=8.8 Hz), 7.56 ( 1H, s), 8.69 (1H, d, 1 = 5.6 Hz), 8.71 (1H, s). Production Example 1 5 6-Amino-4-(3- gas-4-nitrostene)-7- Methane-based 4 phenanthracene 4-chloro-6-cyano-7-methoxy morpholine (0.5 g) obtained in the same manner as in Production Example 7 to give 0.33 g of the title compound. !H-NMR (DMSO-d6) δ (pprn): 4.07 (3H, s), 7.00 (1H, d, J=5.2 Hz), 7.30-7.34 (1H, m), 7.65 (1H, dd, J =2.8 Hz, J=12 Hz)3 7.66 (1Ή, s), 8.30 (1H, t, J=8.8 Hz), 8.72 (1H, s), 8.87 (1H, d, J=5.2 Hz). Example 1 6 4 "4-Amino-3-fluoroindolyl 6-cyano-7-carboyl 4 porphyrin in the same manner as in Production Example 10, from 6-cyano-4-( 3- Fluoro-4-nitrophenoxy)-7-decyloxy The morpholine (0.32 g) gave 0.24 g of the title compound. MH-NMR (DMSO-d6) 5 (ppm): 4.06 (3H, s), 5.26 (2H, s s), 6.54 (1H, d, J = 5.2 Hz) , 6.85-6.91 (2H, m), 7.11 (1H, dd, J=2.0 Hz, 11.2 Hz), 7.59 (1H, s), 8.72: (1H, d, J = 5.2 Hz), 8.73 (1H, s -147- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (142) Manufacturing example 1 7 K 4" 6-Amino-7" 2-A Gas-based Ethyl-based V4-carboline-based (meth)pyrylamine carboxylic acid benzoate 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyl) obtained in Preparation Example 10乙乳基)p-Quinline (3.354 g, 10·0 mmol) was dissolved in dimethyl decylamine (35 ml) under nitrogen atmosphere, followed by the addition of pyridine (2.43 ml, 30.0 mmol) and benzoic acid benzene. Vinegar (1 · 38 ml, 11 · 0 mmol) was then stirred at room temperature for 3 hours. Water (40 ml) was added to the reaction mixture, and the precipitated crystals were filtered. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The obtained crystals were combined with the previous crystals and suspended in hexane/ethyl acetate (5:1). After one night of crystallization, the crystals were filtered and dried under reduced pressure to give a pale. The title compound (4.334 g, 9.52 mmol, 95. 2%). 1H-NMR spectrum (CDCl3) (5 (ppm): 3.53 (3 Η, s), 3.91 (2 Η, t, J - 4.4 Hz), ^.38 (2H, t, J = 4.4 Hz), 6.49 (1H, d, J=5.2 Hz) 7.07 (1H, br), 7.17-7.32 (5H, m), 7.40-7-.45 (2H, m)3 7.44 (1H, s), 7.59 (2H, d, J= 8.8 Hz), 8.67 (1H, d, J = 5.6 Hz), 8.7 〇 (lH, s). ' Manufacturing Example 1 8 cyanomethoxyethane _, porphyrin methoxy amide 4-(4-Amino-3-fluorophenoxy)·6-cyano-7·(2-methoxyethoxy)quinoline (2500 mg) obtained in Preparation Example 12 was dissolved in II·A 2 ml of carbamamine and 1.7 ml of batch pyridine, and cooled to nitrogen. Add -148-

1304061 _ A7 ____ B7 五、發明説明（143) 入氯锬酸苯ί旨0·97 ml，並於室溫攪捽2小時。在反應液中加 入乙酸乙酯及水並分溶於其中。然後將有機層用水及飽和 食鹽水依次洗淨及用無水硫酸鈉乾燥後’減壓濃縮，得到 3 · 7 g殘}查。將其溶於四氫吱喃後，加入正己燒，滤取析出 之固體，得到2.2 g (產率67%)為淡褐色結晶之標題化合 物。 W-NMR 光譜（CDC13) 5 (ppm): 3·36 (3H，s)，3.89-3.94 (2H， m)，4.34-4.39 (2Η，m), 6·52 (1Η，d，J=5.6 Ηζ)，7·01-7·06 (2Η， m)，7.21-7.30 (4H，m)，7·40-7·45 (2H，m)，7·49 (1H，s)，8·26 (1H，br s)，8·66 (1H，s)，8.70 (1H，d，J=5.6 Hz)。 製造例19 迓“4-(6-氰基-7-甲氲基-4-4啉基&gt;)氳茇某）胺甲酸苯酯 將製造例14得到之4-(4-胺基苯氧基）-6-氰基-7-甲氧基 喹啉（747 mg)溶解於二甲基甲醯胺7毫升及吡啶〇·34毫升 中，以及在^氮蒙氣下冷卻至〇°C。在其中加入氯碳酸苯酯 0·34 ml，並於室溫攪拌2小時。在反應液中加入乙酸乙酯及 水，濾取析出之固體，得到590 mg (產率56%)為淡褐色結 晶之標題化合物。 W-NMR光譜（DMSO-d6)5(ppm): 4.04 (3H，s)，6.52 (1H，d， J=5.6 Ηζ)，7·20·7·30 (5H，m)，7·40-7·46 (2H，m)，7.60 (1H， ' s), 7.62-7.68 (2H, m), 8.72 (1H, d, J=5.6 Hz), 8.75 (1H, s), 10.4 (1H，br s)。 製造例20 , 氣-4- (4-_硝基苯氩某）嘧啶 -149 - 本纸張尺度適用中國國冢S準(CNS) A4規格(210 x 297公 13040611304061 _ A7 ____ B7 V. INSTRUCTIONS (143) Into chlorohydric acid Benzene 0. 97 ml, and stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture and dissolved therein. Then, the organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 3 · 7 g residue. After dissolving it in tetrahydrofuran, it was added to a hexane, and the solid which precipitated was collected by filtration to give 2.2 g (yield: 67%) of the title compound as pale brown crystals. W-NMR spectrum (CDC13) 5 (ppm): 3·36 (3H, s), 3.89-3.94 (2H, m), 4.34-4.39 (2Η, m), 6·52 (1Η, d, J=5.6 Ηζ), 7·01-7·06 (2Η, m), 7.21-7.30 (4H, m), 7·40-7·45 (2H, m), 7·49 (1H, s), 8.26 (1H, br s), 8.66 (1H, s), 8.70 (1H, d, J = 5.6 Hz). Production Example 19 4- "4-(6-Cyano-7-methylindol-4-4 phenyl)&gt;) phenyl carbamic acid ester 4-(4-aminophenoxyl) obtained in Production Example 14 The group of 6-cyano-7-methoxyquinoline (747 mg) was dissolved in 7 ml of dimethylformamide and 34 ml of pyridinium, and cooled to 〇 ° C under nitrogen atmosphere. 0. 34 ml of phenyl chlorocarbonate was added thereto, and stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture, and the precipitated solid was collected by filtration to give 590 mg (yield: 56%) as pale brown crystal. The title compound. W-NMR spectrum (DMSO-d6) 5 (ppm): 4.04 (3H, s), 6.52 (1H, d, J = 5.6 Ηζ), 7·20·7·30 (5H, m), 7·40-7·46 (2H,m), 7.60 (1H, 's), 7.62-7.68 (2H, m), 8.72 (1H, d, J=5.6 Hz), 8.75 (1H, s), 10.4 (1H, br s). Production Example 20, gas-4-(4-nitrobenzene argon)-pyrimidine-149 - This paper scale is applicable to China National Standard S (CNS) A4 specification (210 x 297 public 1304061)

將4,6-二氯嘧啶（750 mg)於〇°C加至4-硝基酚（700 mg)及 氫化鈉（60%) (200 mg)懸浮於二甲基曱醯胺（13 ^1)之懸浮 液中’並於80°C加熱攪拌1.5小時。將反應液注入飽和食鹽 水中’以及用乙酸乙酯萃取。將有機層用硫酸鎂乾燥後濃 縮。對於殘餘物進行NH矽凝膠管柱層析（富士希利希亞化 學公司）’用溶媒（乙酸乙酯-己烷=1 - 4)溶出及濃縮，得到 700 mg標題化合物。 lH-NMR (DMSO-d6) (5 (ppm): 7.08 (1H, d, J=〇.8 Hz), 7.30-7.37 (2H，m)，8·32-8·36 (2H，m)，8,60 (1H，d，.j=0.8 Hz)。 製造例2 1 4-(心胺基氣茉氫基7-蕤基tr套淋-6-甲晚 在7-卞氧基-6-夜基-4-(3-氣-4-石肖基苯氧基）ϊ»奎淋2.6g 中，加入三氟乙酸26 ml及硫代苯甲醚2·6 m卜於70°C-72°C 擾摔1 5小時及返回室溫後’將反應系統濃縮，在殘餘物中 加入飽和碳》酸氫鈉水溶液及甲醇以及濾取析出之黃色結 晶。乾燥後，得到2.61 g結晶。在該結晶'之一部分640 mg 中，加入鐵950 mg，氯化铵1,8 g，乙醇10 ml，四氫17夫喃10 ml及水10 ml及回流1小時，將反應液經矽藻土過濾，在濾 液中甲入乙酸乙酯及水以及分液萃取，將有機層濃縮乾固 得到355 mg標題化合物。 iH-NMR光譜（DMSO-d6)c5(ppm)·· 5:·22 (2H，s)，6.42 (1H，d， J=5.8 Hz), 6.80-6.90 (2H, m), 7.08 (2H, d, J=12.0 Hz), 8.60-8.65 (2H, m), 11·60 (1H, br s)。 : 製造例22_ -150- ^紙張尺度適用Θ國家標準(CNS) A4規格（210X297公釐）Add 4,6-dichloropyrimidine (750 mg) to 4-nitrophenol (700 mg) and sodium hydride (60%) (200 mg) at 〇 °C in dimethyl decylamine (13 ^1) The suspension was 'heated and stirred at 80 ° C for 1.5 hours. The reaction solution was poured into saturated brine water' and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to NH(R) gel column chromatography (Fuji-Hilichia Chemical Co., Ltd.) and dissolved and concentrated with a solvent (ethyl acetate-hexane = 1-4) to give the title compound. lH-NMR (DMSO-d6) (5 (ppm): 7.08 (1H, d, J=〇.8 Hz), 7.30-7.37 (2H, m), 8·32-8·36 (2H, m), 8,60 (1H, d, .j = 0.8 Hz). Production Example 2 1 4-(Heartamine-based sulphate-hydrogen 7-fluorenyl-tr-----6-A late in 7-decyloxy-6- In the 2.6g of the night base 4-(3- gas-4-shiosylphenoxy) oxime quinine, add 26 ml of trifluoroacetic acid and 2·6 m of thioanisole at 70 ° C-72 ° C After the disturbance was dropped for 15 hours and returned to room temperature, the reaction system was concentrated, saturated carbon was added to the residue, and aqueous sodium hydrogencarbonate and methanol were added, and the precipitated yellow crystals were filtered. After drying, 2.61 g of crystals were obtained. A part of 640 mg, iron 950 mg, ammonium chloride 1,8 g, ethanol 10 ml, tetrahydro 17-propanol 10 ml and water 10 ml and reflux for 1 hour, the reaction solution was filtered through diatomaceous earth, in the filtrate The organic layer was concentrated to dryness to give 355 mg of the title compound. MH-NMR spectrum (DMSO-d6) c5 (ppm)·· 5:·22 (2H, s), 6.42 (1H,d, J=5.8 Hz), 6.80-6.90 (2H, m), 7.08 (2H, d, J=12.0 Hz), 8.60-8.65 (2H, m), 11·60 (1H, br s ) : Manufacturing Example 22_ -150- ^Paper ruler Applicable to National Standard (CNS) A4 specification (210X297 mm)

裝 訂Binding

線 13〇4〇61 A7 B7 五、發明説明（ι45 U磺醯基苯基胺某甲醢茇酯 將1-胺基-3-甲基硫代苯（1.27 ml，1〇 mmol)溶於四氫吱 喃（10 ml)，然後在氮蒙氣下，於室溫順次滴入三乙胺（丨46 ^11’10.5]11111〇1)及氯甲酸冬酉旨（1.32 1111’10.5 111111〇1)，並授 拌一夜。將反應液在乙酸乙酯與水間分溶，將有機層用飽 和食鹽水洗淨，及用無水硫酸鈉乾燥。餘去溶媒及減壓乾 燥後，將殘餘物溶於二氯甲烷（50 ml)，然後在冰水浴冷卻 下，慢慢加入3-氯過安息香酸（4·93 g , 20 mmolp在反應 液中’加入飽和硫代硫酸鈉水溶液後，濾去不溶物，將滤 液用乙酸乙酯萃取，用飽和碳酸鈉水溶液洗淨，以及用無 水硫酸制乾燥。餘去溶媒’將殘餘物用碎凝膠管柱層析法 (乙酸乙醋：己’虎=! : υ精製，得到為白色結晶之‘題化 合物（2.545 g，8.74 mmol，87.4%)。 lH.NMR^^(CDCl3)5(ppm): 3.07 (3H, s), 7.18^7.29 (4H m), L7.44 (2H，m)，7·55 (1H，t，μ 〇 Hz)，7 68 (ih d’ J=8.0 Hz)，7·80 (1H，d，J=8.0 Hz)，8·〇5(ιΗ、，s)。 ， 製造例23Line 13〇4〇61 A7 B7 V. Description of the invention (ι45 U-sulfonylphenylamine methylation) 1-amino-3-methylthiobenzene (1.27 ml, 1 mmol) is dissolved in four Hydrogen oxime (10 ml), then triethylamine (丨46^11'10.5]11111〇1) and chloroformic acid oxime (1.32 1111'10.5 111111〇1) were added dropwise at room temperature under nitrogen atmosphere. And the mixture was mixed overnight. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. In dichloromethane (50 ml), then under cooling in an ice water bath, slowly add 3-chloroperbenzoic acid (4·93 g, 20 mmolp in the reaction solution to add saturated aqueous sodium thiosulfate solution, and filter out insoluble The filtrate was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium carbonate and dried over anhydrous sulphuric acid. The solvent was removed and the residue was subjected to a gel column chromatography (ethyl acetate: hexane) ! : : υ , , , 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 (4H m), L7.44 (2H, m), 7·55 (1H, t, μ 〇 Hz), 7 68 (ih d' J=8.0 Hz), 7·80 (1H, d, J=8.0 Hz), 8·〇5 (ιΗ, s)., Manufacturing Example 23

4-『（2,2-二甲基-4.6-二酮某-μ ^ 胺基：1-2-甲氣某-芏月杳 將4-胺基-2-氯亨腈（3g)溶於甲| 丞-2-吡洛啶酮（1〇 _，加入甲醇_·12 g)並於i⑽。Ch熱撥掉7小時 應液注入飽和氣化按水溶液中，用 、 叛乙醋萃取，炊接舰 有機層用硫酸鎂乾燥後濃縮。對於得到·、， ”，、便册 凝膠管柱層析，用溶媒（乙酸乙g旨.己 殘餘物進订贿碎 己杈叫-2)溶出’得到苯 -151 -4-((2,2-Dimethyl-4.6-dione-μ^ Amino group: 1-2-methyl---------------------------- 4-amino-2-chloroheptonitrile (3g) A | 丞-2-pyrrolidone (1〇_, added methanol _·12 g) and i (10). Ch hot for 7 hours should be injected into the saturated gasification in aqueous solution, extracted with, vinegar, 炊The organic layer of the ship was dried with magnesium sulfate and concentrated. For the extraction of the gel column chromatography, the solvent (acetic acid, ethyl acetate, and the residue) was dissolved. 'Get benzene-151 -

本紙張尺度適用中國國家標準(CNS) A4規格(210 X297公爱T 1304061 -s Λ, — ____ _ B7 五、發明説明（146) 胺體（1.26 g) ^將該苯胺體（126 g)連同乙氧亞甲基麥爾多 拉姆酸（1 ·7. g)在乙醇中加熱回流。2小時後，濾取析出之固 體，用乙醇洗淨後乾燥，得到標題化合物（丨9g)。 H-NMR光if(DMSO〇5(ppm): 1·66 (6H，s)，3.94 (3H，s)， 7.21-7.26 (1Η, m), 7.46-7.50 (1H, m), 7.72 (1H, d, J=8.4 Hz), 8·70 (1H，s) 〇 製造例24 7-甲-乳.基-嗣某-1,4_二鏡奋琳-6-甲月音 以與製造例457-3同樣之方式，將4-[(2,2-二甲基-4,6-二 酮基-[1，3]亞二氧六圜基甲基）-胺基]·2·甲氧基-芊腈 (1.9 g)加熱閉環，得到為固體之標題化合物（1〇8 g)。 j-NMR光譜（DMSO-d6)5(ppm): 3.96 (3H，s)，6.02 (1H，d， J=7.6 Hz), 7.06 (1H, s), 7.89 (1H, d, 1=7.6 Hz), 8.30 (1H, s)。 製造例25 人 匕甲氧羰基-7-甲氧基-4“ 5-钊哚氣某V杏嗾 將4-氯-7-甲氧基峻琳-6-幾酸甲酯（記載於WO 0050405， P.34 中，8·5 g，33.77 mmol)，5 -經基口弓卜朵（7 g)，二異丙基 乙胺（8.9 ml)及N-甲基吡洛啶酮（8.9 ml)混合，於130。(3加 熱攪拌5小時，繼而於150°C加熱攪拌8小時。使放冷後之溶 液吸著於矽凝膠，在矽凝膠管柱中用己垸-乙酸乙酯系溶 析。在得到之黃色油狀物中加入乙醇、乙謎及己燒，放置 及析出結晶。將其濾取，用乙酸及己衡洗淨及吸引乾燥， 得到淡黃色結晶（3.506 g，10.06 mmol，29.80%)。 152 本紙張尺度適用中國國家標準(CNS) A4規格(210 X297公釐） 1304061 — —- A7 __ B7_ 五、發明説明（U7) W-NMR光譜（DMSO-d6)(5(PPm): 3·86 (3H, s)，3.97 (3H，s)， 6.38 (1H, d, J=5.2 Hz), 6.46 (1H, s), 6.98 (1H, d, J=8.8 Hz) 7.44-7·52 (4H，m)，8·60-8·65 (2H，m)，11·29 (1H，s) 〇 製造例2 6 7-(2-甲氣基乙氣基）-4-酮某-1.4-二說-6-4啉#醢 使用WO 98133 50記載之7-甲氧基-4-酮基-1,4-二氫u奎啦· 6-甲腈（8.0 g)，進行與製造例152-1同樣之操作，得到標題 化合物（6.3 g)。This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X297 public T 1304061 -s Λ, — ____ _ B7 V. Description of invention (146) Amine (1.26 g) ^The aniline (126 g) together Ethoxy methylene merdoram acid (1·7. g) was heated to reflux in ethanol. After 2 hours, the precipitated solid was filtered, washed with ethanol and dried to give the title compound (9 g). - NMR light if (DMSO 〇 5 (ppm): 1.66 (6H, s), 3.94 (3H, s), 7.21-7.26 (1 Η, m), 7.46-7.50 (1H, m), 7.72 (1H, d, J=8.4 Hz), 8·70 (1H, s) 〇 Manufacturing Example 24 7-A-milk. Base-嗣一-1,4_二镜奋琳-6-甲月音音与制造例457 -3 In the same manner, 4-[(2,2-dimethyl-4,6-dione-[1,3] dioxohexylmethyl)-amino]·2·methoxy The title compound (1 〇 8 g) was obtained as a solid. j-NMR spectrum (DMSO-d6) 5 (ppm): 3.96 (3H, s), 6.02 (1H, d , J = 7.6 Hz), 7.06 (1H, s), 7.89 (1H, d, 1 = 7.6 Hz), 8.30 (1H, s). Production Example 25 Human methoxycarbonyl-7-methoxy-4" 5-钊哚气, a V apricot, 4-chloro-7-methoxyjunolin-6-methyl acid ( In WO 0050405, P.34, 8. 5 g, 33.77 mmol), 5 - via the base of the bow (7 g), diisopropylethylamine (8.9 ml) and N-methylpyrrolidine The ketone (8.9 ml) was mixed at 130. (3) heating and stirring for 5 hours, followed by heating and stirring at 150 ° C for 8 hours. The solution after cooling was sorbed on the ruthenium gel, and the ruthenium gel was used in the ruthenium gel column. - Ethyl acetate was eluted. Ethanol, ee and hexane were added to the obtained yellow oil, and the crystals were allowed to stand and precipitated. The mixture was filtered, washed with acetic acid and hexane, and dried to give pale yellow crystals. (3.506 g, 10.06 mmol, 29.80%) 152 This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X297 mm) 1304061 — —- A7 __ B7_ V. Description of invention (U7) W-NMR spectrum (DMSO) -d6)(5(PPm): 3·86 (3H, s), 3.97 (3H, s), 6.38 (1H, d, J=5.2 Hz), 6.46 (1H, s), 6.98 (1H, d, J=8.8 Hz) 7.44-7·52 (4H, m), 8·60-8·65 (2H, m), 11·29 (1H, s) 〇 Manufacturing Example 2 6 7-(2-A gas base Ethyl)-4-keto-1.4-di--6-4 phenyl #醢# 7-methoxy-4-keto-1,4-dihydrou-quina 6- described in WO 98133 50 Formonitrile (8 .0 g) The title compound (6.3 g) was obtained.

iH-NMR光if(DMSO-d6)c5(ppm): 3.33 (3H，s)，3,71-3·73 (2H m), 4.21^4.22 (2H, m), 6.28 (1H, d, J-7.2 Hz), 7.15 (1H, s) 8.59 (1H, d, J=7.2 Hz), 8.40 (1H, s) ^ [實施例] 實施例1 Ν.ϋί 6-亂基-7-(3-(4-ηί:咬基）丙氣基）-4-4喊幕）氣苯莘·— 曱氣茗某）Μ 為在只&amp;例87中合成之6-¾基- 4- (4-( (.4-甲氧基苯胺基） 衆基）胺基笨氧基）-7 -π奎淋酸鋼（200 mg)溶於二甲基甲酿胺 (4 ml) ’然後加入碟酸4甲（130 mg，0.9400 mmol)，埃化神 (3 mg) ’ 1-氣-3,（4-吡啶基）丙烷（80 mg，0.5159 mmol)， 並於80C加熱授掉5時30分鐘。放冷後加入飽和食鹽水，然 後用乙酸乙酯萃取，用飽和食鹽水洗淨，用無水硫酸鎂乾 燥及減壓餾去溶媒，將殘餘物周1^11矽凝膠管柱層析（乙酸 乙酯-甲醇系）精製。藉由將得到之結磊懸浮於乙醇中，用 乙醚稀釋，濾取結晶，用乙醚洗淨及吸引乾燥，得到為淡 -153- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（148) 黃色結晶之標題化合物（60 mg) ^ iH-NMR光譜(DMSO-d6)5(ppm): 2·17 (2H，d)，2·84 (2H，t， J=7.8 Ηζ)，3·70 (3Η，s)，4.28 (2Η，t，J=6.2 Hz), 6.51 (1Η，d， J=5.2 Hz), 6.86 (2H, d, J=9.0 Hz), 7.22 (2H, d, J=9.0 Hz), 7.29 (2H, d, J=6.0 Hz), 7.35 (2H, d, J=9.0 Hz), 7.57 (1H, s), 7.58 (2H, d, J=9.0 Hz), 8.46 (2H, d, J=6.0 Hz), 8.49 (1H, s), 8.71 (1H，d，J=5.2 Hz)，8·74 (1H，s)，8.76 (1H，s)。 實施例2 4-( 6-氨某-7-(4-甲基吡啶氣4:啉革）氧笨基_N’d4_曱 氧苯某）胧 將在實施例87中合成之6-氰基-4-(4-((4-甲氧基苯胺基） 羰基）胺基苯氧基）-7-喹啉酸鈉（100 mg)溶於二甲基甲醯胺 (2 ml)中，然後加入碳酸鉀（97 mg，0.7018 mmol)，碘化鉀 (3 mg)及 4-甲基 p比淀氯（40 mg，0.2462 mmol)，並於 80°C 加 熱攪拌3小日竟。放冷後加入水，然後用乙酸乙酯萃取，用飽 和食鹽水洗淨，用無水疏酸鎮乾燥及減壓餾去溶媒，將殘 餘物用NH矽凝膠管柱層析（乙酸乙酯-甲醇系）精製β藉由 將得到之結晶懸浮於丙酮中’將其用乙趟稀釋，滤取結 晶，用乙醚洗淨及吸引乾燥，得到為淡黃色結晶之標題化 合物（30 mg)。 iH-NMR光譜（DMS〇-d6)(5(ppm): 3.70 (3H，· s)，3.54 (2H，s)， 6.53 (1H, d, J=5.2 Hz), 6.86 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 Hz), 7.5Z· (2H, d, J=6.4 Hz), 7.59 (2H, d, J=8.8 Hz), 7.66 (1H, s), 8.55 (1H, br s), 8.63 -154- 本紙張又度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 〜 A7 ________ B7 _ 五、發明説明（149) (2H, d, J=6.0 Hz), 8.72 (1H, d, J=5.2 Hz), 8.81 (1H, br s), 8·82 (1H，s)。 f施例3 过iXi.-(6·氰.基-7二(j-曱某吡啶氣杏嗾基）氣笨基-Ν，-Γ4-氣笨某1服 使用在實施例87中合成之6-氰基-4-(4-((4-甲氧基苯胺基） 羰基）胺基苯氧基）-7^奎啉酸鈉（2〇〇 mg)，進行與實施例2 同樣之反應，得到標題化合物（68 mg)。 iH-NMR光譜（DMS〇-d6)5(ppm): 3,70 (3H，s)，5.50 (2H，s)， 6.54 (1H, d, J=5.〇 Hz), 6.86 (2H, d5 J=8.8 Hz), 7.22 (2H, d5 J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.49 (2H, dd, J=4.8 Hz, 7.6 Hz), 7.58 (2H, d, J=8.8 Hz), 7.74 (1H, s), 7.95 (1H, d, J=7.6 Hz), 8.49 (1H, s), 8.59 (1H, dd, J=1.6, Hz, 4.8 Hz), 7.83-8.80 (3H，m)。 貫施例4 U4-(6-氰4.Κ2-Π·2·3-三唑-2-基）乙·氣基）-4-0套啉某\ I-菜基）-N，- (4二氟笨某）脲（f施例4_ 过!-(4-(6-氰幕-^^(2“1.2.3-三唑-1-基）乙氣基）-4-4啉某） I苯基氟茉某）脲（實施例4-B) 將在實施例90中合成之Ν-(4-( 6-氰基-7-( 2-氯乙氧基喹啉 基）氧苯基）-N，-(4-氟苯基）脲（210 mg，0.4403 mmol)溶於 N，N二甲基甲醯胺（2.5 ml)，然後加入碳酸鉀（180 mg , 1·3209 mmol)，碘化鉀（15 mg)及 1H-1，2.,3-三唑（0.078 m 卜 1.3209 mmol) ’於60°C加熱攪拌20分鐘，繼而於65°C加熱 __ -155- I紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) '— 1304061 、iH-NMR light if (DMSO-d6) c5 (ppm): 3.33 (3H, s), 3, 71-3·73 (2H m), 4.21^4.22 (2H, m), 6.28 (1H, d, J -7.2 Hz), 7.15 (1H, s) 8.59 (1H, d, J=7.2 Hz), 8.40 (1H, s) ^ [Examples] Example 1 Ν.ϋί 6-乱基-7-(3- (4-ηί: bite base) propane gas base)-4-4 shouting) gas benzoquinone · — 曱 茗 Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ ((.4-Methoxyanilino)-and-yl)amino-p-oxy)-7-π-quinone acid steel (200 mg) dissolved in dimethyl ketoamine (4 ml) ' Then add dish acid 4 A (130 mg, 0.9400 mmol), Essence (3 mg) '1-gas-3, (4-pyridyl)propane (80 mg, 0.5159 mmol), and allowed to heat at 80 C for 5:30 minutes. After cooling, it was added with saturated brine, and the mixture was extracted with EtOAc. EtOAc. EtOAc. Ethyl acetate-methanol was purified. The obtained knot was suspended in ethanol, diluted with diethyl ether, and the crystals were collected by filtration, washed with diethyl ether and dried to obtain a pale-153- paper scale applicable to the Chinese National Standard (CNS) A4 specification (210 X 297). 1304061 A7 B7 V. Description of the Invention (148) Title compound of yellow crystals (60 mg) ^ iH-NMR spectrum (DMSO-d6) 5 (ppm): 2·17 (2H, d), 2·84 ( 2H,t, J=7.8 Ηζ),3·70 (3Η,s), 4.28 (2Η,t,J=6.2 Hz), 6.51 (1Η,d, J=5.2 Hz), 6.86 (2H, d, J =9.0 Hz), 7.22 (2H, d, J=9.0 Hz), 7.29 (2H, d, J=6.0 Hz), 7.35 (2H, d, J=9.0 Hz), 7.57 (1H, s), 7.58 ( 2H, d, J=9.0 Hz), 8.46 (2H, d, J=6.0 Hz), 8.49 (1H, s), 8.71 (1H,d,J=5.2 Hz),8·74 (1H,s), 8.76 (1H, s). Example 2 4-(6-Ammonia-7-(4-methylpyridine gas 4: porphyrin) oxoyl_N'd4-nonyloxybenzene) 66-Cyanide synthesized in Example 87 Sodium 4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinate (100 mg) was dissolved in dimethylformamide (2 ml). Potassium carbonate (97 mg, 0.7018 mmol), potassium iodide (3 mg) and 4-methyl p-precipitated chlorine (40 mg, 0.2462 mmol) were then added and stirred at 80 ° C for 3 hours. After cooling, water was added, and the mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc. Methanol) Purified β was obtained by suspending the obtained crystals in acetone. The residue was crystallized from ethyl acetate. The crystals were filtered, washed with diethyl ether and dried to give the title compound (30 mg). iH-NMR spectrum (DMS 〇-d6) (5 (ppm): 3.70 (3H, · s), 3.54 (2H, s), 6.53 (1H, d, J = 5.2 Hz), 6.86 (2H, d, J =8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 Hz), 7.5Z· (2H, d, J=6.4 Hz), 7.59 (2H, d, J =8.8 Hz), 7.66 (1H, s), 8.55 (1H, br s), 8.63 -154- This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 ~ A7 ________ B7 _ V. INSTRUCTIONS (149) (2H, d, J=6.0 Hz), 8.72 (1H, d, J=5.2 Hz), 8.81 (1H, br s), 8·82 (1H, s). 3 After iXi.-(6·Cyanyl-7-II (j-曱 pyridine apricot base) gas stupid base-Ν,-Γ4-气笨一一服 Use the synthesis of 6-cyanide in Example 87 Sodium 4-(4-((4-methoxyanilinyl)carbonyl)aminophenoxy)-7- quinolate sodium (2 mg) was subjected to the same reaction as in Example 2 to give the title Compound (68 mg). iH-NMR spectrum (DMS 〇-d6) 5 (ppm): 3,70 (3H, s), 5.50 (2H, s), 6.54 (1H, d, J=5.〇Hz) , 6.86 (2H, d5 J=8.8 Hz), 7.22 (2H, d5 J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.49 (2H, dd, J=4.8 Hz, 7.6 Hz), 7.58 (2H, d, J=8.8 Hz), 7.74 (1H, s), 7 .95 (1H, d, J=7.6 Hz), 8.49 (1H, s), 8.59 (1H, dd, J=1.6, Hz, 4.8 Hz), 7.83-8.80 (3H, m). Example 4 U4 -(6-cyanide 4.Κ2-Π·2·3-triazol-2-yl)ethyl·carbyl)-4-0 porphyrins \ I-菜基)-N,- (4 difluoro stupid Urea (f example 4_ over!-(4-(6-cyanate-^^(2"1.2.3-triazol-1-yl)ethane)-4-4 porphyrin) Iphenyl fluoride Urea) (Example 4-B) Ν-(4-(6-Cyano-7-(2-chloroethoxyquinolinyl)oxyphenyl)-N, which was synthesized in Example 90, -(4-Fluorophenyl)urea (210 mg, 0.4403 mmol) dissolved in N,N-dimethylformamide (2.5 ml), then potassium carbonate (180 mg, 1·3209 mmol), potassium iodide (15 mg) And 1H-1,2.,3-triazole (0.078 m Bu 1.3209 mmol) 'heat and stir at 60 ° C for 20 minutes, then heat at 65 ° C __ -155-I paper scale applies to Chinese national standard (CNS ) A4 size (210 X 297 mm) '— 1304061 ,

… AT _ __B7 五、發明説明（150) 攪拌3小時。放冷後加入四氫呋喃及乙酸乙酯，用飽和食鹽 水洗淨’用無水硫酸鎂乾燥及減壓餾去溶媒後，付諸於矽 凝膠管柱層析（乙酸乙酯-甲醇系）進行異構體分離。對於低 極性者’將所得結晶懸浮於乙醇中，洗淨，濾取，溶解於 二甲基亞職中，將其用乙醇稀釋以使結晶析出，濾取結 晶，用乙醇及乙醚接續洗淨及吸引乾燥；對於高極性者， 將所得結晶懸浮於乙醇中，洗淨，濾取，用乙醇及乙醚接 續洗淨及吸引乾燥，藉此分別得到各為無色結晶之低極性 1^(4-(6-氰基-7-(2-(1，2,3-三唑_2-基）乙氧基）-4-喹啉基） 氧苯基）-Ν·-(4-氟苯基）弱：（37 mg，0.0703 mmol， 1 6.02%)，以及高極性 N- (4- ( 6-氰基-7- (2 - (1，2,3 -三峻-1-基）乙氧基）-4-喹啉基）氧苯基）-N，气心氟苯基）脲（62 mg , 0.1182 mmol * 26.85%) ° 低極性（實施例4_A) iH-NMR光讚(DMSO-d6) 5(ppm)·· 4·81 (2H, t, J=4.6 Ηζ)，4·92 (2H，t，J=4.6 Hz)，6·52 (1H，d，J=5.2 Ηζ)，、7·11 (2H，t，J=8.8... AT _ __B7 V. INSTRUCTIONS (150) Stir for 3 hours. After cooling, tetrahydrofuran and ethyl acetate were added, and the mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, and then applied to a gel column chromatography (ethyl acetate-methanol). The structure is separated. For those with low polarity, the obtained crystals were suspended in ethanol, washed, filtered, dissolved in dimethyl sub-sector, diluted with ethanol to precipitate crystals, filtered for crystallization, washed successively with ethanol and diethyl ether. Attracting dryness; for highly polar ones, the obtained crystals are suspended in ethanol, washed, filtered, washed successively with ethanol and diethyl ether, and suction-dried, thereby obtaining low polarity of each colorless crystal 1^(4-( 6-Cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolinyloxyphenyl)-indole-(4-fluorophenyl) Weak: (37 mg, 0.0703 mmol, 1 6.02%), and highly polar N-(4-(6-cyano-7-(2 - (1,2,3-tris)-yl)ethoxy )-4-quinolinyl)oxyphenyl)-N, fluorophenyl phenyl)urea (62 mg, 0.1182 mmol * 26.85%) ° low polarity (Example 4_A) iH-NMR light (DMSO-d6) 5(ppm)·· 4·81 (2H, t, J=4.6 Ηζ), 4.92 (2H, t, J=4.6 Hz), 6.52 (1H, d, J=5.2 Ηζ),, 7 ·11 (2H, t, J=8.8

Hz), 7.22 (2H, d, J=8.8 Hz), 7.46 (2H, dd, J=5.0 Hz, 8.8 Hz), 7.59 (2H, d, J=8.8 Hz), 7.65 (1H, s), 7.80 (2H, s), 8.71 (1H, s), 8·72 (1H，d，J=5.2 Hz)，8.77 (1H，s)，8.86 (1H，s)。 高極性（實施例4-B) iH-NMR光譜(DMSO-d6) 6(ppm): 4·72 (2H，t，J=4.8 Hz)，4·93 (2H, t, J=4.8 Hz), 6.53 (1H, d, J=5.2 Hz), 7.11 (2H, t, J=8.4 Hz), 7.23 (2H, d, J=8.8 Hz), 7.46 (2H, dd, J=4.4 Hz, 8.4 Hz), 7.59 (2H, d, J=8.8 Hz), 7.64 (1H, s), 7.77 (1H, s), 8.18 (1H, -156- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） A7 B7 !304061Hz), 7.22 (2H, d, J=8.8 Hz), 7.46 (2H, dd, J=5.0 Hz, 8.8 Hz), 7.59 (2H, d, J=8.8 Hz), 7.65 (1H, s), 7.80 (2H, s), 8.71 (1H, s), 8·72 (1H, d, J = 5.2 Hz), 8.77 (1H, s), 8.86 (1H, s). High polarity (Example 4-B) iH-NMR spectrum (DMSO-d6) 6 (ppm): 4·72 (2H, t, J = 4.8 Hz), 4·93 (2H, t, J = 4.8 Hz) , 6.53 (1H, d, J=5.2 Hz), 7.11 (2H, t, J=8.4 Hz), 7.23 (2H, d, J=8.8 Hz), 7.46 (2H, dd, J=4.4 Hz, 8.4 Hz ), 7.59 (2H, d, J=8.8 Hz), 7.64 (1H, s), 7.77 (1H, s), 8.18 (1H, -156- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 !304061

五、發明説明（151 s)&gt; 8.73 (1H, d, J=5.2 Hz), 8.73 (1H, s), 8.75 (1H, s), 8.83 (1H，s)。 t施例5 三嗅-2-某）_乙氫某）-4-。杏嗾甚、 氧苯某）服f膏施你丨夂 ^11二（6-见某^2dL2·二（1，2,3-三吐-l-某；^乙氣ng奋嗾甚） 乳U〇-N’-(4」H笨某）脲（會施例 使用在實施例91中合成之N-(4-(6-氰基·7-(2-氯乙氧基）_ ‘喹啉基）氧苯基）·Ν，-(4_甲氧苯基）脲（3〇〇 mg，〇6136 mmol)，進行與實施例4同樣之反應，得到各為無色結晶之 低極性N-(4-(6-氰基-7-(2-(1,2,3-三唑-2-基）乙氧基）-4-喳 琳基）氧苯基）-N，-(4-曱氧苯基）脲（87 mg，〇 1652 mmol， 26.93%)，以及高極性Ν-(4·(卜氰基-7-(2-(1，2,3·三唑小 基）乙氧基）-4-喹啉基）氧苯基）-Ν，-(4·甲氧苯基）脲（83 mg，〇.1576、mmo卜 25.69%)。 低極性（實施例5-A) ·、 H-NMR 光 if(DMSO-d6)5(ppm): 3·70 (3H，s)，4.81 (2H，t， J=5.0 Hz), 4.92 (2H, t, J=5.0 Hz), 6.52 (1H, d, J=5.4 Hz), 6.86 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=9.2 Hz), 7.35 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=9.2 Hz), 7.65 (1H, s), 7.80 (2H, s), 8.49 (1H, s), 8.71 (1H, s), 8.72 (1H, d, J=5.4 Hz), 8.73 (1H, s)。 高極性（實施例5-B) : iH-NMR 光譜（DMS〇-d6)(5(ppm): 3.70 (3H，s)，4.72 (2H，t， -157- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐)V. INSTRUCTIONS (151 s)&gt; 8.73 (1H, d, J=5.2 Hz), 8.73 (1H, s), 8.75 (1H, s), 8.83 (1H, s). t Example 5 Three scent -2-) _ Ethyl hydrogen -4-. Apricot, oxybenzene, sputum, f, cream, sputum, sputum, sputum, sputum, sputum, sputum, sputum, sputum, sputum, sputum, sputum, sputum, sputum, sputum, sputum, sputum, sputum, sputum U〇-N'-(4"H 笨) Urea (N-(4-(6-cyano-7-(2-chloroethoxy))-quino synthesized in Example 91) The same reaction as in Example 4 was carried out to obtain a low polarity N- each of which was colorless crystals, and the same reaction as in Example 4 was carried out. (4-(6-Cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-indolyl)oxyphenyl)-N,-(4-曱Phenylphenyl)urea (87 mg, 〇1652 mmol, 26.93%), and highly polar Ν-(4·(cyano-7-(2-(1,2,3·triazole small)) ethoxylate ))-4-quinolinyl)oxyphenyl)-indole,-(4.methoxyphenyl)urea (83 mg, 〇.1576, mmo, 25.69%). Low polarity (Example 5-A) , H-NMR light if (DMSO-d6) 5 (ppm): 3·70 (3H, s), 4.81 (2H, t, J = 5.0 Hz), 4.92 (2H, t, J = 5.0 Hz), 6.52 (1H, d, J=5.4 Hz), 6.86 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=9.2 Hz), 7.35 (2H, d, J=8.8 Hz), 7.57 (2H , d, J=9.2 Hz), 7.65 (1H, s), 7.80 (2H, s), 8.49 (1H , s), 8.71 (1H, s), 8.72 (1H, d, J = 5.4 Hz), 8.73 (1H, s). High polarity (Example 5-B): iH-NMR spectrum (DMS〇-d6) (5 (ppm): 3.70 (3H, s), 4.72 (2H, t, -157- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

裝 訂Binding

1304061 A7 B71304061 A7 B7

J=5.2 Hz), 4.93 (2H, t5 J=5.2 Hz), 6.53 (1H, d, J=5.2 Hz) 6.85 (2H，d，J=9.0 Hz), 7,21 (2H，d，J=9.0 Hz)，7·35 (2H, (/J=5.2 Hz), 4.93 (2H, t5 J=5.2 Hz), 6.53 (1H, d, J=5.2 Hz) 6.85 (2H,d,J=9.0 Hz), 7,21 (2H,d,J= 9.0 Hz), 7·35 (2H, (/

J=9.0 Hz)，7·57 (2H，d，J=9.0 Hz)，7.64 (1H，s)，7·77 (1H，s)’ 8.18 (1H，s)，8.49 (1H，s)，8.72 (1H，d，J=5.2 Hz)，8·73 (1H s)，8·75 (1H，s)。 ， 實施例6 士1+(6'氰基-7-(2-(1^_三唑-2-基）乙氳基）-‘呤虫一^ 氧-_3·氟笨基Ν’ - (2,4-二氟笨基）啤（實施例6-A) 氰基- 7-(2-(1 v2 三唑-1-基）乙氫某 n-氧-3-氟苯某二氟苯某、脲施例 將氫化鈉（35 mg，0.8774 mmol，60%，在油中）懸浮於 N，N二甲基甲醯胺（2.5 ml)中，於冰冷下添加iH- ns•三味 (0.051 ml，0.8774 mmol)，於室溫攪掉15分鐘直至完全溶 解。在其中添加N-(4-(6-氰基-7-(2,氯乙氧基）·‘峻琳基） 氧苯基）-Ν’:、（2,4-二氟苯基）脲（225 mg，0.4386 mmol)及碘 化鉀（10 mg)及，並於50°C加熱攪摔10小時。放冷後加入 氫呋喃及乙酸乙酯，用飽和食鹽水洗淨，用無水硫酸鎂乾 燥及減壓餾去溶媒後，付諸於矽凝膠管柱層析（己燒乙酸 乙酯·甲醇系）進行異構體分離。對於低極性者，將所得沾 晶溶於二甲基亞颯中，將其用乙醇稀釋以使結晶析出 取結晶，用乙醇及乙醚接續洗淨及吸引乾燥；對於高極性 者，將所得用NH矽凝膠管柱層析（己烷·乙酸乙酷μ系）精 製’將所得結晶懸浮於乙醇中及洗淨，.用將其用己^燒稀^ 後濾取，用己烷洗淨及吸引乾燥，藉此分別得到為=红色 -158-J=9.0 Hz),7·57 (2H,d,J=9.0 Hz), 7.64 (1H,s),7·77 (1H,s)' 8.18 (1H,s),8.49 (1H,s), 8.72 (1H, d, J = 5.2 Hz), 8.73 (1H s), 8.75 (1H, s). Example 6: 1+(6'cyano-7-(2-(1^-triazol-2-yl)ethenyl)-'Aphid-1 Oxygen-_3·Fluorophenyl Ν' - ( 2,4-Difluorophenyl) beer (Example 6-A) Cyano-7-(2-(1 v2 triazol-1-yl)ethylene hydrogen a certain n-oxo-3-fluorobenzene difluorobenzene A solution of urea, sodium hydride (35 mg, 0.8774 mmol, 60% in oil) was suspended in N,N-dimethylformamide (2.5 ml), and iH-ns•Sanwei (0.051) was added under ice cooling. Ml, 0.8774 mmol), stir at room temperature for 15 minutes until completely dissolved. Add N-(4-(6-cyano-7-(2,chloroethoxy)·'junolinyl)oxyphenyl )-Ν':, (2,4-difluorophenyl)urea (225 mg, 0.4386 mmol) and potassium iodide (10 mg), and stirred at 50 ° C for 10 hours. After cooling, add hydrogen furan and The ethyl acetate was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated, and evaporated, and evaporated. For those with low polarity, the obtained smear is dissolved in dimethyl hydrazine, diluted with ethanol to precipitate crystals, and washed with ethanol and diethyl ether. And the drying is attracted; for those with high polarity, the obtained product is purified by NH(R) gel column chromatography (hexane/acetic acid), and the obtained crystal is suspended in ethanol and washed, and used for use. After burning and diluting, it is filtered, washed with hexane and attracted to dryness, thereby obtaining = red-158-

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 〜 - A7 __B7 五、發明説明（153) 結晶之低極性N-(4-(6-氰基- 7-(2-( 1，2,3-三唑-2-基）乙氧 基）-4-喹啉基）氧-3-氟苯基）-Ν’·（2,4-二氟苯基）脲（15 mg，0.0275 mmol，6.27%)，以及為無色結晶之高極性Ν· (4-(6-夜基-7-(2-(1，2,3 -二吐-1-基）乙氧基奎淋基）氧_ 3-氟本基）-Nf-(2,4-二氟苯基）月尿（30 mg，0.0550 mmol， 12.54%)。 低極性（實施例6-A) tH-NMR光譜（DMSO-d6)5(ppm): 4·82 (2H，t，J=4.8 Hz)，4.92 (2H, t, J=4.82 Hz), 6.63 (1H, d, J=5.0 Hz), 7.05 (1H, m), 7.14 (1H, d, J=9.6 Hz), 7.32 (1H, m), 7.40 (1H, m), 7.66 (1H, s), 7.80 (2H, s), 8.11 (1H, m), 8.26 (1H, t, J=9.6 Hz), 8.70 (1H，s)，8.75 (1H，d，J=5.0 Hz), 8·99 (1H，s)，9.07 (1H，s)。 高極性（實施例6-B) iH-NMR光if(DMSO-d6)占（ppm): 4·73 (2H，t，J=5.2 Hz)，4·93 (2H, t, J=5.2 Hz), 6.63 (1H, d, J=5.2 Hz), 7.05 (1H, m)3 7.15 (1H, m), 7.32 (1H, ddd, J-2.8 Hz, 8.8 Hz, 11.6 Hz), 7.40 (1H, dd, J=2.8 Hz, 11.6 Hz), 7.66 (1H, s)3 7.77 (1H, s), 8.11 (1H, m), 8.18 (1H, s), 8.26 (1H, t, J=8.8 Hz), 8.74 (1H, s), 8.75 (1H, d, J=5.2 Hz), 8.99 (1H, d, J-2.2 Hz), 9.07 (1H, d, J=2.2 Hz)。 實施例7 U4- ( 6-氰基-7- ( 3-(嗎福淋二4-基丄g氣基）· 4· g套啉基）氯苽 基）-〜“4-甲氣笨基）脲 將在貫施例87中合成之6-氰基、4、（4-((4-甲氧基苯胺基） -159- 本紙張尺度適用中國國家揉準(CNS) A4規格(210 X 297公釐） 1304061 、 A7 ' ___ B7 五、發明説明（154) 羰基）胺基苯氧基）-7-喹啉酸鈉（100 mg)溶於二甲基甲酿胺 (2·5 ml)中，然後加入碳酸钾（65 mg，0,4690 mmol)，及l 氯-3 -(嗎福琳-4-基）丙烷（38 mg，0.2345 mmol，用 j.This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ~ - A7 __B7 V. Description of invention (153) Crystallized low polarity N-(4-(6-cyano-7-(2) -( 1,2,3-triazol-2-yl)ethoxy)-4-quinolyl)oxy-3-fluorophenyl)-indole·(2,4-difluorophenyl)urea 15 mg, 0.0275 mmol, 6.27%), and a highly polar Ν·(4-(6-yl)-7-(2-(1,2,3-dioxa-1-yl)ethoxy group奎 基 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Spectrum (DMSO-d6) 5 (ppm): 4·82 (2H, t, J = 4.8 Hz), 4.92 (2H, t, J = 4.82 Hz), 6.63 (1H, d, J = 5.0 Hz), 7.05 (1H, m), 7.14 (1H, d, J=9.6 Hz), 7.32 (1H, m), 7.40 (1H, m), 7.66 (1H, s), 7.80 (2H, s), 8.11 (1H, m), 8.26 (1H, t, J = 9.6 Hz), 8.70 (1H, s), 8.75 (1H, d, J = 5.0 Hz), 8·99 (1H, s), 9.07 (1H, s). High polarity (Example 6-B) iH-NMR light if (DMSO-d6) accounted for (ppm): 4·73 (2H, t, J = 5.2 Hz), 4·93 (2H, t, J = 5.2 Hz ), 6.63 (1H, d, J=5.2 Hz), 7.05 (1H, m)3 7.15 (1H, m), 7.32 (1H, d Dd, J-2.8 Hz, 8.8 Hz, 11.6 Hz), 7.40 (1H, dd, J=2.8 Hz, 11.6 Hz), 7.66 (1H, s)3 7.77 (1H, s), 8.11 (1H, m), 8.18 (1H, s), 8.26 (1H, t, J=8.8 Hz), 8.74 (1H, s), 8.75 (1H, d, J=5.2 Hz), 8.99 (1H, d, J-2.2 Hz), 9.07 (1H, d, J = 2.2 Hz). Example 7 U4-(6-Cyano-7-(3-(m-fos bis- 4-yl 丄g gas group)· 4·g trocartoyl) chloro苽基)-~ "4-methyl azide" urea will be synthesized in Example 87, 6-cyano, 4, (4-((4-methoxyanilino)-159-) China National Standard (CNS) A4 Specification (210 X 297 mm) 1304061, A7 ' ___ B7 V. Description of Invention (154) Sodium Carbonyl)Aminophenoxy)-7-quinolinate (100 mg) Dimethylmethaneamine (2.5 ml), then potassium carbonate (65 mg, 0,4690 mmol), and l-chloro-3-(moffin-4-yl)propane (38 mg, 0.2345 mmol) With j.

Chem. Soc.紅，736 ( 1945)記載之方法合成），並於8(rc加 熱攪拌2小時。放冷後加入飽和食鹽水後，用乙酸乙醋萃 取，用飽和食鹽水洗淨，用無水硫酸鎂乾燥及減壓餘去溶 媒，將殘餘物用NH矽凝膠管柱層析（乙酸乙酯-甲醇系）精 製。將得到之結晶懸浮於乙酸乙酯中，將其用乙謎稀釋， 濾取結晶，用乙醚洗淨及吸引乾燥，得到為淡黃色結晶之 標題化合物(；120 mg)。 lH-NMR光譜(DMSO-d6)(5(ppm): 1.99 (2H，m)，2·38 (4H，br s), 2.49 (2H, m)3 3.57 (4H, t, J=4.6 Hz), 3.70 (3H, s), 4.33 (2H，t，J=6.2 Hz)，6·51 (1H，d，J=5.6 Hz), 6·86 (2H，d，J=9.2 Hz), 7.22 (2H, d, J=9.2 Hz), 7.35 (2H, d, J=9.2 Hz), 7.58 (2H, d, J=9.2 Hzj, 7.59 (1H, s), 8.49 (1H, s)5 8.71 (1H, d5 J=5.6 Hz)，8·74 (1H，s)，8.75(1H，s)。 實施例8 N-_(4- ( 6-氣基-_7-( 3 - Π，2,3 -三唾- 丙氫某）-4· 氧笨基l Ν’-M-甲氯苯基）脲 藉由與實施例7同樣之操作，從實施例87合成之氰基-4- (4-((4-曱氧基苯胺基）談基）胺基笨氧基）· 7- $ α林酸鈉及 2-(3-氯丙基）-1，2,3-三唑，得到標題化合物。 j-NMR光譜(DMSO-d6)(5(ppm): 2·41 (2衫 m) 3 70 (3H，5)， 4.29 (2H，t，J=6.0 Hz)，4.68 (2H，t，j=6 6 Hz)，6 52 (lH, d， -160- 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） 1304061 A7Chem. Soc. Red, 736 (1945) method of synthesis), and stirred at 8 (rc for 2 hours). After cooling, add saturated brine, extract with ethyl acetate, wash with saturated saline, use anhydrous After drying over magnesium sulfate and decompression, the solvent was evaporated, and the residue was purified by ethylamine gel column chromatography (ethyl acetate-methanol). The crystals were filtered, washed with diethyl ether and evaporated to dryness crystals crystals crystals crystalssssssssssssssssssssssss 38 (4H, br s), 2.49 (2H, m)3 3.57 (4H, t, J=4.6 Hz), 3.70 (3H, s), 4.33 (2H, t, J=6.2 Hz), 6·51 ( 1H,d,J=5.6 Hz), 6·86 (2H,d,J=9.2 Hz), 7.22 (2H, d, J=9.2 Hz), 7.35 (2H, d, J=9.2 Hz), 7.58 ( 2H, d, J=9.2 Hzj, 7.59 (1H, s), 8.49 (1H, s)5 8.71 (1H, d5 J=5.6 Hz), 8.74 (1H, s), 8.75 (1H, s). Example 8 N--(4-(6-Gasyl-_7-(3- fluorene, 2,3-tris-propanyl)-4. Oxyphenyl 1 Ν'-M-methylchlorophenyl) Urea was synthesized from Example 87 by the same operation as in Example 7. Cyano-4-(4-((4-decyloxyanilinyl) yl)amino) phenyloxy)· 7- $ sodium sulphate and 2-(3-chloropropyl)-1,2 , 3-triazole, the title compound was obtained. j-NMR spectrum (DMSO-d6) (5 (ppm): 2·41 (2 br.) 3 70 (3H,5), 4.29 (2H,t,J=6.0 Hz), 4.68 (2H, t, j=6 6 Hz), 6 52 (lH, d, -160- This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1304061 A7

五、發明説明（155) J=5.2 Hz), 6.86 (2H, d, J=8.8 Hz), 7,22 (2H, d, 1=8.8 H^)? 7.35 (2H, d, J=8.8 Hz), 7.54 (1H, s), 7.58 (2H, d, 1=8.8 Hz), 7.78 (2H，s)，8·49 (1H，s)，8.71 (1H，d，J=5.2 HZ)，8.74 (1H， s)，8.77(1H，s)。 實施例9 N- (4- ( 6-氰基_'7- ( 3- (1,2,3-三兔基）丙氧基）-4- 生基X 氳茇甲氣笨基）脲 藉由與實施例7同樣之操作’徒實施例87合成之6-氣基-4- (4- ((4-甲氧基苯胺基）羰基）胺基苯氧基）· 7〃奎淋酸納及 1-(3-氯丙基）-1，2,3-三唑，得到標題化合物。 iH-NMR光譜(DMS〇-d6)5(ppm): 2.41 (2H，m)，3.70 (3H，s)， 4·28 (2H，t，J=6.0 Hz)，4.63 (2H，t，J=6.6 Ηζ)，6·52 (1H，d， J=5.4 Hz), 6.86 (2H, d5 J=8.8 Hz), 7.22 (2H, d, J==8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.57 (1H3 s), 7.58 (2H, d, J=8.8 Hz), 7·73 (1H，sX 8·19 (1H，s)，8·49 (1H，s)，8·72 (1H，d，J=5.4V. INSTRUCTIONS (155) J=5.2 Hz), 6.86 (2H, d, J=8.8 Hz), 7,22 (2H, d, 1=8.8 H^)? 7.35 (2H, d, J=8.8 Hz ), 7.54 (1H, s), 7.58 (2H, d, 1 = 8.8 Hz), 7.78 (2H, s), 8·49 (1H, s), 8.71 (1H, d, J = 5.2 HZ), 8.74 (1H, s), 8.77 (1H, s). Example 9 N-(4-(6-Cyano-'7-(3-(1,2,3-trityl)propoxy)-4-shengyl X 氲茇 气 )) urea The same procedure as in Example 7 was carried out as described in Example 87. 6-Alkyl-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7 quinolate And 1-(3-chloropropyl)-1,2,3-triazole gave the title compound. mp NMR (DMS 〇-d6) 5 (ppm): 2.41 (2H, m), 3.70 (3H, s), 4·28 (2H, t, J=6.0 Hz), 4.63 (2H, t, J=6.6 Ηζ), 6.52 (1H, d, J=5.4 Hz), 6.86 (2H, d5 J= 8.8 Hz), 7.22 (2H, d, J==8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.57 (1H3 s), 7.58 (2H, d, J=8.8 Hz), 7.73 (1H, sX 8·19 (1H, s), 8·49 (1H, s), 8.72 (1H, d, J=5.4

Hz)，8·74 (1H，s)，8.77(1H，s)。 ·、 實施例10 N- (4- ( 6-氛基-7- (2-甲乳基乙氧甚卜淋基）氫笨美）-Ν'二 (4-氣表基）腺 將4-(4-胺基苯氧基）-7-(2-甲氧基乙氧基）-6-氰基4啉 (109 mg，0.325 mmol)於加熱下溶解於甲苯（5 ml)後，加入 異见酸4-氟苯酯（0·057 ml ’ 0.488 mmol)並加熱回流1小 時。放冷後濾取析出之結晶，用乙酸乙酯洗淨，減壓乾 燥’得到為白色結晶之標題化合物（148 mg，0.3 11 mmol， -161 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7Hz), 8.74 (1H, s), 8.77 (1H, s). · Example 10 N-(4-(6-Akyl-7-(2-methyllacyl ethionyl)hydrogen stupid)-Ν'di(4-Gasyl) gland will be 4- (4-Aminophenoxy)-7-(2-methoxyethoxy)-6-cyano-4 (109 mg, 0.325 mmol) was dissolved in toluene (5 ml) with heating See 4-Fluorophenyl acid (0.057 ml '0.488 mmol) and heated to reflux for 1 h. EtOAc (EtOAc) 148 mg, 0.3 11 mmol, -161 - This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304061 A7 B7

五、發明説明（156: 96·4%” ^-NMR光譜（DMSOd6)5(ppm): 3.36 (3Η，s)，3.76-3.79 (2Η m)，4.41-4.43 (2H，xn)，6.52 (1H，d，J=5.2 Hz), 7.11 (2H，t J=9.0 Hz)，7·23 (2H，d，J=9.0 Hz)，7·46 (2H，q，J=4.8 Hz) 7.57-7.62 (3H，m)，8.71-8.76 (3H，m)，8.82 (1H，s)。 實施例11 基-7-(2-甲乳基乙氧基）-4-4淋基）氣笨多^^ (2 - 口比咬基）月尿 將N-(4-(6 -讯基- 7-(2-甲氧基乙氧基卜4-。奎淋基）氧苯基） 胺基甲酸苯酯（104 mg，0.228 mmol)溶於二甲基亞礙（} ml) 後’加入2 -胺基p比淀（43 mg，Ο ·4 5 7 mmol)，於85 °C及撥掉 下加熱3小時。放冷後，將其在乙酸乙酯與水間分溶，將有 機層用飽和食鹽水洗淨’及用無水硫酸鋼乾燥。〉慮除乾燥 劑及減壓濃縮後，在殘餘物中加入乙酸乙酯-己境，〉慮取析 出之結晶，&amp;減&gt;1：乾燥，得到為白色結晶之標題化合物（86 mg，0· 1 89 mmol，82.7%)。 ·、 iH-NMR光譜（DMSO-d6) (5(ppm): 3·36 (3H，s)，3.75-3.78 (2H， m), 4.39-4.42 (2Η, m), 6.53 (1H, d, J=5.2 Hz), 6.99 (1H, m), 7.18 (1H, d, J=8.4 Hz), 7.26 (2H, d, J=9.2 Hz), 7.56 (1H, d, J=8.4 Hz), 7.62 (1H, s), 7.68-7.77 (3H, m), 8.26 (1H, d, J=5.2 Hz)，8·72 (1H，d, J=5.2 Hz)，8,77 (1H, s)，9·89 (1H, br s) 〇 實施例1 2 Ν_:·( 4- ( 6-氛基-7- ( 2-甲氧基乙氣某) - 4- 口杳琳美） 162- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)V. Description of the invention (156: 96. 4%) ^-NMR spectrum (DMSOd6) 5 (ppm): 3.36 (3Η, s), 3.76-3.79 (2Η m), 4.41-4.43 (2H, xn), 6.52 ( 1H, d, J = 5.2 Hz), 7.11 (2H, t J = 9.0 Hz), 7·23 (2H, d, J = 9.0 Hz), 7·46 (2H, q, J = 4.8 Hz) 7.57- 7.62 (3H, m), 8.71-8.76 (3H, m), 8.82 (1H, s). Example 11 -7-(2-methyllacylethoxy)-4-4) ^^ (2 - mouth to bite base) moon urine will be N-(4-(6-gramyl-7-(2-methoxyethoxyb4-ethylidene)oxyphenyl) carbamic acid Phenyl ester (104 mg, 0.228 mmol) was dissolved in dimethyl sigma (} ml), then '2-amino-p-precipitate (43 mg, Ο · 4 5 7 mmol) was added at 85 ° C and dialed off After heating for 3 hours, after allowing to cool, it is partitioned between ethyl acetate and water, and the organic layer is washed with saturated brine and dried with anhydrous sulfuric acid steel. > After dehumidifying agent and concentration under reduced pressure, residual The title compound (86 mg, 0·1 89 mmol, 82.7%) was obtained as white crystals from the ethyl acetate-hexanes, and the crystals of the precipitates were taken from &lt;&gt; -NMR spectrum (DMSO-d6) (5 (ppm): 3· 36 (3H, s), 3.75-3.78 (2H, m), 4.39-4.42 (2Η, m), 6.53 (1H, d, J=5.2 Hz), 6.99 (1H, m), 7.18 (1H, d, J=8.4 Hz), 7.26 (2H, d, J=9.2 Hz), 7.56 (1H, d, J=8.4 Hz), 7.62 (1H, s), 7.68-7.77 (3H, m), 8.26 (1H, d, J = 5.2 Hz), 8.72 (1H, d, J = 5.2 Hz), 8, 77 (1H, s), 9·89 (1H, br s) 〇 Example 1 2 Ν _:·( 4 - (6-Alkyl-7-(2-methoxyethane) - 4-port 杳美) 162- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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1304061 s1304061 s

AT _ B7____, 五、發明説明（157) Π·3“塞唑-2-基）Μ 以與實施例Π同樣之手法，從Ν-( 4-(6-氰基-7-(2-甲氧基 乙氧基）-4-喹啉基）氧苯基）胺基甲酸苯酯（106 mg，0.233 mmol)得到為淡褐色結晶之標題化合物（37 mg，0·08 mmol，34.4%) 0 iH-NMR光譜(DMSO-d6)5(ppm): 3.36 (3H，s)，3·75-3·79 (2H， m)，4.40-4.43 (2H，m)，6·53 (1H，d，J=5.6 Hz)，7·10 (1H，d， J=3.2 Hz), 7.72 (1H, d, J=8.8 Hz), 7.37 (1H, m), 7.57-7.67 (3H, m), 8.72 (1H, d, J=5.2 Hz), 8.77 (1H, s), 9.53 (1H, br s) ° 實施例13 N-(4二(6-氰基-7-( 2-甲氣基乙氣基）-4-〃杳啉基）氣苯某）-Ν·-(4-羥笨某）脲 以與實施例11同樣之手法，從Ν-(4-(6-氰基-7-(2-甲氧基 乙氧基）-4y奎啉基）氧苯基）胺基甲酸苯酯（in mg，0.257 mmol)得到為淡褐色結晶之標題化合物（52 mg，0.110 mmol，43.0%)。 iji-NMR 光譜（DMS〇-d6) 5 (ppm): 3·36 (3H，s)，3.77-3.79 (2H， m), 4.41-4.43 (2H, m), 6.51 (1H, d5 J=5.2 Hz), 6.67 (2H, d, J=8.0 Hz), 7.15-7.25 (3H, m), 7.57 (2H, d, J=8.0 Hz), 7.62 (1H, s), 8·37 (1H, s), 8·70-8·76 (3H, m)，9.05 (1H，s)。 實施例14 . N-(4_(6 -说基- 7- (2-甲氣基乙氣基）-4 -口杳说基、氧笨基 ί3-曱氣笨基）脲 -163- 本紙張尺度適用中國國家標準(CMS) Α4規格(210 X 297公釐) 1304061 -s A7 _____ B7 五、發明説明（158) 以與實施例11同樣之手法，從Ν·(4·(6•氰基·7 “入甲氧基 乙氧基）-4-峻琳基）氧苯基）胺基甲酸苯酯（12〇 mg，〇.263 mmol)得到為白色結晶之標題化合物（5〇 mg , 〇 i〇3 mm〇1 , 39.2%)。 H-；NMR光if(DMSO-d6)5(ppm): 3·36 (3H，s)，3.72 (3H，s)， 3.76-3.79 (2Η, m), 4.39-4.43 (2H, m), 6.50-6.57 (2H, m), 6·93 (1H，d, J=8.0 Hz)，7.14-7.19 (2H，m)，7·24 (2H，d，J=8.8AT _ B7____, V. Description of the invention (157) Π·3 "pyrazol-2-yl" Μ In the same manner as in Example ,, from Ν-( 4-(6-cyano-7-(2-A) The title compound (37 mg, 0.08 mmol, 34.4%) was obtained as yyyyyyyy. iH-NMR spectrum (DMSO-d6) 5 (ppm): 3.36 (3H, s), 3·75-3·79 (2H, m), 4.40-4.43 (2H, m), 6·53 (1H, d , J=5.6 Hz), 7·10 (1H, d, J=3.2 Hz), 7.72 (1H, d, J=8.8 Hz), 7.37 (1H, m), 7.57-7.67 (3H, m), 8.72 (1H, d, J = 5.2 Hz), 8.77 (1H, s), 9.53 (1H, br s) ° Example 13 N-(4 bis(6-cyano-7-(2-carbyl)ethane )-(4-(6-Cyano-7-() is the same as in Example 11 in the same manner as in Example 11 Phenyl 2-methoxyethoxy)-4y quinolyloxyphenyl)carbamate (in mg, 0.257 mmol) gave the title compound (m. Iji-NMR spectrum (DMS〇-d6) 5 (ppm): 3·36 (3H, s), 3.77-3.79 (2H, m), 4.41-4.43 (2H, m), 6.51 (1H, d5 J=5.2 Hz ), 6.67 (2H, d, J=8.0 Hz), 7.15-7.25 (3H, m), 7.57 (2H, d, J=8.0 Hz), 7.62 (1H, s), 8·37 (1H, s) , 8·70-8·76 (3H, m), 9.05 (1H, s). Example 14 . N-(4_(6 - syl- 7-(2-methyl ethane))杳 杳 、 氧 氧 氧 氧 氧 脲 脲 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 158 In the same manner as in Example 11, phenyl (4·(6·cyano-7) methoxyethoxy)-4-phenylphenoxy)phenylphenyl carbamate (12) The title compound (5 〇 mg, 〇i 〇 3 mm 〇 1 , 39.2%) was obtained as white crystals. H-; NMR light if (DMSO-d6) 5 (ppm): 3·36 (3H, s), 3.72 (3H, s), 3.76-3.79 (2Η, m), 4.39-4.43 (2H, m), 6.50-6.57 (2H, m), 6.93 (1H, d, J=8.0 Hz), 7.14-7.19 (2H, m), 7·24 (2H, d, J=8.8

Hz), 7.59 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.69-8.73 (2H, m), 8.76 (1H，s), 8.80 (1H，s)。 實施例1 5Hz), 7.59 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.69-8.73 (2H, m), 8.76 (1H, s), 8.80 (1H, s). Example 1 5

Nzi—基乙氧幕丄·4·4啉某、氫苽某w (__3 -羥笨某）脹 以與實施例11同樣之手法，從N-(4-(卜氰基甲氧基 乙氧基）-4·喹啉基）氧苯基）胺基甲酸苯酯（1〇2 mg , 〇·234 mmol)得到，淡褐色結晶之標題化合物（25呵，〇 〇53 mmol，23.7%) 〇 H-NMR光譜（DMSO-d6)5(ppm): 3·36 (3H，s)，3.75-3.79 (2H， m)，4·40-4·43 (2H，m)，6.36 (1H，d，J=9.2 Ηζ)，6·52 (1H，d， J-5·2 Hz)，6·79 (1H，d，J=8.0 Hz)，7·〇〇-7·06 (2H，m)，7·23 (2H, d, J=9.2 Hz), 7.58 (2H, d, J-8.8 Hz), 7.62 (1H, s), 8.59 (1H，s)，8·71 (1H，d，J=4.8 Hz)，8·76 (1H，s)，9.31 (1H，br s) 〇 實施例1 6 氰基-7-丄?一-甲氧棊乙氧^心崦。床某）氣笨基w _ -164- 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 A7 B7 五、發明説明（159) 〔2-轉茉某）月展 以與實施例11同樣之手法，從&gt;1-(4-(6-氰基-7-(2-甲氧基 乙氧基）-4-，奎啉基）氧苯基）胺基曱酸苯酯（1〇8 mg，0.237 mmol)得到為淡褐色結晶之標題化合物（78 mg，0.166 mmol，69.9%) 〇 1H-NMR光譜（DMSO-d6)5(ppm): 3·36 (3H，s)，3.76-3.79 (2H， m), 4.40-4.43 (2H, m), 6.52 (1H, d5 J=5.6 Hz), 6.69-6.85 (3H, m), 7.22 (2H, d, J=8.8 Hz), 7.57-7.62 (3H, m), 7.99 (1H3 d, J=8.0 Hz), 8.34 (1H, br), 8.71 (1H, d, 1=5.2 Hz), 8.76 (1H, s), 9.62 (1H, br s) 〇 實施例1 7 ( 6-氰基-7- (2-甲氧基乙氣基[心?杏g林某）氣苯某）·Ν，· Π Η- 2 -咪峻基）脲 將2-胺基咪唑（132 mg，1.0 mmol)溶於二甲基甲醯胺（2 ml) 及水（1 ml)本混合溶媒中後，於室溫加入三乙胺（0.42 ml , 3.〇111111〇1)及氯甲酸苯酯（〇.14 1111，1.1111111〇1)，並攪拌1〇分 鐘。在其中加入4-(4-胺基苯氧基）-7-(2-甲氧基乙氧基）·6· 氰基喹啉（168 mg，0·5 mmol)並攪掉一夜。將反應液用乙 酸乙酯（30 ml)稀釋後，用水（1〇 mi x 2)及飽和食鹽水（10 ml)洗淨，以及有機層用無水硫酸鈉乾燥。遽除乾燥劑，將 遽液減壓濃縮’殘餘物藉由碎凝膠管柱層析（溶出液：乙酸 乙醋：乙醇==95 ·· 5)精製，得到為白色結晶之標題化合物 (20 mg，0.045 mmol，8.98%) 〇 · iH-NMR光譜（DMS〇-d6)5(ppm): 3.36 (3H，s)，3·76-3·79 (2H， -165- 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 〜 、- A7 __B7 五、發明説明（160) m), 4.40-4.43 (2H, m), 6.53 (1H, d, J=5.2 Hz), 6.70 (1H, s), 7.24 (2H, d, J=8.8 Hz), 7.57-7.67 (3H, m), 8.72 (1H, d, 1=5.6 Hz), 8·76 (1H，s)。 實施例1 8 N-(4“6-氰基-7-(2-甲氣基乙氣基）-4-4啉基）氲苯某 (2,4·二氯苽某）服 藉由與實施例10同樣之方法，從4-(4-胺基苯氧基）-7-(2-曱氧基乙氧基）-6-氰基峻琳（106 mg，0.3 16 mmol)得到為白 色結晶之標題化合物（136 mg，0.277 mmol，87·7%)。 iH-NMR光譜(DMSO-d6)5(ppm): 3,36 (3Η, s)，3.76-7.79 (2Η m)，4.40-4.43 (2H，m)，6.52 (1H，d，J=5.2 Hz)，7·04 (1H，m)， 7.23-7.34 (3H，m)，7.57-7.62 (3H, m)，8.06 (1H，m)，8·52 (1H，s)，8·71 (1H，d，J=5.6 Hz)，8·76 (1H，s)，9.16 (1H3 s)。 實施例1 9 坠（4-(6-氨某-7“2-甲氫某匕氫某）-4“奎啉基）氧苯基）1^_ (3-亂基笨某、月尿 ' 藉由與實施例11同樣之方法，從N-(4-(6-氰基-7-(2-甲氧 基乙氧基）-4-喹啉基）氧苯基）胺基甲酸苯酯（1〇9 mg，〇·239 mmol)得SiJ為淡黃色結晶之標題化合物（38 mg，〇·〇79 mmol，33.1%)。 iH-NMR光譜（DMS〇-d6)d(ppm): 3.36 (3H，s)，3.76-3.79 (2H， m)，4.40-4.43 (2H，m)，6.52 (1H，d，J=5.2 Hz), 7.26 (2H，d， J=8.8 Hz), 7.41 (1H, d, J=6.4 Hz), 7.49-· (1H, t, J=8.0 Hz), 7·55-7.62 (3H，m)，7.68 (1H，dd，J=1.2, 8·8 Hz)，7.97 (1H，s)， -166- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 〜 〜- A7 _B7 五、發明説明(~~^7)~~ 8·71 (1H，d，J=6.4 Ηζ)，8·76 (1H，s)，9.00 (1H，s)，9·05 (1H， s) 0 實施例20 N-(4'd_氰基-7-(2-甲氧基乙氣某夸啉基）氣笨某 f 2-氣笨基）脲 藉由與實施例10同樣之方法，從4-(4-胺基苯氧基）-7-( 2-甲氧基乙氧基）-6*氰基p奎淋（109 mg，0.325 mmol)得到為白 色結晶之標題化合物（75 mg，0· 1 59 mmol，48·8 %)。 iH-NMR光譜(DMSO-d6) 5 (ppm): 3·36 (3Η，s)，3.76-3.79 (2Η， m)，4·40-4·43 (2H，m)，6·52 (1H，d，J=5.2 Hz), 7.01 (1H，m)， 7.13 (1H, t, J=8.0 Hz), 7.20-7.27 (3H, m), 7.55-7.63 (3H, m)3 8.14 (1H, t, J=8.0 Hz), 8.56 (1H, br s), 8.72 (1H, d, J-6.4 Hz)，8.76 (1H, s)，9·22 (1H，s) 〇 實施例2 1 N-(4-(_6-氰曱氫基乙氣某）-4-4啉基）氣笨基Ν’-(3-(甲磺醯基）笨某）服 ·、 使4-(4-胺基苯氧基）-7-(2-甲氧基乙氧基）-6-氰基喹啉 (100 mg，0.298 mmol)與二異丙基乙胺（0.057 ml，0.328 mmol)及N-[3-(曱磺醯基）苯基]胺基甲酸苯酯（96 mg， 0.328 mmol)反應，藉由與實施例34同樣之方法，得到為白 色結晶之標題化合物（120 mg，0·225 mmol，75.6%)。 1H-NMR光譜(DMSO-d6)5(ppmV· 3.19 (3H，s)，3.36 (3H，s)， 3.76-3.79 (2H, m), 4.40-4.43 (2H, m), 6.53 (1H, d, 1=5.6 Hz), 7.26 (2H, d, J-8.8 Hz), 7.50-7.69 (6H, m), 8.16 (1H, br s), -167- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 - A7 ___B7______ 五、發明説明（162) 8.72 (1H, d, J=5.2 Hz), 8.76 (1H, s), 8.95 (1H, s), 9.15 (1H, s) 〇 實施例2?. N-(4-(6-氡基-7-(2-甲氩某乙氫某Λ - 4-4啉基）氧苯基）-Nf-(3 -(甲硫某、芡某、驿 藉由與實施例11同樣之方法，從N-(4-(6-氰基-7-(2-甲氧 基乙氧基）·4-喹啉基）氧苯基）胺基甲酸苯酯（193 mg，0.424 mmol)得到為白色結晶之標題化合物（210 mg，0.420 mmol，98.9%) 〇 iH-NMR光譜（DMSO-d6)5(ppm): 2.43 (3H，s)，3·36 (3H，s)， 3.76-3.79 (2Η，m)，4.40-4.43 (2Η，m)，6.52 (1Η，d，J=5.2 Ηζ)， 6.83 (1H, d, J=7.2 Hz), 7.14-7.24 (4H, m)3 7.48 (1H, s), 7.58-7.61 (3H, m), 8.71 (1H, d, J=5.2 Hz), 8.75 (1H, s), 9.62 (1H，s)，9·76 (1H, s)。 實施例23人 4-(6-氨基-7-(2-甲氣基乙氳某）-4-4啉某）氫茉基VN’-環丙基脲 藉由與實施例11同樣之方法，從N-( 4-(6-氰基-7-(2-甲氧 基乙氧基）-4-喹啉基）氧苯基）胺基甲酸苯酯（195 mg，0.428 mmol)得到為白色結晶之標題化合物（145 mg，0.347 mmol，80.9%) 0 1H-NMR光譜(DMSO-d6)5(ppm): 0·4 (2H，br s)，0·63 (2H，d， J=6.8 Hz), 2.53 (1H, m), 3.36 (3H, m),-· 3.76-3.79 (2H, m), 4.40-4.43 (2H, m), 6.42 (1H, s), 6.48 (1H, d, J=5.2 Hz), 6.97 -168 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 装 訂Nzi-based ethoxy oxime·4·4 porphyrin, hydroquinone, w (__3 - hydroxy), in the same manner as in Example 11, from N-(4-(cyanomethoxyethoxy) The title compound (25 〇〇, 〇〇 53 mmol, 23.7%) of bromo-bromo crystall. H-NMR spectrum (DMSO-d6) 5 (ppm): 3·36 (3H, s), 3.75-3.79 (2H, m), 4·40-4·43 (2H, m), 6.36 (1H, d , J=9.2 Ηζ),6·52 (1H,d, J-5·2 Hz),6·79 (1H,d,J=8.0 Hz),7·〇〇-7·06 (2H,m) ,7·23 (2H, d, J=9.2 Hz), 7.58 (2H, d, J-8.8 Hz), 7.62 (1H, s), 8.59 (1H, s), 8.71 (1H, d, J = 4.8 Hz), 8.76 (1H, s), 9.31 (1H, br s) 〇 Example 1 6 Cyano-7-indole-methoxy-methoxycholine. Bed a) gas stupid base w _ -164- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Invention description (159) [2-turned to Mo Mou] The same procedure as in Example 11 was carried out from &gt; 1-(4-(6-cyano-7-(2-methoxyethoxy)-4-, quinolinyl)oxyphenyl)amino decanoic acid. The title compound (78 mg, 0.166 mmol, 69.9%) was obtained as a pale brown crystal. </RTI> <RTIgt; </RTI> NMR (DMSO-d6) 5 (ppm): 3·36 (3H, s), 3.76-3.79 (2H, m), 4.40-4.43 (2H, m), 6.52 (1H, d5 J=5.6 Hz), 6.69-6.85 (3H, m), 7.22 (2H, d, J=8.8 Hz), 7.57-7.62 (3H, m), 7.99 (1H3 d, J=8.0 Hz), 8.34 (1H, br), 8.71 (1H, d, 1=5.2 Hz), 8.76 (1H, s), 9.62 (1H, br s) 〇 Example 1 7 (6-Cyano-7-(2-methoxyethane group [heart? Apricot g Lin) gas benzene) · Ν, · Π Η - 2 - After the 2-aminoimidazole (132 mg, 1.0 mmol) was dissolved in dimethylformamide (2 ml) and water (1 ml), then triethylamine (0.42) was added at room temperature. Ml , 3.〇111111〇1) and phenyl chloroformate (〇.14 1111,1.1111111〇1), and Mix 1〇 minutes. 4-(4-Aminophenoxy)-7-(2-methoxyethoxy)·6·cyanoquinoline (168 mg, 0.5 mmol) was added and stirred overnight. The reaction solution was diluted with ethyl acetate (30 ml), EtOAc (EtOAc) The desiccant was removed, and the hydrazine was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: ethyl alcohol:==95. Mg, 0.045 mmol, 8.98%) 〇· iH-NMR spectrum (DMS〇-d6) 5 (ppm): 3.36 (3H, s), 3·76-3·79 (2H, -165- This paper size applies China National Standard (CNS) A4 Specification (210 x 297 mm) 1304061 ~ , - A7 __B7 V. Description of Invention (160) m), 4.40-4.43 (2H, m), 6.53 (1H, d, J=5.2 Hz ), 6.70 (1H, s), 7.24 (2H, d, J=8.8 Hz), 7.57-7.67 (3H, m), 8.72 (1H, d, 1=5.6 Hz), 8·76 (1H, s) . Example 1 8 N-(4"6-Cyano-7-(2-methylglycolyl)-4-ylolinyl) anthracene (2,4·dichloropyrene) by means of Example 10 was obtained in the same manner from 4-(4-aminophenoxy)-7-(2-decyloxyethoxy)-6-cyanyl phenyl (106 mg, 0.3 16 mmol). The title compound was crystallized (136 mg, 0.277 mmol, 87.7%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 3,36 (3 Η, s), 3.76-7.79 (2 Η m), 4.40- 4.43 (2H, m), 6.52 (1H, d, J = 5.2 Hz), 7·04 (1H, m), 7.23-7.34 (3H, m), 7.57-7.62 (3H, m), 8.06 (1H, m), 8·52 (1H, s), 8.71 (1H, d, J = 5.6 Hz), 8.76 (1H, s), 9.16 (1H3 s). Example 1 9 Fall (4-( 6-Ammonia-7 "2-methylhydrogen hydrazine"-4 "quinoline)oxyphenyl) 1^_ (3- disordered sulphate, urinary urethane) by the same method as in Example 11. , from N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxyphenyl)carbamic acid phenyl ester (1〇9 mg, 〇·239 The title compound (38 mg, 〇·〇 79 mmol, 33.1%) was obtained as a pale yellow crystal. iH-NMR spectrum (DMS 〇-d6) d (ppm): 3.36 (3H, s), 3.76-3.79 (2H, m) 4.40-4.43 (2H,m), 6.52 (1H,d,J=5.2 Hz), 7.26 (2H,d, J=8.8 Hz), 7.41 (1H, d, J=6.4 Hz), 7.49-· (1H , t, J=8.0 Hz), 7·55-7.62 (3H, m), 7.68 (1H, dd, J=1.2, 8·8 Hz), 7.97 (1H, s), -166- This paper size applies China National Standard (CNS) A4 Specification (210 x 297 mm) 1304061 ~ ~- A7 _B7 V. Invention Description (~~^7)~~ 8·71 (1H,d,J=6.4 Ηζ),8·76 (1H, s), 9.00 (1H, s), 9·05 (1H, s) 0 Example 20 N-(4'd-cyano-7-(2-methoxyethane gas) By the same method as in Example 10, 4-(4-aminophenoxy)-7-(2-methoxyethoxy)-6*cyanide was obtained. The title compound (75 mg, 0·1 59 mmol, 48.8%) was obtained as white crystals. iH-NMR spectrum (DMSO-d6) 5 (ppm): 3·36 (3Η, s), 3.76-3.79 (2Η, m), 4·40-4·43 (2H, m), 6·52 (1H ,d,J=5.2 Hz), 7.01 (1H,m), 7.13 (1H, t, J=8.0 Hz), 7.20-7.27 (3H, m), 7.55-7.63 (3H, m)3 8.14 (1H, t, J=8.0 Hz), 8.56 (1H, br s), 8.72 (1H, d, J-6.4 Hz), 8.76 (1H, s), 9·22 (1H, s) 〇 Example 2 1 N- (4-(_6-cyanohydrazinylethane)-4-4 phenyl)) 笨 Ν - '-(3-(methylsulfonyl) phenyl), · 4-(4-amino group Phenoxy)-7-(2-methoxyethoxy)-6-cyanoquinoline (100 mg, 0.298 mmol) with diisopropylethylamine (0.057 ml, 0.328 mmol) and N-[3 The title compound (120 mg, 0. 225 mmol, m. m. m. 75.6%). 1H-NMR spectrum (DMSO-d6) 5 (ppmV· 3.19 (3H, s), 3.36 (3H, s), 3.76-3.79 (2H, m), 4.40-4.43 (2H, m), 6.53 (1H, d , 1=5.6 Hz), 7.26 (2H, d, J-8.8 Hz), 7.50-7.69 (6H, m), 8.16 (1H, br s), -167- This paper size applies to the Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) 1304061 - A7 ___B7______ V. Description of invention (162) 8.72 (1H, d, J=5.2 Hz), 8.76 (1H, s), 8.95 (1H, s), 9.15 (1H, s 〇Example 2?. N-(4-(6-Mercapto-7-(2-methyl argon) - 4-4 phenyl) oxyphenyl)-Nf-(3 -(methyl sulphide) A, 芡, 驿 from N-(4-(6-cyano-7-(2-methoxyethoxy)·4-quinolinyl)oxyphenyl group by the same method as in Example 11. The title compound (210 mg, 0.420 mmol, 98.9%) was obtained as white crystals of phenyl phenyl phenyl ester ( EtOAc ( EtOAc) ), 3·36 (3H, s), 3.76-3.79 (2Η, m), 4.40-4.43 (2Η, m), 6.52 (1Η, d, J=5.2 Ηζ), 6.83 (1H, d, J=7.2 Hz), 7.14-7.24 (4H, m)3 7.48 (1H, s), 7.58-7.61 (3H, m), 8.71 (1H, d, J=5.2 Hz), 8.75 (1H, s), 9.62 (1H ,s),9·76 (1H, s). Example 23: Human 4-(6-amino-7-(2-methylethylidene)-4-4 porphyrin) Hydrogen yl-VN'-cyclopropylurea Example 11 In the same manner, phenyl N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxyphenyl)carbamate (195 mg, The title compound (145 mg, 0.347 mmol, 80.9%) was obtained as white crystals (1H-NMR spectrum (DMSO-d6) 5 (ppm): 0·4 (2H, br s), 0·63 (2H) ,d, J=6.8 Hz), 2.53 (1H, m), 3.36 (3H, m), -· 3.76-3.79 (2H, m), 4.40-4.43 (2H, m), 6.42 (1H, s), 6.48 (1H, d, J=5.2 Hz), 6.97 -168 - This paper size applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) Binding

線 1304061 % 〜· A7 ___B7 五、發明説明（163) (2H, d, J=9.2 Hz), 7.53 (2H, d, 1=9.2 Hz), 7.60 (1H, s), 8.44 (1H，s)，8.70 (1H，d，J=4.8 Hz)，8.74 (1H，s)。 實施例24 (6-氰基-7-(2-甲氧基乙氫某4-4啉某）氳茉某Nf-L4-氟-2-軺某茇某、Μ 藉由與實施例11同樣之方法，從N-( 4-(6-氰基-7-( 2-甲氧 基乙氧基）-4-0奎琳基）氧苯基）胺基甲酸苯酯（156 mg，0.343 mmol)得到為淡黃色結晶之標題化合物（132 mg，〇 27〇 mmol，78.9%)。 W-NMR光譜（DMS〇-d6) 5 (ppm): 3.36 (3H，s)，3.76-3.79 (2H， m), 4.40-4.43 (2H, m), 6.52 (1H, d, J=5.6 Hz), 6.57 (1H, m), 6.62 (1H, m), 7.23 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 7.62 (1H, s), 7.98 (1H, m), 8.12 (1H5 s), 8.71 (1H, d, J=5.6 Hz)，9.40 (1H, s), 10.47 (1H，s)。 賞施例2 5 人 6-氨基- 7-(2-曱氣某乙氫D-4- ♦啉基）氣-2-氩苯 Ρ-Ν、Π.3-嘍唑-2-某）脹Line 1304061 % ~· A7 ___B7 V. Description of invention (163) (2H, d, J=9.2 Hz), 7.53 (2H, d, 1=9.2 Hz), 7.60 (1H, s), 8.44 (1H, s) , 8.70 (1H, d, J = 4.8 Hz), 8.74 (1H, s). Example 24 (6-Cyano-7-(2-methoxyethylhydrogen 4-4 morphine) 氲Num-Nf-L4-fluoro-2-indole Μ, 藉 By the same as Example 11 N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-0 quinolinyl)oxyphenyl)carbamic acid phenyl ester (156 mg, 0.343 mmol) The title compound (132 mg, 〇27〇mmol, 78.9%) was obtained as pale yellow crystals. W-NMR spectrum (DMS 〇-d6) 5 (ppm): 3.36 (3H, s), 3.76-3.79 (2H, m), 4.40-4.43 (2H, m), 6.52 (1H, d, J=5.6 Hz), 6.57 (1H, m), 6.62 (1H, m), 7.23 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 7.62 (1H, s), 7.98 (1H, m), 8.12 (1H5 s), 8.71 (1H, d, J=5.6 Hz), 9.40 (1H, s) , 10.47 (1H, s). Appreciation Example 2 5 People 6-Amino- 7-(2-helium-a certain hydrogen hydride D-4- ♦ morpholinyl) gas-2-argon benzoquinone-Ν, Π.3- Oxazole-2-one)

將N-(4-(6-氰基-7-(2-甲氧基乙氧基）-4-喹啉基）氧-2-氟 苯基）胺基甲酸苯酯（200 mg)及2-胺基嘍唑（85 mg)溶於二 甲基甲醯胺（1 ml)中，在其中加入三乙胺0· 12 ml，並於90 °C加熱攪拌2小時。放冷後，加入水及濾取析出之個體，將 其用乙酸乙酯洗淨，得到為淡褐色結晶之標題化合物110 mg (產率 57%)。 J iH-NMR光譜（DMSO-d6)5(PPm): 3.37 (3H，s)，3.75-3.80 (2H， _ _ -169- 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） !3〇4〇61Phenyl N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxy-2-fluorophenyl)carbamate (200 mg) and 2 -Aminocarbazole (85 mg) was dissolved in dimethylformamide (1 ml), triethylamine 0. 12 ml was added thereto, and the mixture was stirred under heating at 90 °C for 2 hours. After the mixture was allowed to cool, water was added, and the precipitated product was filtered, and ethyl acetate was evaporated to give the title compound 110 mg (yield: 57%). J iH-NMR spectrum (DMSO-d6) 5 (PPm): 3.37 (3H, s), 3.75-3.80 (2H, _ _ -169- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297吨) !3〇4〇61

五、發明説明（164) m), 4.40-4.45 (2H, m), 6.63 (1H, d, J=5.6 Hz), 7.14 (1H, d, J=3.2 Hz), 7.16-7.20 (1H, m), 7.39 (1H, d, J=3.2 Hz), 7.42- 7.47 (1H, m), 7.64 (1H, s), 8.21-8.27 (1H, m), 8.74-8.76 (2H, m) 〇 f施例26 Ηζ1·4-(6-氰基- 7-(2·甲氧基乙氧基）_4· g奋啉基）氫·2_最茉 基）-Ν’-瑷丙某月尿 藉由與實施例25同樣之方法，從Ν-(4-(6-氰基-7-(2-甲氧 基乙氧基）-4-喳啉基）氧-2-氟苯基）胺基甲酸苯酯（147 mg , 〇·310 mmol)得到為白色結晶之標題化合物（83 mg，〇.19〇 mmol，61.3%) 0 iH-NMR 光譜（DMS〇-d6)5(ppm): 0.40 (2H，br)，0.61-0.66 (2H, m), 2.53 (1H, m), 3.36 (3H, s), 3.76-3.79 (2H, m), 4.40-4.43 (2H, m), 6.58 (1H, d, J=5.6 Hz), 6.79 (1H5 d, J=2.0 Hz), 7.08 (1H, dd·, J=2.0, 10.4 Hz), 7.32 (1H, dd, J=2.4, 11.6 Hz), 7.62 (1H，s)，8.18-8.22 (2H，m)，8.71-8.74-(2H，m)。 f施例27 也1_( 4- ( 6-氰基-7- (2-曱氧基乙氡基）-4- g奎g林基）氣笨基）-n，- 環丙曱某脲 藉由與實施例11同樣之方法，從N-( 4-(6-氰基-7-(2-甲氧 基乙氧基）-4-喹啉基）氧苯基）胺基甲酸苯酯（157 mg，0.345 mmol)得到為白色結晶之標題化合物（144 mg，0.333 mmol，96.6%)。 ： 1H-NMR 光譜（DMS〇-d6)d (ppm): 0.16-0.18 (2H，m)，0.39- -170 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐）V. INSTRUCTIONS (164) m), 4.40-4.45 (2H, m), 6.63 (1H, d, J=5.6 Hz), 7.14 (1H, d, J=3.2 Hz), 7.16-7.20 (1H, m ), 7.39 (1H, d, J=3.2 Hz), 7.42- 7.47 (1H, m), 7.64 (1H, s), 8.21-8.27 (1H, m), 8.74-8.76 (2H, m) 〇f施Example 26 Ηζ1·4-(6-Cyano-7-(2·methoxyethoxy)_4·g-propionyl)hydrogen·2_maximyl)-Ν'-瑷In the same manner as in Example 25, from Ν-(4-(6-cyano-7-(2-methoxyethoxy)-4-indolyl)oxy-2-fluorophenyl)carbamic acid The title compound (83 mg, 〇.19 〇 mmol, 61.3%) was obtained as white crystals (yield: 147 mg, EtOAc) , br), 0.61-0.66 (2H, m), 2.53 (1H, m), 3.36 (3H, s), 3.76-3.79 (2H, m), 4.40-4.43 (2H, m), 6.58 (1H, d , J=5.6 Hz), 6.79 (1H5 d, J=2.0 Hz), 7.08 (1H, dd·, J=2.0, 10.4 Hz), 7.32 (1H, dd, J=2.4, 11.6 Hz), 7.62 (1H , s), 8.18-8.22 (2H, m), 8.71 - 8.74 - (2H, m). f Example 27 also 1_(4-(6-cyano-7-(2-decyloxyethyl)-4-g-quinegyl))-n,-cyclopropanone From the same procedure as in Example 11, phenyl N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxyphenyl)carbamate ( The title compound (144 mg, 0.333 mmol, 96.6%) : 1H-NMR spectrum (DMS〇-d6)d (ppm): 0.16-0.18 (2H, m), 0.39- -170 This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm)

% 訂% order

線 1304061 A7 B7 165 五、發明説明（ 0·43 (2H，m)，0·94 (1H，m)，2.97 (2H，t，J=6.4 Ηζ)，3·36 (3H， s)5 3.76-3.79 (2H, m), 4.40-4.43 (2H, m), 6.22 (1H, m), 6.49 (1H, d, J=5.6 Hz), 7.17 (2H, d, J=8.8 Hz), 7.52 (2H, d, J=8.8Line 1304061 A7 B7 165 V. Description of invention (0·43 (2H, m), 0·94 (1H, m), 2.97 (2H, t, J=6.4 Ηζ), 3·36 (3H, s)5 3.76 -3.79 (2H, m), 4.40-4.43 (2H, m), 6.22 (1H, m), 6.49 (1H, d, J=5.6 Hz), 7.17 (2H, d, J=8.8 Hz), 7.52 ( 2H, d, J=8.8

Hz)，7.61 (1H，s)，8.60 (1H，s)，8.70 (1H，d，J=5.2 Hz), 8.75 (1H，s)。 實施例28 1.(4-(6-讯基..-7-(2-甲^^氧基）-4二邊啉某）氛_2_氣笨 基）-N、環丙基甲某服 藉由與實施例25同樣之方法，從N-(zU(卜氰基·7_(2•甲氧 基乙氧基）-4-喹淋基）氧-2-氟苯基）胺基甲酸苯酯（147 mg， 0·310 mmol)得到為白色結晶之標題化合物（83 mg , 〇 19〇 mmol，61.3%)。 1H.NMR^#(DMS〇.d6)5(ppm): 〇.i6.〇.18 (2H? m)j 〇 41-0·46 (2H, m)，0·94 (1H，m)，2·99 (2H，t，J==6 〇 Hz)，3 % (3H， s)，3.76-3.7M2H，m)，4.40-4.43 (2H，m)，6·58 (1H，d，j=5 j Hz), 6.71 (1H，t，J=5.6 Hz)，7.08 (1H, d，A9.2 Hz)，7 ’33 (1H dd，&gt;2.8, 11.6 Hz)，7.63 (1H，s)，8·24 (1H，t，jL92 8.38 (1H，s)，8·55-8·59 (2H，m)。 ’ ’’ 實施例29 N-(4-( 6-氰基-7-Π-(嗎福二体-4-基）丙氣〇 使用N- (4- ( 6-氰基-7-經基4淋-4-基氧）〇 -氣苯基） (2,4·二氟苯基）脲（100 mg，0.2220 &amp; _ 丁王』為淡黃色結 晶之標題化合物（35 mg，0.0606 mmol，27.30%) 171 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 — s- A7 B7 五、發明説明（166) iH-NMR光譜（DMS〇-d6)5(ppm): 1·99 (2H，m)，2·38 (4H，br s)，2·50 (2H，t，J=7.2 Hz)，3.57 (4H，t，J=4.6 Hz)，4.33 (2H，t， J=6.4 Hz), 6.62 (1H, d, J=5.4 Hz), 7.06 (1H, m), 7.15 (1H5 m)，7·32 (1H，ddd，J=2.8 Hz，8·8 Hz，11·6 Hz)，7.41 (1H，dd， J=2.8 Hz, 11·6 Hz)，7.61 (1H，s)，8.12 (1H，m)，8.27 (1H，dt， J=2.0 Hz，9.2 Hz)，8.74 (1H，s)，8·74 (1H，d，J=5.4 Hz)，8.99 (1H，m)，9.07 (1H，m)。 實施例30 N-(4-(6-氰基(二乙胺基）丙氣基）-4-4啉氣）笨基V 氟笨基）脲 藉由與實施例7同樣之方法，從6-氰基-4-(4-((4-氟苯胺 基）羰基）胺基苯氧基）-7-4啉酸鈉（110 mg，0.252 mmol)， 得到為淡褐色結晶之標題化合物（69 mg，0.13 1 mmol， 51.9%)。 1H-NMR 光镨（DMS〇-d6)5(ppm)·· 0.95 (6H，t，J=7.2 Hz)， 1.89-1.95 (2H, m), 2.44-2.49 (4H, m), 2：58-2.62 (2H, m), 4.31 (2H, t, J=6.0 Hz), 6.51 (1H, d, J=5.2 Hz), 7.11 (2H3 t, J=8.4 Hz), 7.23 (2H, d, J=8.8 Hz), 7.44-7.48 (2H, m), 7.56-7.57 (2H, m), 7.60 (1H, s)5 8.71 (1H, d, J=5.2 Hz), 8.74-8.76 (2H, m)，8·85 (1H，s)。 實施例3 1 N-i4-(6-氰基- 7-Π“4-嗎福啉基）丙基）-4- 4啉基）氣笨 基）-N’-M-氣笨基）脲 藉由與實施例7同樣之方法，從6-氰基-4-(4-((4-氟苯胺 -172- 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 1304061 A7 _____B7 五、發明説明（167) 基）羰基）胺基苯氧基）-7-喹啉酸鹽（11〇 mg，0.252 mmol)， 仔到為淡褐色結日日之標題化合物（73 mg，0.135 mmol， 53.5%) 〇 iH-NMR 光譜（DMSO-d6)(5(ppin): 1·99 (2Η，t，J=6.4 Hz), 2.30-2.60 (6H, m), 3.55-3.58 (4H, m), 4.31-4.34 (2H, m), 6.51 (1H，d，J=5.2 Hz)，7·11 (2H，t，J=8,8 Hz)，7·23 (2H，d， J=9.2 Hz)，7.44-7.48 (2H，m)，7·57-7·60 (3H，m)，8.70-8.75 (3H，m)，8·82 (1H，s) 〇 實施例32 K 6-氰基-Ό二甲氧乙氧基4-4啉基、氣氯苽某v 藉由與實施例25同樣之方法，從N-(4-(6-氰基-7-(2-甲氧 基乙氧基）-4-喹啉基）氧-2-氟苯基）胺基甲酸苯酯（25〇 mg) 及2-胺基吡啶（100 mg)，得到為淡褐色結晶之標題化合物 210 mg(產争84%)。 W-NMR光譜（DMS〇-d6)5(ppm): 3.36 (3H;、s)，3.75-3.80 (2H， m), 4.39-4.45 (2H, m), 6.64 (1H, d, J=5.2 Hz), 7.00-7.05 (1H, m), 7.15-7.19 (1H, m), 7.37-7.47 (2H, m), 7.64 (1H, s), 7.50-7.80 (1H, m), 8.25-8.30 (1H, m)5 8.3 1-8.37 (1H, m), 8.74 (1H，d，J=5.2 Hz), 8·76 (1H，s), 9·87 (1H, s)。 實施例33 Ν·- (4- ( 6-氰基-7-丄2-甲氣基乙氣基心4 g林基）氧-2-氟苯 基W-Π-甲硫墓）茉某-* 藉由與實施例25同樣之方法，從N-( 4-(6-氰基-7-( 2-甲氧 -173- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） !3〇4〇61 、 A7 ---------- B7 五、發明説明（168) 基乙氧基）-4-喹啉基）氧-2-氟苯基）胺基甲酸苯酯（160 mg) 及3-(甲硫基）苯胺（88 mg)，得到為淡褐色結晶之標題化合 物 100 mg(產率 61%)。 ^-NMR光譜（DMSO-d6)5(ppm): 2.43 (3H，s)，3.36 (3H，s)， 3.75- 3.80 (2H, m)3 4.40-4.45 (2H, m), 6.62 (1H, d, J=5.6 Hz), 6.86-6.89 (1H，m)，7.11-7.17 (2H，m)，7.20-7.25 (1H，m)， 7.37-7.43 (1H, m), 7.47 (1H, s), 7.63 (1H, s), 8.21-8.28 (1H, m)，8.66 (1H，br s)，8.73-8.76 (2H，m)，9.11-9.13 (1H，m)。 實施例34 6-氰某-7-f 2-甲氫基乙氣基4-4啉某）氣-2-氯芡 甲磺醯某）茉某）脲 將4-(4-胺基-3-氟苯氧基）-6-氰基-7-(2-甲氧基乙氧基）-喹啉（106 mg)及N-(3-(甲磺醯基）苯基）胺基甲酸苯酯（96 mg)加至甲苯5 ml中，再加入二異丙基乙胺0.06 ml，並加熱 回流3小時4放冷後加入乙酸乙酯，以及過濾析出之不溶 物。將濾液濃縮得到之殘餘物用四氫呋喃溶解，在其中加 入甲苯，濾取析出之固體，得到為淡褐色結晶之標題化合 物13 mg(產率8%)。 1H-NMR光譜（DMS〇-d6)5(ppm): 3·20 (3H，s)，3.35 (3H，s)， 3.75- 3.80 (2H, m), 4.38-4.43 (2H, m), 6.63 (1H, d, J=5.2 Hz), 7.14-7.17 (1H, m), 7.39-7.45 (1H, m), 7.51-7.61 (2H, m), 7.62-7.70 (2H, m), 8.16-8.27 (2H, m), 8.73-8.76 (3H, m), 9.47-9.49 (1H, m)。 ： 實施例3 5 -174- 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） 1304061 A7 B7 五、發明説明（169) 氰皋：7-(2-甲氧摹乙氧基）-4-,套啉某、氧^2_氣^ 基）-N1-(2-( i·茇甚、啤 將4-(4-胺基-3-氟苯氧基）-6-氰基-7-(2-甲氧基乙氧基） 4啦（100 mg)加至甲苯4·5 mi中，並加熱回流。在其中加入 異氰酸（2-氟苯基）酯（0.05 mi)並加熱回流丨小時。放冷後， 濾取析出之固體，用乙酸乙酯/甲苯洗淨，得到為淡褐 色結晶之標題化合物1 〇〇 mg(產率72%)。 lH-NMR^lt(DMSO-d6) 5 (ppm): 3.37 (3H, s), 3.75-3.80 (2H, m)，4.4CM.45 (2H，m)，6·62 (1H，d，5·6 Hz), 6.97-7·05 (1H， m)，7·11-7·18 (1H，m)，7.21-7.28 (1H，m)，7.38-7.45 (1H，m)， 7.64 (1H, s), 8.14-8.20 (1H, m), 8.26-8.33 (1H, m), 8.73- 8·76 (2H，m)，9·06 (1H，br s)，9.14 (1H，br s)。 實施例36 10(6-氰棊-7-甲氡基-4-4氧苯某）_Ν，“2·心二氟 苯基）脹 - 將4-(4-胺基苯氧基）-6-氰基-7_甲氧基喳啉（18〇 mg)加至 甲苯5·5 ml中，並加熱回流。在其中加入異氰酸（2,4•二氟 苯基）酯（0.12 ml)並加熱回流1小時。放冷後，濾取析出之 固體，用乙酸乙酯/曱苯=1/1洗淨，得到為淡褐色結晶之標 題化合物195 mg(產率70%)。 iH-NMR光譜（DMS〇-d6)5(ppm): 4,〇5 (3H，s), 6.52 (m，d, 卜5·2 Hz)，7.01-7.08 (1H，m)，7.21-7.34 (3H，m)，7.56-7.62 (3H, m), 8.02-8.10 (1H, m), 8.52 (1H, sy, 8.72 (1H, d, J=5.2 Hz)，8·76 (1H，s)，9·18 (1H，s) 〇 _ -175^ 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 ' --· 一 A7 ______B7 五、發明説明（170) 實施例37 氰基甲氧基-心呤啉基）氫茉基）-N，-苯 將4-(4-胺基苯氧基）-6-氰基-7-甲氧基喹啉（148 mg)加至 甲苯5.5 ml中，並加熱回流。在其中加入異氰酸苯酯（〇〇8 ml)並加熱回流1小時。放冷後，遽取析出之固體，用乙酸 乙g旨/甲苯=in洗淨，得到為淡褐色結晶之標題化合物15〇 mg。 iH-NMR光譜（DMS〇-d6) &lt;5(ppm): 4·05 (3H，s)，6.50-6.54 (1H， m), 6.96 (ΐ, 1Η, 7.2 Hz), 7.23 (2H, d, J=9.2 Hz), 7.27 (2H, d, J=7.2 Hz), 7.44 (2H, d, J=7.2 Hz), 7.56^7.62 (3H, m), 8.68-8.77 (3H，m)，8.83 (1H，br s)。 實施例3 8 (4- (6-氰基-7-甲氧基- 4-4淋某）氣笨基）- N，- ( u 丁基）腺 將4-(4-胺基苯氧基）-6-氰基-7·曱氧基喹淋（150 mg)加至 甲苯2.5 ml及乙腈2·5 ml中，並加熱回流。在其中加入異氰 酸正-丁 g旨（〇. 12 ml)並加熱回流1小時。政冷後，滤取析出 之固體，用乙酸乙酯/甲苯=1/1洗淨，得到為淡褐色結晶之 標題化合物110 mg(產率55%)。 iH-NMR 光譜（DMSO-d6) &lt;5 (ppm): 0.88 (3H，t，J=7.6 Hz), 1.25^1.45 (4H, m), 3.04-3.11 (2H, m), 4.05 (3H, s), 6.13 (1H, t, J=5.6 Hz), 6.49 (1H, d, J=5.6 Hz), 7.16 (2H, d, J=9.2 Hz), 7.52 (2H, d, 1=9.2 Hz), 7.58 (1H, s), 8.55 (1H, s), 8.71 (1H, d，J=5.6 Hz), 8·75 (1H，s)。 : 實施例3 9 -176- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 _____B7 五、發明説明（171) N二(4_ ( 6-氣基氧基:企喳啉我丄氧笨基N，· f 4_氟苯某、 a 將4-(4-胺基苯氧基）-6_氰基-7_甲氧基乙氧基喹啉（15〇 mg)加至甲苯5.0 ml及乙腈2·5…中，並加熱回流。在其中 加入異氰酸4-氟苯酯（〇. 12 ml)並加熱回流丨小時。放冷後， 濾取析出之固體，用乙酸乙酯/甲苯=丨/〗洗淨，得到為淡褐 色結晶之標題化合物150 mg(產率68%)。 W-NMR光譜（DMS〇-d6)5(ppm): 4·05 (3H，s)，6.52 (1H，d， J=5.6 Hz), 7.08-7.14 (2H, m), 7.23 (2H, d, J=8.8 Hz), 7.43- 7.49 (2H，m)，7.56-7.61 (3H，m)，8·71-8·76 (3H，m)，8.85 (1H, s)。 實施例40 土（4-(6-氰基甲氣某套啉某、氣笨基_Ν··Γ2_吡啶某、 將N-(4-(f氰基-7-曱氧基-4-喹啉基）氧苯基）胺基甲酸苯 酯（150 mg)及2-胺基吡啶（69 mg)溶於二申基亞躐1 mi中， 於80°C下加熱攪拌1.5小時。放冷後，加入水及濾取析出之 個體，將其用乙酸乙酯洗淨，得到為淡褐色結晶之標題化 合物82 mg (產率54%)。 iH-NMR光譜（DMS〇-d6)5(PPm): 4·05 (3H，s)，6.54 (1H，d， J=5.6 Hz), 6.98-7.03 (1H, m), 7.26-7.30 (2H, m), 7.45-7.52 (1H, m)，7.60 (1H，s)，7.63-7.78 (3H，m), 8.25-8.30 (1H，m)， 8.73 (1H, d, J=5.6 Hz), 8.78 (1H, s), 9.5? (1H, s), 10.67 (1H, -177- t紙張尺度適用中國國家標準(CNS) A4規祐297公愛) 1304061 〜 - A7 _ B7 ___ 五、發明説明（172) f施例41 N-(4-(6-氨基-7-甲i篡乙氫某-4-4啉基）氧笨基Ν’- η-口比 &lt; 基）月尿 以與實施例40同樣之方法，從Ν-(4-(6-氰基-7-甲氧基-4-喹啉基）氧苯基）胺基甲酸苯酯（100 mg)及3-胺基吡啶（46 mg)，得到為淡褐色結晶之標題化合物32 mg(產率32%)。 iH-NMR光譜（DMSO-d6)5(ppm): 4.05 (3H，s)，6·53 (1H，d， J=5.2 Hz), 7.22-7.34 (3H, m), 7.57-7.63 (3H, m), 7.91-7.96 (1H，m)，8.17-8.20 (1H，m)，8.59-8.63 (1H，m)，8.73 (1H，d， J=5.2 Hz)，8·76 (1H，s)，8·91 (1H，br s)，9.00 (1H，br s)。 f施例42 N-(4 -(6-¾基-7-甲氣基乙氣基g林基）氣笨某- (4- 口比 &lt; 基）月尿 以與實施例40同樣之手法，從N-(4-(6-氰基-7-曱氧基-4-峻啉基）氧苯基）胺基甲酸苯酯（150 mg)及4-胺基吡啶（69 mg)，得到為淡褐色結晶之標題化合物45 ^ng(產率30%)。 iH-NMR 光譜（DMS〇-d6)5(ppm): 4.05 (3H，s)，6·54 (1H，d， J=5.2 Hz), 7.26 (2H, d, J=9.0 Hz), 7.43 (2H, d, J-7.0 Hz), 7.57-7.64 (3H, m)，8·35 (2H，d, J=7.〇 Hz), 8.71-8.77 (2H，m), 9·05 (1H，br s)，9.16 (1H，br s) 〇 會施例43 4- ( 6-氨某-7- (3 -二乙胺基）丙氧莘）-4-。杏说其、氮笨基、· 甲氮苽某）脲 : 以與實施例7同樣之手法，從6-氰基-4-(4-((4-甲氧苯胺 -178- 本紙張尺度適用中國國家標準(CNS)Α4規格(210 &lt;297公爱）Hz), 7.61 (1H, s), 8.60 (1H, s), 8.70 (1H, d, J = 5.2 Hz), 8.75 (1H, s). Example 28 1. (4-(6-Tenyl..-7-(2-methyl^oxy)-4di- porphyrin)) _2 _ _ _ _ _ _ _ _ _ By the same method as in Example 25, from N-(zU(cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)carbamic acid The title compound (83 mg, 〇19 mmol, 61.3%) was obtained as white crystal. 1H.NMR^#(DMS〇.d6)5(ppm): 〇.i6.〇.18 (2H? m)j 〇41-0.46 (2H, m),0·94 (1H,m), 2·99 (2H, t, J==6 〇Hz), 3 % (3H, s), 3.76-3.7M2H, m), 4.40-4.43 (2H, m), 6·58 (1H, d, j =5 j Hz), 6.71 (1H, t, J = 5.6 Hz), 7.08 (1H, d, A9.2 Hz), 7 '33 (1H dd, &gt; 2.8, 11.6 Hz), 7.63 (1H, s ), 8·24 (1H, t, jL92 8.38 (1H, s), 8·55-8·59 (2H, m). ' '' Example 29 N-(4-( 6-Cyano-7-) Π-(?福二-4-yl)propene gas using N-(4-(6-cyano-7-carbyl-4-oxo-4-yloxy)phosphonium-phenyl) (2,4· Difluorophenyl)urea (100 mg, 0.2220 & _ Dingwang) is the title compound of light yellow crystals (35 mg, 0.0606 mmol, 27.30%) 171 - This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 x 297 mm) 1304061 — s- A7 B7 V. Description of invention (166) iH-NMR spectrum (DMS〇-d6) 5 (ppm): 1·99 (2H, m), 2·38 (4H, br s), 2·50 (2H, t, J = 7.2 Hz), 3.57 (4H, t, J = 4.6 Hz), 4.33 (2H, t, J = 6.4 Hz), 6.62 (1H, d, J=5.4 Hz), 7.06 (1H, m), 7.15 (1H5 m), 7·32 (1H, ddd, J=2.8 Hz 8·8 Hz, 11·6 Hz), 7.41 (1H, dd, J=2.8 Hz, 11·6 Hz), 7.61 (1H, s), 8.12 (1H, m), 8.27 (1H, dt, J= 2.0 Hz, 9.2 Hz), 8.74 (1H, s), 8.74 (1H, d, J = 5.4 Hz), 8.99 (1H, m), 9.07 (1H, m). Example 30 N-(4- (6-Cyano(diethylamino)propenyl)-4-4 porphyrin) (indolyl V fluorophenyl)urea in the same manner as in Example 7, from 6-cyano-4-(4) -((4-Fluoroanilinyl)carbonyl)aminophenoxy)-7- oxalate (110 mg, <RTI ID=0.0></RTI> </RTI> <RTIgt; ). 1H-NMR 镨 (DMS〇-d6) 5 (ppm)·· 0.95 (6H, t, J=7.2 Hz), 1.89-1.95 (2H, m), 2.44-2.49 (4H, m), 2:58 -2.62 (2H, m), 4.31 (2H, t, J=6.0 Hz), 6.51 (1H, d, J=5.2 Hz), 7.11 (2H3 t, J=8.4 Hz), 7.23 (2H, d, J =8.8 Hz), 7.44-7.48 (2H, m), 7.56-7.57 (2H, m), 7.60 (1H, s)5 8.71 (1H, d, J=5.2 Hz), 8.74-8.76 (2H, m) , 8.85 (1H, s). Example 3 1 N-i4-(6-cyano-7-anthracene 4-tetrafolinyl)propyl)-4- 4 phenyl)m-phenyl)-N'-M-gas-based urea By the same method as in Example 7, from the 6-cyano-4-(4-((4-fluoroaniline-172-) paper scale applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 _____B7 V. Description of the invention (167) carbonyl)aminophenoxy)-7-quinolinate (11 mg, 0.252 mmol), as the title compound (73 mg, 0.135 mmol, 53.5%) 〇iH-NMR spectrum (DMSO-d6) (5 (ppin): 1·99 (2Η, t, J=6.4 Hz), 2.30-2.60 (6H, m), 3.55-3.58 (4H , m), 4.31-4.34 (2H, m), 6.51 (1H,d,J=5.2 Hz),7·11 (2H,t,J=8,8 Hz),7·23 (2H,d,J =9.2 Hz), 7.44-7.48 (2H, m), 7.57-7.60 (3H, m), 8.70-8.75 (3H, m), 8.82 (1H, s) 〇 Example 32 K 6 -Cyano-indenyloxyethoxy 4-4 phenyl group, chloroquinone v, by the same method as in Example 25, from N-(4-(6-cyano-7-(2-A) Phenoxyethoxy)-4-quinolinyl)oxy-2-fluorophenyl)carbamic acid phenyl ester (25 mg) and 2-aminopyridine (100 mg), The title compound is 210 mg (yield 84%) to light brown crystals. W-NMR spectrum (DMS 〇-d6) 5 (ppm): 3.36 (3H;, s), 3.75-3.80 (2H, m), 4.39 -4.45 (2H, m), 6.64 (1H, d, J=5.2 Hz), 7.00-7.05 (1H, m), 7.15-7.19 (1H, m), 7.37-7.47 (2H, m), 7.64 (1H , s), 7.50-7.80 (1H, m), 8.25-8.30 (1H, m)5 8.3 1-8.37 (1H, m), 8.74 (1H,d,J=5.2 Hz), 8·76 (1H, s), 9·87 (1H, s). Example 33 Ν·- (4-(6-Cyano-7-fluorene-2-methyl ethane-based 4 g forest) oxy-2-fluorobenzene Base W-Π-methylsulfide tomb) Momo-* by the same method as in Example 25, from N-(4-(6-cyano-7-(2-methoxy-173-) paper scale China National Standard (CNS) A4 specification (210 X 297 mm) !3〇4〇61, A7 ---------- B7 V. Description of invention (168) ethoxylated)-4-quino Phenylphenyl)oxy-2-fluorophenyl)carbamate (160 mg) and 3-(methylthio)aniline (88 mg) afforded the title compound 100 mg (yield: 61%) . ^-NMR spectrum (DMSO-d6) 5 (ppm): 2.43 (3H, s), 3.36 (3H, s), 3.75- 3.80 (2H, m)3 4.40-4.45 (2H, m), 6.62 (1H, d, J=5.6 Hz), 6.86-6.89 (1H, m), 7.11-7.17 (2H, m), 7.20-7.25 (1H, m), 7.37-7.43 (1H, m), 7.47 (1H, s) , 7.63 (1H, s), 8.21-8.28 (1H, m), 8.66 (1H, br s), 8.73-8.76 (2H, m), 9.11-9.13 (1H, m). Example 34 6-Cyanide-7-f 2-methylhydroethane group 4-4 phenyl) gas-2-chloroindole methane sulfonate a) hydrazine urea 4-(4-amino-3 -fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)-quinoline (106 mg) and N-(3-(methylsulfonyl)phenyl)carbamic acid benzene The ester (96 mg) was added to 5 ml of toluene, and then 0.06 ml of diisopropylethylamine was added thereto, and the mixture was heated under reflux for 3 hours. 4 After cooling, ethyl acetate was added, and the precipitated insoluble material was filtered. The residue obtained by concentrating the filtrate was dissolved in tetrahydrofuran, toluene was added, and the precipitated solid was filtered to give the title compound (yield 8%) as pale brown crystals. 1H-NMR spectrum (DMS〇-d6) 5 (ppm): 3·20 (3H, s), 3.35 (3H, s), 3.75- 3.80 (2H, m), 4.38-4.43 (2H, m), 6.63 (1H, d, J=5.2 Hz), 7.14-7.17 (1H, m), 7.39-7.45 (1H, m), 7.51-7.61 (2H, m), 7.62-7.70 (2H, m), 8.16-8.27 (2H, m), 8.73-8.76 (3H, m), 9.47-9.49 (1H, m). : Example 3 5 -174- This paper scale applies to China National Standard (CNS) A4 specification (21〇x 297 mm) 1304061 A7 B7 V. Description of invention (169) Cyanogenic hydrazine: 7-(2-methoxy oxime Oxy)-4-, porphyrin, oxygen^2_qi^)-N1-(2-(i·茇,, beer 4-(4-amino-3-fluorophenoxy)-6 -Cyano-7-(2-methoxyethoxy) 4 (100 mg) was added to toluene 4·5 mi and heated to reflux. (2-fluorophenyl)isocyanate was added thereto. The mixture was heated to reflux for EtOAc (3 mL). EtOAc (EtOAc:EtOAc) ^lt(DMSO-d6) 5 (ppm): 3.37 (3H, s), 3.75-3.80 (2H, m), 4.4CM.45 (2H, m), 6·62 (1H, d, 5·6 Hz ), 6.97-7·05 (1H, m), 7·11-7·18 (1H, m), 7.21-7.28 (1H, m), 7.38-7.45 (1H, m), 7.64 (1H, s) , 8.14-8.20 (1H, m), 8.26-8.33 (1H, m), 8.73- 8·76 (2H, m), 9·06 (1H, br s), 9.14 (1H, br s). 36 10(6-Cyanide-7-methylindol-4-4 oxoyl)_Ν, "2. Cardiodifluorophenyl" swell - 4-(4-aminophenoxy) -6-Cyano-7-methoxyporphyrin (18 mg) was added to 5·5 ml of toluene and heated to reflux, and (2,4•difluorophenyl) isocyanate was added thereto (0.12) The mixture was heated to reflux for 1 hr. EtOAc (EtOAc m. -NMR spectrum (DMS 〇-d6) 5 (ppm): 4, 〇5 (3H, s), 6.52 (m, d, 5.2 Hz), 7.01-7.08 (1H, m), 7.21-7.34 ( 3H,m), 7.56-7.62 (3H, m), 8.02-8.10 (1H, m), 8.52 (1H, sy, 8.72 (1H, d, J=5.2 Hz), 8.76 (1H, s), 9·18 (1H, s) 〇 _ -175^ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 ' --· A7 ______B7 V. Description of invention (170) Example 37 Cyanomethoxy-inosolinyl)hydromethane)-N,-benzene 4-(4-aminophenoxy)-6-cyano-7-methoxyquinoline (148 mg) To 5.5 ml of toluene and heat to reflux. Phenyl isocyanate (〇〇 8 ml) was added thereto and heated under reflux for 1 hour. After cooling, the solid which precipitated was taken, and washed with ethyl acetate / toluene = to afford the title compound 15 g. iH-NMR spectrum (DMS 〇-d6) &lt;5 (ppm): 4·05 (3H, s), 6.50-6.54 (1H, m), 6.96 (ΐ, 1Η, 7.2 Hz), 7.23 (2H, d , J=9.2 Hz), 7.27 (2H, d, J=7.2 Hz), 7.44 (2H, d, J=7.2 Hz), 7.56^7.62 (3H, m), 8.68-8.77 (3H,m),8.83 (1H, br s). Example 3 8 (4-(6-Cyano-7-methoxy-4-4) oxa)-N,-(u butyl) gland 4-(4-aminophenoxy) 6-Cyano-7-decyloxyquinone (150 mg) was added to 2.5 ml of toluene and 2·5 ml of acetonitrile, and heated to reflux. Thereto was added n-butyl isocyanate (〇. 12 ml) and heated under reflux for 1 hour. After cooling, the precipitated solid was filtered, washed with ethyl acetate / toluene = 1/1 to give the title compound 110 mg (yield 55%) as pale brown crystals. iH-NMR spectrum (DMSO-d6) &lt;5 (ppm): 0.88 (3H, t, J = 7.6 Hz), 1.25^1.45 (4H, m), 3.04-3.11 (2H, m), 4.05 (3H, s), 6.13 (1H, t, J=5.6 Hz), 6.49 (1H, d, J=5.6 Hz), 7.16 (2H, d, J=9.2 Hz), 7.52 (2H, d, 1=9.2 Hz) , 7.58 (1H, s), 8.55 (1H, s), 8.71 (1H, d, J = 5.6 Hz), 8·75 (1H, s). : Example 3 9 -176- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 _____B7 V. Invention description (171) N II (4_ (6-alkoxy group: enterprise) Porphyrin I oxo-based N, · f 4 fluorobenzene, a 4-(4-aminophenoxy)-6-cyano-7-methoxyethoxyquinoline (15 〇 mg Add to 5.0 ml of toluene and acetonitrile 2·5... and heat to reflux. Add 4-fluorophenyl isocyanate (〇. 12 ml) and heat to reflux for hrs. After cooling, filter out solids. The title compound 150 mg (yield: 68%) was obtained as pale brown crystals. </ br> </ RTI> </ RTI> </ RTI> (DMS 〇-d6) 5 (ppm): 4·05 ( 3H, s), 6.52 (1H, d, J = 5.6 Hz), 7.08-7.14 (2H, m), 7.23 (2H, d, J = 8.8 Hz), 7.43- 7.49 (2H, m), 7.56-7.61 (3H, m), 8·71-8·76 (3H, m), 8.85 (1H, s). Example 40 Soil (4-(6-cyanomethyl) a certain set of porphyrins, gas base _ Ν ··Γ2_pyridine, phenyl N-(4-(f-cyano-7-decyloxy-4-quinolinyl)oxyphenyl)carbamate (150 mg) and 2-aminopyridine ( 69 mg) dissolved in dimethoprim 1 mi at 80 ° C The mixture was heated and stirred for 1.5 hours. After cooling, the mixture was evaporated and evaporated to ethylamine. 〇-d6)5(PPm): 4·05 (3H, s), 6.54 (1H, d, J=5.6 Hz), 6.98-7.03 (1H, m), 7.26-7.30 (2H, m), 7.45- 7.52 (1H, m), 7.60 (1H, s), 7.63-7.78 (3H, m), 8.25-8.30 (1H, m), 8.73 (1H, d, J = 5.6 Hz), 8.78 (1H, s) , 9.5? (1H, s), 10.67 (1H, -177- t paper scale applicable to Chinese National Standard (CNS) A4 Regulation 297 public) 1304061 ~ - A7 _ B7 ___ V. Description of invention (172) f 41 N-(4-(6-Amino-7-methyl hydrazine)-4-yl phenyl) oxoyl Ν '- η-port ratio &lt; base) urinary urine in the same manner as in Example 40 From phenyl-(4-(6-cyano-7-methoxy-4-quinolinyl)oxyphenyl)carbamic acid phenyl ester (100 mg) and 3-aminopyridine (46 mg) The title compound was 32 mg (yield 32%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 4.05 (3H, s), 6.53 (1H, d, J = 5.2 Hz), 7.22-7.34 (3H, m), 7.57-7.63 (3H, m), 7.91-7.96 (1H, m), 8.17-8.20 (1H, m), 8.59-8.63 (1H, m), 8.73 (1H, d, J = 5.2 Hz), 8.76 (1H, s) , 8.91 (1H, br s), 9.00 (1H, br s). f Example 42 N-(4 -(6-3⁄4yl-7-methyl-glycolyl g-yl)-gas--- 4-portage &lt; base) month urine in the same manner as in Example 40 From N-(4-(6-Cyano-7-methoxy-4-pylinyl)oxyphenyl)carbamic acid phenyl ester (150 mg) and 4-aminopyridine (69 mg). 45 mmol (yield 30%) of the title compound as light brown crystals. iH-NMR spectrum (DMS 〇-d6) 5 (ppm): 4.05 (3H, s), 6·54 (1H, d, J=5.2 Hz), 7.26 (2H, d, J=9.0 Hz), 7.43 (2H, d, J-7.0 Hz), 7.57-7.64 (3H, m), 8·35 (2H,d, J=7.〇Hz ), 8.71-8.77 (2H,m), 9·05 (1H,br s),9.16 (1H,br s) 〇例例 43 4- (6-Ammonia-7-(3-diethylamino) ) propionate -4-). Apricot says it, nitrogen, carbazide, urea: in the same manner as in Example 7, from 6-cyano-4-(4-((4-A) Oxyaniline-178- This paper scale applies to China National Standard (CNS) Α 4 specifications (210 &lt; 297 public)

訂Order

線 1304061 — A7 B7 五、發明説明（173 ) 基）談基）胺基苯氧基）-7〃奎淋酸鈉（1 3 1 mg)，得到標題化 合物10 mg。 lH-NMR (CDC13) 5 (ppm): 2.02-2.15 (2H, m), 2.27 (6H, s), 2.54 (2H, t, J=7.4 Hz), 3.80 (3H, s)3 4.28 (2H, t, J=7.4 Hz), 6.42 (1H, d, J=5.3 Hz), 6.80 *(1H, br s), 6.90 (2H, d, J=9.3 Hz), 7.03 (1H, br s), 7.08 (2H, d, J=9.3 Hz), 7.28 (2H, d, J=9.3 Hz), 7.46 (1H, s), 7.48 (2H, d5 J=9.3 Hz), 8.62 (1H, d, J=5.3 Hz)，8·66 (1H，s)。 實施例44 基- 7-(2 -二甲胺基）乙氣基）-4-邊淋基）氣笨某 甲氣苯某）服 以與實施例7同樣之手法，從6-氰基-4-(4-((4-甲氧苯胺 基）羰基）胺基苯氧基）-7-喹啉酸鈉（145 mg)，得到標題化 合物110 mg。 lH-NMR (I&gt;MSO-d6) δ (ppm): 2.2 8 (6H, s), 2.76 (2H, t, J=5.3 Hz), 3.70 (3H, s), 4.37 (2H, t, J=5.3 Hz), δ.51 (1H, d, J=5.4 Hz)3 6.86 (2H, d, J=8.7 Hz), 7.21 (2H, d, J=8.7 Hz), 7.35 (2H, d, J=8.7 Hz), 7.58 (2H, d, J=8.7 Hz), 7.62 (1H, s), 8.50 (1H, s)，8·72 (1H，d, J=5.4 Hz)，8.75 (2H，s)。 實施例4 5 ( $-讯基-7· ( 3· ( 1- p比哈淀基）丙氫1- 4- g奎淋基）氧笨 基）-ΝΉ-甲氣笨某）脲 將N-(4-(6-氰基-7-(3 -氯丙氧基）-‘4啉基）氧苯基）-N，-(4-甲氧苯基）脉（140 mg)溶於二甲基甲醯胺中，加入吡咯 -179- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂Line 1304061 - A7 B7 V. INSTRUCTION DESCRIPTION (173) Base) Aminophenoxy)-7-quinone sodium (1 3 1 mg) gave the title compound 10 mg. lH-NMR (CDC13) 5 (ppm): 2.02-2.15 (2H, m), 2.27 (6H, s), 2.54 (2H, t, J=7.4 Hz), 3.80 (3H, s)3 4.28 (2H, t, J=7.4 Hz), 6.42 (1H, d, J=5.3 Hz), 6.80 *(1H, br s), 6.90 (2H, d, J=9.3 Hz), 7.03 (1H, br s), 7.08 (2H, d, J=9.3 Hz), 7.28 (2H, d, J=9.3 Hz), 7.46 (1H, s), 7.48 (2H, d5 J=9.3 Hz), 8.62 (1H, d, J=5.3 Hz), 8.66 (1H, s). Example 44: 7-(2-dimethylamino)ethenyl)-4-ylidene-based gas, a gas, a benzene, and the like, in the same manner as in Example 7, from 6-cyano- Sodium 4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinoline (145 mg) gave the title compound 110 mg. lH-NMR (I&gt;MSO-d6) δ (ppm): 2.2 8 (6H, s), 2.76 (2H, t, J = 5.3 Hz), 3.70 (3H, s), 4.37 (2H, t, J= 5.3 Hz), δ.51 (1H, d, J=5.4 Hz)3 6.86 (2H, d, J=8.7 Hz), 7.21 (2H, d, J=8.7 Hz), 7.35 (2H, d, J= 8.7 Hz), 7.58 (2H, d, J=8.7 Hz), 7.62 (1H, s), 8.50 (1H, s), 8·72 (1H, d, J=5.4 Hz), 8.75 (2H, s) . Example 4 5 ($- 信基-7·(3·(1-p-haha-based)-hydrogen-1-4-g-quinoyl)oxyphenyl)-ΝΉ-甲气”) U will be N -(4-(6-Cyano-7-(3-chloropropoxy)-'4 phenyl)oxyphenyl)-N,-(4-methoxyphenyl) vein (140 mg) dissolved in two In the case of methylformamide, pyrrole-179 is added. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm).

線 1304061 A7Line 1304061 A7

嗓（163微升），以及於80。(：加熱攪拌6小時。將反應液注入 飽和食鹽水中及用乙酸乙酯萃取。將有機層用硫酸鎂乾燥 及濃縮。將殘餘物加至NH矽凝膠管柱（富士希利希亞化學 公司）中，用溶媒（乙酸乙酯）溶出，再用溶媒（乙酸乙酯-甲 醇==10〜1)溶出及濃縮，得到標題化合物3丨mg。 H^NMR (DMSO-d6) (5 (ppm): 1.67-1.73 (4H, m), 1.96-2.04 ' (2H，m)，2.44-2.49 (4H，m)，2·61 (2H，t，J=6.8 Hz)，3·72 (3H， s), 4.34 (2H3 t, J=6.4 Hz), 6.53 (1H, d, J=5.2 Hz)3 6.88 (2H, d, J=8.8 Hz), 7.23 (2H, d, J=9.2 Hz), 7.37 (2H, d, J=8.8 Hz), 7·6〇 (1H，s)，7.61 (2H，d，J=9.2 Hz)，8·63 (1H，br s)，8.73 (1H，d，J=5.2 Hz)，8.76 (1H，s)，8.88 (1H，br s)。 貫施例46 过_: (4- ( 6-氰基-7- ( 3 -〔 1-六藍‘p比咬基）丙氧某）4 g枝甚）^ 蓋甲1茇某）月早 以與實施嗍7同樣之手法，從6-氰基-4-(4-((4-甲氧苯胺 基）羧基）胺基苯氧基）-7-4淋酸鈉（156 fng)，得到標題化 合物67 mg。 ^-NMR (DMSO^d6) 5 (ppm): 1.30-1.57 (6H, m), 1.93-2.03 (2H，m)，2.31-2.53 (6H，m)，3·72 (3H，s)，4,33 (2H，t，J=6 5 Hz), 6.52 (1H，d，J=4.9 Hz)，6.87 (2H，d，J=8.9 Hz)，7.23 d，J=8.9 Hz)，7.38 (2H，d，J=8.9 Hz)，7.57-7.63 (3H，m)，8.53 (1H，br s)，8.72 (1H，d，J=4.9 Hz)，8.76 (1H，s)，8·79 (1H，br s)。 -· 實施例47 -180- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 訂嗓 (163 μl), and at 80. (The mixture was heated and stirred for 6 hours. The reaction solution was poured into saturated brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was applied to the NH 矽 gel column (Fuji Hilithia Chemical Co., Ltd. The solvent was dissolved in ethyl acetate (ethyl acetate), and the solvent was evaporated (yield ethyl acetate-methanol ===1~1) and concentrated to give the title compound (3 mg). H NMR (DMSO-d6) (5 (ppm) ): 1.67-1.73 (4H, m), 1.96-2.04 ' (2H,m),2.44-2.49 (4H,m),2·61 (2H,t,J=6.8 Hz),3·72 (3H, s), 4.34 (2H3 t, J=6.4 Hz), 6.53 (1H, d, J=5.2 Hz)3 6.88 (2H, d, J=8.8 Hz), 7.23 (2H, d, J=9.2 Hz), 7.37 (2H, d, J=8.8 Hz), 7·6〇(1H,s), 7.61 (2H,d,J=9.2 Hz),8·63 (1H,br s),8.73 (1H,d, J = 5.2 Hz), 8.76 (1H, s), 8.88 (1H, br s). Example 46: _: (4-(6-cyano-7-(3 -[1-hexa blue'p ratio) Bite base) propoxygen) 4 g branch even ^ ^ cover armor 1 茇 a) early in the same way as the implementation of 嗍7, from 6-cyano-4-(4-((4-methoxyanilinyl)) Sodium carboxy)aminophenoxy)-7-4 sodium hydride (156 fng) gave the title compound 67 mg. ^-NMR (DMSO^d6) 5 (ppm): 1.30-1.57 (6H, m), 1.93-2.03 (2H, m), 2.31-2.53 (6H, m), 3·72 (3H, s), 4 , 33 (2H, t, J = 6 5 Hz), 6.52 (1H, d, J = 4.9 Hz), 6.87 (2H, d, J = 8.9 Hz), 7.23 d, J = 8.9 Hz), 7.38 (2H ,d,J=8.9 Hz), 7.57-7.63 (3H,m), 8.53 (1H,br s),8.72 (1H,d,J=4.9 Hz),8.76 (1H,s),8·79 (1H , br s). -· Example 47 -180- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

線 1304061 〜Line 1304061 ~

AT B7___ 五、發明説明（175) N-( 4-(6-氰基-7-( 2“ 1-毗咯走JO乙氧基林某）H 基甲氧苯某、月尿 以與實施例7同樣之手法，從6-氰基-4-(4-((4-甲氧苯胺 基）羰基）胺基苯氧基）-7-4啉酸鈉（188 m§)，得到標題化 合物54 mg β ^-NMR (DMSO-d6) 5 (ppm)： 1.68-1.74 (4H, m), 2.58-2.65 (4H，m)，2.93 (2H，t，J=6.4 Hz)，3.72 (3H，s)，4.40 (2H，t， J=6.4 Hz), 6.53 (1H, d, J=5.7. Hz), 6.88 (2H, d, J=9.1 Hz), 7.24 (2H，d，&gt;9·1 Hz)，7·3 7 (2H，d，J=9.1 Hz)，7·60 (2H，d， J=9.1 Hz)，7.62 (1H，s)，8·52 (1H，s)，8.73 (1H，d，J=5.7 Hz)， 8·77 (2H，s)。 實施例48 N-M-(6-氰基-7-Π“二乙脖基）丙氧基）-4- 4说基）—氧茇 基曱氣笨某、月尿 以與實施-例7同樣之手法，從6-氰基-4-(4-((4-甲氧苯胺 基）羰基）胺基苯氧基）-7-4琳酸鈉（134 ihg)，得到標題化 合物45 mg。 !H-NMR (DMSO-d6) 5 (ppm): 0.97 (6H, t, J=7.8 Hz), 1.88-1.96 (2H, m), 2.43-2.53 (4H, m), 2.61 (2H, t, J=7.8 Hz), 3.72 (3H, s), 4.33 (2H, t, J=7.8 Hz), 6.53 (1H, d, J=5.2 Hz), 6.88 (2H，d, J=8.8 Hz), 7.24 (2H, d, J=8.8 Hz), 7·38 (2H，d，J=8.8 Hz), 7.53-7.63 (3H, m), 8.55 (1H, s), 8.73 (1H, d, J=5.2 Hz), 8·76 (1H，s)，8.80 (1H，s)。 : 實施例49 -181 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（176)AT B7___ V. Description of the Invention (175) N-(4-(6-Cyano-7-( 2" 1-Pyro-J-Ethyloxy)H-methoxybenzophenone, Moon-urine and Examples 7 In the same manner, from sodium 6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7- phenyl sulphate (188 m s), Mg β ^-NMR (DMSO-d6) 5 (ppm): 1.68-1.74 (4H, m), 2.58-2.65 (4H, m), 2.93 (2H, t, J = 6.4 Hz), 3.72 (3H, s ), 4.40 (2H, t, J = 6.4 Hz), 6.53 (1H, d, J = 5.7. Hz), 6.88 (2H, d, J = 9.1 Hz), 7.24 (2H,d,&gt;9·1 Hz),7·3 7 (2H,d,J=9.1 Hz), 7·60 (2H,d, J=9.1 Hz), 7.62 (1H,s),8·52 (1H,s), 8.73 ( 1H, d, J = 5.7 Hz), 8·77 (2H, s). Example 48 NM-(6-Cyano-7-indole "diethenyl)propoxy)-4-4) - oxonyl hydrazine, urinary urinary, in the same manner as in Example 7, from 6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)- 7-4 Sodium sulphate (134 ihg) gave the title compound 45 mg. !H-NMR (DMSO-d6) 5 (ppm): 0.97 (6H, t, J = 7.8 Hz), 1.88-1.96 (2H, m), 2.43-2.53 (4H, m), 2.61 (2H, t, J=7.8 Hz), 3.72 (3H, s), 4.33 (2H, t, J=7.8 Hz), 6.53 (1H, d, J=5.2 Hz), 6.88 (2H,d, J=8.8 Hz), 7.24 (2H, d, J=8.8 Hz), 7·38 (2H, d, J=8.8 Hz), 7.53-7.63 (3H, m), 8.55 (1H, s), 8.73 (1H, d, J=5.2 Hz), 8·76 (1H, s), 8.80 (1H, s). : Example 49 -181 - This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of invention (176)

十（卜讯1·^!^甲胺基啉基、孝 以與實施例7同樣之手法，從6·氰基-4-(4-((2,4,二氟苯 胺基）羰基）胺基-3-氟苯氧基）_7_喳啉酸鈉（1〇〇 mg),得 標題化合物35 mg。 ， H-NMR (DMSO-d6) 5 (ppm): 1.94輯2.01 (2H, m)，2·43 (2H t J=7.2 Hz)，2.50 (6H，s)，4.33 (2H，t，J=7.2 Ηζ)，6·64 (iH，d J=5.2 Hz), 7.04-7.46 (4H, m), 7.61 (1H, s), 8.09-8.34 (2H m)，8.74-8.78 (2H，m)，9.06 (1H，br s)，9·14 (1H，brs)。 實施例5 0 1(4-(6-氰某-7-(_3-(二乙胺某、丙氣某&gt;|-4^奋嗾某&gt;&gt;單^^ 星基）-：^，-(2,4-二氩苯葚、碎 以與實施例7同樣之手法，從6-氰基-4-(4-((2,4-二氟苯 肤基）致基）胺基-3-敦苯氧基）-7-p奎淋酸制（95 mg)，得到標 題化合物43ng。 lH-NMR (DMSO-d6) (5 (ppm): 0.97 (6H, t；^J=7.8 Hz), 1.88-1.98 (2H, m), 2.45-2.52 (4H, m), 2.61 (2H, t, J=7.8 Hz), 4.33 (2H, t, J=7.8 Hz), 6.63 (1H, d, J=5.9 Hz), 7.03-7.45 (4H, m), 7.60 (1H, s), 8.09-8.17 (1H, m), 8.28 (1H, t, J=11.5 Hz), 8.74-8.78 (2H, m)，9.03 (1H，br s), 9·11 (1H, br s)。 實施例5 1 U4-(6-氨基- 7-(4-(二曱胺某）丁氣基V4-崦喊基）氧笨 基l-N’-M-甲氣茉某）脲 - 將N-(4-(6-氰基-7-(4-氣丁氧基）-4-喹啉基）氧苯基）·Ν’- -182- 本纸張尺度適用中國國家標準(CNS) Α4規格QlO X 297公釐）X (Buxin 1·^!^Methylaminophenyl), Xiao in the same manner as in Example 7, from 6·cyano-4-(4-((2,4, difluoroanilino)carbonyl)amine Sodium 3-fluorophenoxy)-7-porphyrin (1 mg), the title compound 35 mg, H-NMR (DMSO-d6) 5 (ppm): 1.94 series 2.01 (2H, m) ,2·43 (2H t J=7.2 Hz), 2.50 (6H, s), 4.33 (2H, t, J=7.2 Ηζ), 6.64 (iH, d J=5.2 Hz), 7.04-7.46 (4H , m), 7.61 (1H, s), 8.09-8.34 (2H m), 8.74-8.78 (2H, m), 9.06 (1H, br s), 9·14 (1H, brs). Example 5 0 1 (4-(6-cyanyl-7-(_3-(diethylamine, propaneone &gt;|-4^ 嗾 嗾&gt;&gt; single ^^ star base)-:^,-(2, 4-Di-argon benzoquinone, crushed in the same manner as in Example 7, from 6-cyano-4-(4-((2,4-difluorophenyl)))amino-3-phenylene Prepared by oxy)-7-p-quinonic acid (95 mg) to give the title compound 43 ng. lH-NMR (DMSO-d6) (5 (ppm): 0.97 (6H, t; ^J = 7.8 Hz), 1.88- 1.98 (2H, m), 2.45-2.52 (4H, m), 2.61 (2H, t, J=7.8 Hz), 4.33 (2H, t, J=7.8 Hz), 6.63 (1H, d, J=5.9 Hz ), 7.03-7.45 (4H, m), 7.60 (1H, s), 8.09-8.17 (1H, m), 8.28 (1H, t, J=11.5 Hz ), 8.74-8.78 (2H, m), 9.03 (1H, br s), 9·11 (1H, br s). Example 5 1 U4-(6-Amino-7-(4-(diamine) ) butyl group V4-崦 base) oxy stupyl l-N'-M-methyl sulphate) urea - N-(4-(6-cyano-7-(4- gas-butoxy)- 4-quinolinyl)oxyphenyl)·Ν'- -182- This paper scale applies to Chinese National Standard (CNS) Α4 specification QlO X 297 mm)

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線 1304061 A7 B7 五、發明説明（ 177 (4-曱氧苯基）脲（120 mg)溶於二甲基甲醯胺（3 ml)中，加入 50%二甲胺水溶液（93微升），以及於7〇。(：加熱攪拌5小時。 將反應液注入飽和食鹽水中，用乙酸乙酯萃取，有機層用 硫酸鎂乾燥後濃縮。將得到之殘餘物加至NH矽凝膠管柱 (富士希利希亞化學公司）中，用溶媒（乙酸乙酯·甲醇=1〇_ 1)溶出及濃縮。將得到之固體加至用四氫呋喃平衡之默克 (Merck)矽凝膠管柱中，用四氫呋喃及乙酸乙酯溶出不純物 後，用溶媒（四氫呋喃-曱醇-三乙胺=1〇U，乙酸乙醋-曱醇-三乙胺=10-1-1)溶出及濃縮，得到為固體之標題化 合物10 mg。 ^-NMR (DMSO-d6) δ (ppm): 1.71-1.78 (2H, m), 1.82-1.91 (2H, m)3 2.42 (6H, s), 2.64-2.72 (2H, m), 3.72 (3H, s), 4.33 (2H, t, J=6.0 Hz), 6.54 (1H, d, J=5.2 Hz), 6.88 (2H5 d5 J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hzh 7.61 (1H, s), 8.64 (1H, br s), 8.73 (1H, d5 J=5.2 Hz), 8·78 (1H, s)，8·91 (1H，br s) 〇 、 實施例52 N_- (4- ( 6,氰基-7“ 4-嗎福啉某丁氣基）-4-4啉某）氮茇篡V 曱氫基笨某1月尿 以與實施例51同樣之方法，從N-(4-(6-氰基-7-(4-氣丁氧 基）-4-喹啉基）氧苯基）-N'-(4-甲氧基苯基）脲（110 mg)，得 到標題化合物11 mg。 lH-NMR (DMSO-d6) 5 (ppm): 1.65-1.77-(2H, m), 1.84-1.93 (2H，m)，2.32-2.48 (6H，m)，3.51-3.66 (4H，m)，3.72 (3H，s)， -183- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐)Line 1304061 A7 B7 V. Description of the invention (177 (4-oxaxyphenyl) urea (120 mg) was dissolved in dimethylformamide (3 ml) and 50% aqueous dimethylamine (93 μL) was added. And the mixture was stirred for 5 hours. (The mixture was heated and stirred for 5 hours. The reaction solution was poured into saturated brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. In Helicia Chemical Co., Ltd., it was dissolved and concentrated with a solvent (ethyl acetate·methanol = 1〇_1), and the obtained solid was added to a Merck(R) gel column equilibrated with tetrahydrofuran. After the impurity was dissolved in tetrahydrofuran and ethyl acetate, it was dissolved and concentrated with a solvent (tetrahydrofuran-nonanol-triethylamine = 1 〇U, ethyl acetate-decyl alcohol-triethylamine = 10-1 -1) to give a solid. Title compound 10 mg. ^-NMR (DMSO-d6) δ (ppm): 1.71-1.78 (2H, m), 1.82-1.91 (2H, m)3 2.42 (6H, s), 2.64-2.72 (2H, m ), 3.72 (3H, s), 4.33 (2H, t, J=6.0 Hz), 6.54 (1H, d, J=5.2 Hz), 6.88 (2H5 d5 J=8.8 Hz), 7.23 (2H, d, J =8.8 Hz), 7.37 (2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hzh 7.61 (1H, s), 8 .64 (1H, br s), 8.73 (1H, d5 J=5.2 Hz), 8·78 (1H, s), 8·91 (1H, br s) 〇, Example 52 N_- (4- ( 6 , cyano-7 "4-norfosin, a butyl group)-4-4 oxo), hydrazine, hydrazine, hydrogen, hydrazine, hydrazine, January urine, in the same manner as in Example 51, from N-(4- (6-Cyano-7-(4-cyclobutoxy)-4-quinolinyl)oxyphenyl)-N'-(4-methoxyphenyl)urea (110 mg) Mg. lH-NMR (DMSO-d6) 5 (ppm): 1.65-1.77-(2H, m), 1.84-1.93 (2H, m), 2.32-2.48 (6H, m), 3.51-3.66 (4H, m ), 3.72 (3H, s), -183- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

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線 1304061Line 1304061

〜…· AT __ B7 五、發明説明（178) 4·33 (2H, t, J=6.0 Hz), 6.53 (1H, d, J-4.8 Hz), 6.88 (2H, d, J==8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.4 Hz)? 7·60 (2H, d, J=8.4 Hz), 7.61 (1H, s), 8.57 (1H, br s), 8.73 (1H，d, J=4.8 Hz)，8·78 (1H，s), 8.82 (1H，br s)。 5 3 Ν’（ 4J 6-氰基-7-(3-( 1- (4-乙基）穴1？并基）丙氣基）-4- 口奎 进氣茉某）-Nf“4-甲氣基苯某）脹 以與實施例51同樣之方法，從N-(4-(6-氰基-7-(3-氯丙氧 基）-4-p奎琳基）氧苯基）-Ν’-(4-曱氧基苯基）躲（150 mg)，得 到標題化合物16 mg。 ^-NMR (DMSO-d6) 5 (ppm): 0.98 (3H, t, J=7.2 Hz), 1.91-2·〇6 (2H，m)，2.26-2.48 (12H，m)，3·72 (3H，s)，4·33 (2H，t， J=6.0 Hz), 6.53 (1H, d, J=5.2 Hz), 6.88 (2H, d, J=8.8 Hz), 7.23 (2H, d5 J=8.8 Hz), 7.37 (2H, d, J=8.8 Hz), 7.59 (1H, s), 7.60 (2H, d-J=8.8 Hz), 8.58 (1H, br s), 8.73 (1H, d, J=5.2 Hz)，8·76 (1H，s)，8·83 (1H，br s)。 、 實施例5 4 1(4-(6-氨某-7-(2“4-嗎福嗾&amp;)?」氫基上-4-喹_味基..）氧-2-1苯基Ν’-ί2.4-二氣笨某）Μ 以與實施例7同樣之方法，從6-氰基-4“4-((2,4-二氟苯 胺基）羰基）胺基-3-氟苯氧基）-7^奎啉酸納（200 m§) ’得到 標題化合物1 0 mg。 1H-NMR (DMSO-d6)5(ppm): 2.56 (4H/t，J=4·4 Hz)，2.83 (2H，t，J=5.6 Hz), 3.59 (4H，t，J=4.4 Hz)，4·43 (2H，L J=5·6 -184·__ 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）~...· AT __ B7 V. INSTRUCTIONS (178) 4·33 (2H, t, J=6.0 Hz), 6.53 (1H, d, J-4.8 Hz), 6.88 (2H, d, J==8.4 Hz ), 7.24 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.4 Hz)? 7·60 (2H, d, J=8.4 Hz), 7.61 (1H, s), 8.57 (1H , br s), 8.73 (1H, d, J = 4.8 Hz), 8.78 (1H, s), 8.82 (1H, br s). 5 3 Ν'( 4J 6-Cyano-7-(3-( 1-(4-ethyl)) 1 mercapto) propane group)-4- 奎 进气 进气 )) -Nf "4- Methane-based benzene swelled in the same manner as in Example 51, from N-(4-(6-cyano-7-(3-chloropropoxy)-4-p- cylinyl)oxyphenyl) - Ν '-(4-decyloxyphenyl) occlusion (150 mg), mp. 1.91-2·〇6 (2H,m), 2.26-2.48 (12H,m),3·72 (3H,s),4·33 (2H,t, J=6.0 Hz), 6.53 (1H, d, J=5.2 Hz), 6.88 (2H, d, J=8.8 Hz), 7.23 (2H, d5 J=8.8 Hz), 7.37 (2H, d, J=8.8 Hz), 7.59 (1H, s), 7.60 ( 2H, dJ=8.8 Hz), 8.58 (1H, br s), 8.73 (1H, d, J=5.2 Hz), 8.76 (1H, s), 8·83 (1H, br s). 5 4 1(4-(6-Ammonia-7-(2"4-isofon&amp;)?" Hydrogen-based 4-quino-flavor..) Oxy-2-1 phenyl hydrazine-- Ί2.4-二气笨)) In the same manner as in Example 7, from 6-cyano-4"4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy Base) - 7^ quinolate sodium (200 m §) '. </ RTI> <RTI ID=0.0></RTI> =4·4 Hz), 2.83 (2H, t, J=5.6 Hz), 3.59 (4H, t, J=4.4 Hz), 4·43 (2H, LJ=5·6 -184·__) Applicable to China National Standard (CNS) A4 specification (210 x 297 mm)

裝 玎装

線 1304061 A7 B7Line 1304061 A7 B7

Ηζ)，6·64 (1H，d，&gt;5·2 Ηζ)，7·04-7·10 (1H，m)，7.14-7·19 (1H，m)，7.30-7.36 (1H，m)，7·42 (1H，dd，J=2.8 Hz，J=i2 H2)，7·66 (1H，s)，8.10-8.16 (1H，m)，8·28 (1H，t，J=9.2 Hz) 8.75 (1H5 s)5 8.76 (1H, d, J=5.2 Hz), 9.02-9.05 (1H, m) 9·09-9·13 (1H，m)。 ’ _實施例5 5 N- (4- f 6-氰基-7- ( 3-氰基丙氧基）-4- 4 林某）氧-9·荦，节 化二_(2,4-二氣苯某1脹 以與實施例7同樣之方法，從6-氰基-4-(4-((2,4-二氣笨 胺基）羰基）胺基-3-氟苯氧基）-7-4琳酸鈉（300 mg),得到 標題化合物1 5 mg。 lH-NMR (DMSO-d6) 5 (ppm): 2.14-2.21 (2H, m), 2.73 (2H t J=7.2 Hz), 4.38 (2H, t, J=6.4 Hz)3 6.65 (1H, d, 1=5.2 Hz) 7.04-7.11 (1H, m), 7.15-7.19 (1H, m), 7.31^7.37 (1H3 m) 7.43 (1H, d&lt;i，J=2.8 Hz, J=11.6 Hz)，7.67 (1H，s)，8·10,8·16 (1H, m)3 8.29 (1H, t, J=9.2 Hz), 8.77 (ΙΗ/d, J=5.2 Hz), 8.79 (1H，s)，9·03-9·06 (1H，m)，9.11-9.14 (1H，m)。 實施例56 N-(4-6-亂基- 7-(2-(甲硫基）乙氧呆-4-°奎？林基）氣-2-主 基）-N，-(2,4-二氣茇葚）啡Ηζ),6·64 (1H,d,&gt;5·2 Ηζ), 7·04-7·10 (1H,m), 7.14-7·19 (1H,m), 7.30-7.36 (1H,m ), 7·42 (1H, dd, J=2.8 Hz, J=i2 H2), 7·66 (1H, s), 8.10-8.16 (1H, m), 8·28 (1H, t, J=9.2 Hz) 8.75 (1H5 s)5 8.76 (1H, d, J=5.2 Hz), 9.02-9.05 (1H, m) 9·09-9·13 (1H, m). ' _ Example 5 5 N-(4- f 6-Cyano-7-( 3-cyanopropoxy)-4- 4 lin) oxygen-9·荦, 节化二_(2,4- Dioxane benzene was expanded in the same manner as in Example 7 from 6-cyano-4-(4-((2,4-dioxaamino)carbonyl)amino-3-fluorophenoxy) -7-4 Sodium sulphate (300 mg) gave the title compound 1 5 mg. lH-NMR (DMSO-d6) 5 (ppm): 2.14-2.21 (2H, m), 2.73 (2H t J = 7.2 Hz) , 4.38 (2H, t, J=6.4 Hz)3 6.65 (1H, d, 1=5.2 Hz) 7.04-7.11 (1H, m), 7.15-7.19 (1H, m), 7.31^7.37 (1H3 m) 7.43 (1H, d&lt;i, J=2.8 Hz, J=11.6 Hz), 7.67 (1H, s), 8·10, 8·16 (1H, m)3 8.29 (1H, t, J=9.2 Hz), 8.77 (ΙΗ/d, J=5.2 Hz), 8.79 (1H, s), 9·03-9·06 (1H, m), 9.11-9.14 (1H, m). Example 56 N-(4-6 - 乱基- 7-(2-(methylthio) ethoxylated 4-° 奎·林基) gas-2-hostyl)-N,-(2,4-dioxan)

以與實施例7同樣之方法，從6-氰基-4·(4-((2,4-二氟笨 胺基）羰基）胺基-3-氟苯氧基）-7-喹啉酸鈉（130 mg)，得到 標題化合物95 mg ^ J lH-NMR (DMSO-d6) (5 (ppm): 2.25 (3H, s), 2.99 (2H, t, J=6 〇 -185- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 - 〜一· A7 B7 五、發明説明（180)In the same manner as in Example 7, from 6-cyano-4(4-((2,4-difluoroamino)carbonyl)amino-3-fluorophenoxy)-7-quinolinic acid Sodium (130 mg) gave the title compound 95 mg^JlH-NMR (DMSO-d6) (5 (ppm): 2.25 (3H, s), 2.99 (2H, t, J=6 〇-185- Applicable to China National Standard (CNS) A4 Specification (210 x 297 mm) 1304061 - ~1·A7 B7 V. Invention Description (180)

Hz), 4.49 (2H, t, J=6.0 Hz), 6.64 (1H, d, J=5.2 Hz), 7.04-7.11 (1H, m), 7.15-7.19 (1H, m), 7.30-7.37 (1H, m), 7.43 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.66 (1H, s), 8.09-8.17 (1H, m)，8.29 (1H，t，J=9.2 Hz)，8.76 (1H，d，J=5.2 Hz), 8·77 (1H， s)，9.01-9.05 (1H，m)，9.09-9.13 (1H，m)。 實施例57 N“ 4“ 6-氰基-7-( 2-(甲磺醯基）乙氣基4-4啉基）氣-2-氣 笨基二氣笨墓）脲 將N-( 4-6-氰基-7-(2-(曱硫基）乙氧基-4-喹啉基）氧-2-氟 苯基）-N、（2,4-二氟苯基）脲（84 mg)溶於甲醇（1 ml)與二氯 甲烷（5 ml)之混合溶媒中，然後在0°C及攪拌下加入2當量 之間過安息香酸並攪拌30分鐘。將反應液注入飽和碳酸氫 制水溶液中，用乙酸乙醋萃取，以及將有機層用硫酸鎂乾 燥後濃縮。將殘餘物加至NH矽凝膠管柱（富士希利希亞化 學公司）中 &gt;、用溶媒（乙酸乙酯-己烷=10- 1)溶出及濃縮， 得到21 mg標題化合物。 、 lH-NMR (DMSO-d6) 5(ppm): 3.02 (3H5 s), 3.79 (2H, t, J=4.8 Hz), 4.67 (2H, t5 J=4.8 Hz), 6.67 (1H? d, J=5.2 Hz), 7.04-7.10 (1H，m)，7.15-7.19 (1H，m)，7.31-7.34 (1H，m)，7.43 (1H, dd, J=2.8 Hz, J=12 Hz), 7.73 (1H, s), 8.10-8.16 (1H, in), 8.28 (1H，t，J=9.2 Hz), 8·79 (1H，d，J=5.2 Hz)，8.81 (1H，s)， 9.02-9.05 (1H，m)，9.11-9.14 (1H，m)。 實施例5 8 -Hz), 4.49 (2H, t, J=6.0 Hz), 6.64 (1H, d, J=5.2 Hz), 7.04-7.11 (1H, m), 7.15-7.19 (1H, m), 7.30-7.37 (1H , m), 7.43 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.66 (1H, s), 8.09-8.17 (1H, m), 8.29 (1H, t, J=9.2 Hz), 8.76 (1H, d, J = 5.2 Hz), 8·77 (1H, s), 9.01-9.05 (1H, m), 9.09-9.13 (1H, m). Example 57 N "4" 6-Cyano-7-(2-(methylsulfonyl)ethane group 4-4 phenyl) gas-2-gas stupid base gas tomb) urea N-( 4 -6-Cyano-7-(2-(indolyl)ethoxy-4-quinolinyloxy-2-fluorophenyl)-N, (2,4-difluorophenyl)urea (84 Mg) was dissolved in a mixed solvent of methanol (1 ml) and dichloromethane (5 ml), then 2 equivalents of benzoic acid was added and stirred for 30 minutes at 0 ° C with stirring. The reaction solution was poured into a saturated aqueous solution of hydrogen carbonate, and extracted with ethyl acetate. The residue was added to a NH(R) gel column (Fuji-Hilichia Chemical Co., Ltd.) &gt;, dissolved in a solvent (ethyl acetate-hexane = 10-1), and concentrated to give 21 mg of the title compound. , lH-NMR (DMSO-d6) 5 (ppm): 3.02 (3H5 s), 3.79 (2H, t, J = 4.8 Hz), 4.67 (2H, t5 J = 4.8 Hz), 6.67 (1H? d, J =5.2 Hz), 7.04-7.10 (1H,m), 7.15-7.19 (1H,m),7.31-7.34 (1H,m),7.43 (1H, dd, J=2.8 Hz, J=12 Hz), 7.73 (1H, s), 8.10-8.16 (1H, in), 8.28 (1H, t, J = 9.2 Hz), 8·79 (1H, d, J = 5.2 Hz), 8.81 (1H, s), 9.02- 9.05 (1H, m), 9.11-9.14 (1H, m). Example 5 8 -

N“4-(6-氨基- 7-(2-(甲硫基）乙氣基）-4-4啉基）氣笨基V __-186-_ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 — 、· · A7 _____B7__ 五、發明説明（181) 忙-(4-氟茉某）胧 以與實施例7同樣之方法，從6-氰基-4_(4-((2,4·二氟苯 胺基）羰基）胺基-3-氟苯氧基）-7-4啉酸納（300 mg)，得到 標題化合物112 mg。 !H.NMR (DMSO-d6) 5(ρρτη): 2.25 (3Η, s), 2.99 (2H, ΐ, 1=6.0N"4-(6-Amino-7-(2-(methylthio)ethenyl)-4-4 phenyl)) gas base V __-186-_ This paper scale applies to Chinese National Standard (CNS) A4 Specification (210 X 297 mm) 1304061 — , · · A7 _____B7__ V. Description of the invention (181) Busy-(4-fluoromosa) 胧 In the same manner as in Example 7, from 6-cyano-4_(4 -((2,4·Difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7- benzoic acid sodium (300 mg) afforded the title compound 112 mg..H.NMR (DMSO-d6 5(ρρτη): 2.25 (3Η, s), 2.99 (2H, ΐ, 1=6.0

Hz)，4.49 (2H，t，J=6.0 Hz)，6.54 (1H，d，J=5.2 Hz)，7.13 (2H， t, J=8.8 Hz), 7.25 (2H, d, J=8.8 Hz), 7.46-7.51 (2H, m), 7.61 (2H, d, J=8.8 Hz), 7.65 (1H, s), 8.74 (1H, d5 J=5.2 Hz), 8.78 (1H，s)，8.82 (1H，br s)，8.91 (1H，br s)。 實施例59 氨基- 7-Γ2&quot;甲磺醯某）i氧基查啉基）氧笨-基l-N’-M-氟茉某、胧 以與實施例56同樣之方法，從N“4-(6-氰基-7·(2-甲硫基） 乙氧基）-4-喹啉基）氧苯基）-Ν’-(4-氟苯基）脲（1〇〇 mg)，得 到標題化合淑11 mg。 lH-NMR (DMSO-d6) ά (ppm): 3.20 (3H, s),^3.79 (2H, t, J=5.6 Hz), 4.69 (2H, t, J=5.6 Hz), 6.57 (1H, d, J=5.2 Hz), 7.13 (2H, t, J=8.8 Hz), 7.25 (2H, d3 J=8.8 Hz), 7.46-7.52 (2H, m), 7.62 (2H, d, J=8.8 Hz), 7.72 (1H, s), 8.76 (1H, d, J=5.2 Hz), 8.82 (1H，s)，8.90 (1H，br s), 8.99 (1H，br s)。 實施例60 N-(4“6- f. _5.7-二曱氣基-4- 口争淋立）氧-2·氟笨基）-…' (2，4 _ —亂尽基）月尿 * 以與實施例1〇同樣之方法，從4-(4-胺基-3-氟苯氧基）-6- -187- 本紙蒗尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 — ________ Β7 五、發明説明（182) 氯-5,7-二曱氧基喹啉（235 mg)及異氰酸（2,4-二氟苯基） 酯，得到標題化合物173 mg。 lH-NMR (DMSO-d6)(5(ppm): 3.93 (3H, s), 4.07 (3H, s), 6.67 (1H, d, J=5.2 Hz)3 6.91-6.96 (1H, m), 7.00 (1H, s), 7.03-7.09 (1H, m), 7.20 (1H, dd, J=2.8 Hz, J=8.0 Hz), 7.30-7.37 (1H, m), 8.08-8.20 (2H, m), 8.69 (1H, d, 1=5.2 Hz), 9.01 (1H, brd, J=2.0 Hz)，9·04 (1H，brd，J=2.0 Hz)。 實施例6 1 6-氰茱-7-曱氫基-4-4啉基）氣-2-氣茉某 二氣苯某1脹 以與貫施例10同樣之方法，從4-(4-胺基-3-氟苯氧基）-6-氰基-7-曱氧基喹，林基（238 mg)及異氰酸（2，心二氟苯基） 酯，得到標題化合物13 0 mg。 H-NMR (DMSO-d6) δ (ppm): 4.08 (3H, s), 6.64 (1H, d, J=5.2 Hz), 7.04-7.10 (1H, m), 7.15-7.19 (1H, m)5 7.31-7.37 (1H, m), 7.43 (1H, dd, 1=2.8 Hz, J=12 Hz)/7.63 (1H, s), 8.13 (1H, dt, J=6.4 Hz, J=9.2 Hz), 8.29 (1H, t, J=9.2 Hz), 8.77 (1H, d, J=5.2 Hz), 8.78 (1H, s), 9.05 (1H, br s), 9.13 (1H, br s)。 實施例62Hz), 4.49 (2H, t, J = 6.0 Hz), 6.54 (1H, d, J = 5.2 Hz), 7.13 (2H, t, J = 8.8 Hz), 7.25 (2H, d, J = 8.8 Hz) , 7.46-7.51 (2H, m), 7.61 (2H, d, J=8.8 Hz), 7.65 (1H, s), 8.74 (1H, d5 J=5.2 Hz), 8.78 (1H, s), 8.82 (1H , br s), 8.91 (1H, br s). Example 59 Amino- 7-Γ2&quot;Methanesulfonate) i-oxychalinyl)oxyphenyl-l-N'-M-fluoromethane, hydrazine in the same manner as in Example 56, from N "4 -(6-Cyano-7(2-methylthio)ethoxy)-4-quinolinyl)oxyphenyl)-indole-(4-fluorophenyl)urea (1 mg), The title is obtained by the title of 11 mg. lH-NMR (DMSO-d6) ά (ppm): 3.20 (3H, s), ^3.79 (2H, t, J = 5.6 Hz), 4.69 (2H, t, J = 5.6 Hz ), 6.57 (1H, d, J=5.2 Hz), 7.13 (2H, t, J=8.8 Hz), 7.25 (2H, d3 J=8.8 Hz), 7.46-7.52 (2H, m), 7.62 (2H, d, J=8.8 Hz), 7.72 (1H, s), 8.76 (1H, d, J=5.2 Hz), 8.82 (1H, s), 8.90 (1H, br s), 8.99 (1H, br s). Example 60 N-(4"6-f. _5.7-dioxane-4-pyrene)-oxy-2.fluorophenyl)-...' (2,4 _ - chaos) Urine* In the same manner as in Example 1, the Chinese National Standard (CNS) A4 specification (210 X 297) was applied from the 4-(4-amino-3-fluorophenoxy)-6--187-paper scale. 1304061 A7 — ________ Β7 V. Inventive Note (182) Chloro-5,7-dimethoxyoxyquinoline (235 mg) and isocyanate (2,4-difluorophenyl) ester, titled compound 173 mg. lH-NMR (DMSO-d6) (5 (ppm): 3.93 (3H, s), 4.07 (3H, s), 6.67 (1H, d, J = 5.2 Hz) 3 6.91-6.96 (1H, m), 7.00 (1H, s), 7.03-7.09 (1H, m), 7.20 (1H, dd, J=2.8 Hz, J=8.0 Hz), 7.30-7.37 (1H, m), 8.08-8.20 (2H, m), 8.69 (1H, d, 1 = 5.2 Hz), 9.01 (1H, brd, J = 2.0 Hz), 9·04 (1H, brd, J = 2.0 Hz). Example 6 1 6-Cyanide-7-曱Hydrogenyl-4-4 phenyl) gas-2-gas sulphide benzene swells in the same manner as in Example 10, from 4-(4-amino-3-fluorophenoxy)-6 -Cyano-7-methoxy quinoxaline, linyl (238 mg) and isocyanate (2, centifluorophenyl) ester gave the title compound 13 0 mg. H-NMR (DMSO-d6) δ (ppm): 4.08 (3H, s), 6.64 (1H, d, J = 5.2 Hz), 7.04-7.10 (1H, m), 7.15-7.19 (1H, m)5 7.31-7.37 (1H, m), 7.43 (1H, dd, 1=2.8 Hz, J=12 Hz)/7.63 (1H, s), 8.13 (1H, dt, J=6.4 Hz, J=9.2 Hz), 8.29 (1H, t, J=9.2 Hz), 8.77 (1H, d, J=5.2 Hz), 8.78 (1H, s), 9.05 (1H, br s), 9.13 (1H, br s). Example 62

Hib(卜氰某-7-i氧基-4-44基）氣笨某）·Ν，·Γ4_甲晏茇 基）月尿 以與實施例10同樣之方法，從4-胺基{4-胺基苯氧基）-6-氰基-7-甲氧基喹啉（17〇 mg)及異氰酸（4-甲氧苯基）酯，得 __-188- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公愛） l3〇4〇6lHib (Cyanide-7-ioxy-4-44-based) gas 笨)·Ν,·Γ4_methionine) Moon urine in the same manner as in Example 10, from 4-amino {4-amine Phenoxy)-6-cyano-7-methoxyquinoline (17〇mg) and (4-methoxyphenyl) isocyanate, get __-188- This paper scale applies to Chinese national standards (CNS) A4 specification (210 X 297 public) l3〇4〇6l

A7 B7 五、發明説明（ 到標題化合物5 5 mg ^ lH-NMR (DMSO-d6)&lt;5(ppm): 3.72 (3H, s), 4.07 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.88 (2H, d, J=8.8 Hz), 7.24 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz), 7.61 (1H, s), 8.62 (1H, br s), 8.74 (1H, d, J=5.2 Hz), 8.78 (1H, s), 8.87 (1H，br s) e f施例63 K4J6-老.某-7J2J4-噁福啉基）乙氧基'4-4啉某）氫茉 基甲氩笨基）脲 以與實施例7同樣之方法’從6-氰基- 4-(4-((4-甲氧基苯 胺基）羰基）胺基苯氧基）-7-喹啉酸鈉，得到標題化合物。 lH-NMR (DMSO-d6) (5 (ppm): 2.50-2.55 (4H, m), 2.87 (2H, t, J-5.6 Hz), 3.57 (4H, t, J-4.4 Hz), 3.60 (3H, s), 4.38 (2H, t, J-5.6 Hz), 6.85 (2H, d, J=8.8 Hz), 7.02 (1H, s), 7.06 (1H, d, ^5.2 Hz), 7.21 (2H, d, 1=8.8 Hz), 7.36 (2H, d, J=8.8 Hz),A7 B7 V. Description of the invention (to the title compound 5 5 mg ^ lH-NMR (DMSO-d6) &lt; 5 (ppm): 3.72 (3H, s), 4.07 (3H, s), 6.54 (1H, d, J =5.2 Hz), 6.88 (2H, d, J=8.8 Hz), 7.24 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz), 7.61 (1H, s), 8.62 (1H, br s), 8.74 (1H, d, J=5.2 Hz), 8.78 (1H, s), 8.87 (1H, br s) ef Example 63 K4J6- Old. Some -7J2J4-oxalinyl)ethoxy '4-4 oxo) hydrazinyl arsonyl urea in the same manner as in Example 7 'from 6-cyano-4-(4- Sodium ((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinate gave the title compound. lH-NMR (DMSO-d6) (5 (ppm): 2.50-2.55 (4H, m), 2.87 (2H, t, J-5.6 Hz), 3.57 (4H, t, J-4.4 Hz), 3.60 (3H , s), 4.38 (2H, t, J-5.6 Hz), 6.85 (2H, d, J=8.8 Hz), 7.02 (1H, s), 7.06 (1H, d, ^5.2 Hz), 7.21 (2H, d, 1=8.8 Hz), 7.36 (2H, d, J=8.8 Hz),

H 7.58 (2H, d? J-8.8 Hz), 8.65 (1H, s), 8.68 (1H, br s), 8.73 (1H, (1^=5.2 Hz), 8·92 (1H, br s)。 實施例64 化（4“6-鲞某-7“2-甲氩基乙氧基）-4:凌咪基）氡笨基^-環己基脲 以與實施例1〇同樣之方法，從4·(4-胺基苯氧基）-6-氰基-7-(2-甲氧基乙氧基）喹啉（60 mg)及異氰酸環己酯，得到標 題化合物25 mg。 lH-NMR (DMSO-d6) (5 (ppm): 1.12-1.24 (3H, m), 1.26-1.38 _— ___ -189 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x297公釐） 1304061 A7 &quot; ______B7 1、發明説明（~~'~' —- (2H，m)，1.5H.59 (1H，m)，1.63-1.72 (2H，m)，ι·78]·86 (2Η, m), 3.38 (3Η, s), 3.42-3.52 (1H, m), 3.78-3.80 (2H, m), 4.42- 4.44 (2H, m), 6.18 (1H, brd, J=8.0 Hz), 6.50 (1H d J=5.2 Hz), 7.18 (2H, d, J=9.2 Hz), 7.53 (2H, d, J,9.2 Hz)[ 7.63 (1H, s), 8.55 (1H, br s)3 8.72 (lH, d, J=5.2 Hz) 8 77 (lH，s)。 ’ 實施例65 苯基月尿 將4-(4-胺基苯氧基）-6-氰基-7-(2-甲氧基乙氧基）喹啉 (600 mg)懸浮於甲苯（15 ml)並加熱回流，一旦溶解，滴入 異氰酸苯酯（292微升）並加熱回流3〇分鐘。放冷後，濾取析 出之固體’用乙醚及乙酸乙酯洗淨，乾燥，得到標題化合 物 760 mg 〇 !H-NMR (DMSO-d6)5(ppm): 3.3 8 (3H, s), 3.78-3.81 (2H, m), 4.42- 4.45 (2H，m)，6·54 (1H，d，J=5.2 Ηζ)，%6·98 (1H，t，J=7.2H 7.58 (2H, d? J-8.8 Hz), 8.65 (1H, s), 8.68 (1H, br s), 8.73 (1H, (1^=5.2 Hz), 8.92 (1H, br s). Example 64 (4"6-鲞--7"2-methylarylethoxy)-4: oxamidyl) hydrazino-cyclohexylurea in the same manner as in Example 1 from 4-Aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (60 mg) and cyclohexyl isocyanate afforded the title compound 25 mg. lH-NMR (DMSO-d6) (5 (ppm): 1.12-1.24 (3H, m), 1.26-1.38 _— ___ -189 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x297 mm) 1304061 A7 &quot; ______B7 1. Description of invention (~~'~' —- (2H,m), 1.5H.59 (1H,m),1.63-1.72 (2H,m),ι·78]·86 ( 2Η, m), 3.38 (3Η, s), 3.42-3.52 (1H, m), 3.78-3.80 (2H, m), 4.42- 4.44 (2H, m), 6.18 (1H, brd, J=8.0 Hz) , 6.50 (1H d J=5.2 Hz), 7.18 (2H, d, J=9.2 Hz), 7.53 (2H, d, J, 9.2 Hz) [ 7.63 (1H, s), 8.55 (1H, br s)3 8.72 (lH, d, J = 5.2 Hz) 8 77 (lH, s). Example 65 Phenyl monthly urine 4-(4-aminophenoxy)-6-cyano-7-(2- Methoxyethoxy)quinoline (600 mg) was suspended in toluene (15 ml) and heated to reflux. Once dissolved, phenyl isocyanate (292 μL) was added dropwise and heated to reflux for 3 min. The precipitated solid was collected by chromatography <RTI ID=0.0></RTI> eluted elut elut elut elut elut elut elut elut elut , m), 4.42- 4.45 (2H,m),6·54 (1H,d,J=5.2 Ηζ),%6·98 (1H,t,J=7.2

Hz), 7.24-7.31 (4H, m), 7.47 (2H, d, J=7.2 Hz), 7.62 (2H, d, J=8.8 Hz), 7.64 (1H, s), 8.74 (1H, d, J=5.2 Hz), 8.79 (1H, s), 8.85 (1H, br s), 8·99 (1H，br s)。 實施例66 Μ_—ί 4- ( ό爾 f I - 7· ( 2- Ψ 1 1 ) - 4養I ) t · 2_ 基）2,4--乱本基）腺 將4-(4-胺基-3-氟苯氧基）-6-氰基2-甲氧基乙氧基） 4啉（352 mg)懸浮於甲苯（20 ml)並加熱回流溶解後滴入異 -190- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（185)Hz), 7.24-7.31 (4H, m), 7.47 (2H, d, J=7.2 Hz), 7.62 (2H, d, J=8.8 Hz), 7.64 (1H, s), 8.74 (1H, d, J =5.2 Hz), 8.79 (1H, s), 8.85 (1H, br s), 8·99 (1H, br s). Example 66 Μ_-ί 4- ( όr f I - 7· ( 2- Ψ 1 1 ) - 4 养 I ) t · 2 yl) 2,4--random base) gland 4-(4-amine 3-fluorophenoxy)-6-cyano 2-methoxyethoxy) 4 phenyl (352 mg) suspended in toluene (20 ml) and heated to reflux to dissolve and then dropped into iso-190- paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (185)

氰酸（2,4-二氟苯）酯（236微升），並加熱回流30分鐘。故^ 後，濾取析出之固體，用乙醚及乙酸乙酯洗淨，乾燥，^ 到標題化合物3 80 mg β 1 H-NMR (DMSO-d6) δ (ppm): 3.3 8 (3H, s), 3.78-3.81 (2¾ 4.42^4.46 (2H, m), 6.64 (1H, d, J=5.2 Hz), 7.04-7.11 (iH m) 7.15-7.19 (1H, m), 7.31-7.37 (1H, m)5 7.43 (1H, dd, J=2.8 Hz J=8.0 Hz), 7.66 (1H, s), 8.13 (1H, dt5 J=6 Hz, J=9.2 Hz), 8.28 (1H, t, J=9.2 Hz), 8.76 (1H, d, J=5.2 Hz), 8.77 (lH, s)3 9.05 (IH, br s)，9.13 (IH, br s)。 實施例67 N-(4-(6-氨基- 7-(2-甲氳某乙氲某V4-4淋某）氛氣I 基）-N1 “甲氣茉基）Μ 以與實施例10同樣之方法，從4-(4-胺基-3-氟苯氧基）-6-氰基-7-(2-甲氧基乙氧基）喹啉（620 mg)及異氰酸（4-曱氧基 苯）酯’得到、標題化合物5 70 mg。 lH-NMR (DMSO-d6) 5 (ppm): 3.38 (3H, %s), 3.73 (3H, s), 3.78-3.81 (2H, m), 4.43^4.45 (2H, m), 6.63 (1H, d, J=5.2 Hz), 6.89 (2H, d3 J=8.8 Hz), 7.13-7.17 (1H, m), 7.37 (2H, d, J=8.8 Hz), 7.41 (IH, dd, J=2.8 Hz, J=11.6 Hz), 7.65 (1H, s), 8.28 (1H, t, J=8.8 Hz), 8.60 (1H, br s), 8.76 (1H, d, J=5.2 Hz), 8.77 (1H，s), 8·94 (IH, br s) o 實施例68 N-丄4- ( 6-氰基- 7-(甲氧基乙氧基）-4- η杏·.〃林基）氳笨基）二 甲氣某茇某、Μ _ -191- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公¢)(2,4-Difluorophenyl)cyanate (236 μL) and heated to reflux for 30 minutes. After that, the precipitated solid was filtered, washed with diethyl ether and ethyl acetate, and dried to give the title compound 3 80 mg β 1 H-NMR (DMSO-d6) δ (ppm): 3.3 8 (3H, s) , 3.78-3.81 (23⁄4 4.42^4.46 (2H, m), 6.64 (1H, d, J=5.2 Hz), 7.04-7.11 (iH m) 7.15-7.19 (1H, m), 7.31-7.37 (1H, m ) 5 7.43 (1H, dd, J=2.8 Hz J=8.0 Hz), 7.66 (1H, s), 8.13 (1H, dt5 J=6 Hz, J=9.2 Hz), 8.28 (1H, t, J=9.2 Hz), 8.76 (1H, d, J = 5.2 Hz), 8.77 (lH, s)3 9.05 (IH, br s), 9.13 (IH, br s). Example 67 N-(4-(6-Amino) - 7-(2-A 氲 氲 氲 氲 ) ) ) ) ) ) ) ) ) ) ) ) - - - - - - - - - - Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ 3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (620 mg) and (4-nonyloxyphenyl)isocyanate were obtained as the title compound 5 70 mg. lH-NMR (DMSO-d6) 5 (ppm): 3.38 (3H, %s), 3.73 (3H, s), 3.78-3.81 (2H, m), 4.43^4.45 (2H, m), 6.63 (1H, d, J=5.2 Hz), 6.89 (2H, d3 J=8.8 Hz), 7.13-7.17 (1H, m), 7.37 (2H, d, J=8.8 Hz), 7.41 (IH, dd, J =2.8 Hz, J=11.6 Hz), 7.65 (1H, s), 8.28 (1H, t, J=8.8 Hz), 8. 60 (1H, br s), 8.76 (1H, d, J = 5.2 Hz), 8.77 (1H, s), 8·94 (IH, br s) o Example 68 N-丄4-(6-Cyano) - 7-(methoxyethoxy)-4- η apricot·〃林基)氲氲基) dimethyl 茇, Μ _ -191- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂Binding

k 1304061 〜 A7 〜-一. B7 五、發明説明（186) 以與實施例10同樣之方法，從4-(4-胺基苯氧基）-6-氰基-7-(2-甲氧基乙氧基）喳啉（ 890 mg)及異氰酸4-曱氧苯酯， 得到標題化合物450 mg。 lH-NMR (DMSO-d6) δ (ppm): 3.36 (3H, s), 3.70 (3H, s), 3.76-3.79 (2H, m), 4.40-4.42 (2H, m), 6.51 (1H, d, J=5.6 Hz), 6.86 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.53 (1H, br s), 8.71 (1H，d，J=5.6 Hz)，8·76 (1H，s)，8.80 (1H，br s)。 實施例69 N- ((4-喊啶基）氧苯基）-Ν· - (4-甲氣笨某）月尿 在6-氯-4- (4-硝基苯氧基）嘧淀（3〇〇 mg)溶於乙酸乙酯（1〇 ml)-甲醇（10 ml)之混合溶媒中，加入氫氧化鈀（2〇 mg),並 在常壓之氫氣蒙氣下於室溫攪拌13小時。將反應液過遽， 濃縮滤液以及將殘餘物加至ΝΗ碎凝膠管柱（富士希利希亞 化學公司）电。用溶媒（乙酸乙酯-己烷：=丨_ 2)溶出及濃縮， 得到70 mg 4-(4-胺基苯氧基）嘧啶。以與實施例1〇同樣之方 式攸所彳于4- (4-胺基苯氧基）p密淀（70 mg)及異氰酸（4-甲氧基 苯）酯，得到標題化合物1 〇7 mg。 H-NMR (DMSO-d6) δ (ppm): 3.72 (3H, s), 6.87 (2H, d, J=8.8 Hz), 7.09 (1H, dd, J=1.6 Hz, J=5.6 Hz), 7.12 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz), 8.56 (1H, s)，8·66 (1H, d, J=5.6 Hz)，8.74-8.76 (2H，m)。 實施例70 : ϋ·:·.(-4- ( 6-讯皋：( 3 -甲乳識丙氧基）‘ ?套g休基）氧苯其、_ N，. ___ -192- 本纸張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 13〇4〇61k 1304061~A7~-一. B7 V. Description of Invention (186) In the same manner as in Example 10, from 4-(4-aminophenoxy)-6-cyano-7-(2-methoxy Ethyl ethoxy) porphyrin (890 mg) and 4-nonoxyphenyl isocyanate gave the title compound 450 mg. lH-NMR (DMSO-d6) δ (ppm): 3.36 (3H, s), 3.70 (3H, s), 3.76-3.79 (2H, m), 4.40-4.42 (2H, m), 6.51 (1H, d , J=5.6 Hz), 6.86 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.58 (2H, d, J =8.8 Hz), 7.62 (1H, s), 8.53 (1H, br s), 8.71 (1H, d, J = 5.6 Hz), 8.76 (1H, s), 8.80 (1H, br s). Example 69 N-((4-indanyl)oxyphenyl)-indole- (4-methyl phenoxy) monthly urine in 6-chloro-4-(4-nitrophenoxy)pyrazine ( 3 〇〇mg) was dissolved in a mixed solvent of ethyl acetate (1 〇ml)-methanol (10 ml), palladium hydroxide (2 〇mg) was added, and stirred at room temperature under atmospheric pressure of hydrogen gas. hour. The reaction solution was filtered, the filtrate was concentrated, and the residue was applied to a smashed gel column (Fuji Hilithia Chemical Co., Ltd.). It was dissolved and concentrated with a solvent (ethyl acetate-hexane: = 丨 2) to give 70 mg of 4-(4-aminophenoxy)pyrimidine. 4-(4-Aminophenoxy)p-precipitate (70 mg) and (4-methoxyphenyl)isocyanate were obtained in the same manner as in Example 1 to give the title compound. 7 mg. </ RTI> <RTIgt; (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz), 8.56 (1H, s), 8.66 (1H, d, J = 5.6 Hz), 8.74 - 8.76 (2H, m). Example 70: ϋ·:·.(-4-(6- 皋 皋:( 3 -甲乳知丙氧)' 套套克休基) Oxybenzene, _ N,. ___ -192- 本 本The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 13〇4〇61

A7 B7 五、發明説明（ 187 )A7 B7 V. Description of invention ( 187 )

甲氣笨基）脲 以與實施例7同樣之方法，從6-氰基、 、（4,((4-甲S甚笑 胺基）羰基）胺基苯氧基）-7-喹啉酸鈉得到標題彳匕人 1 H-NMR (DMS〇-d6) 5 (ppm): 2·09 (2H tt τ 物 ，L &gt;6·4 Hz” J=6.4In the same manner as in Example 7, from 6-cyano, (4,((4-methylsuccinyl)carbonyl)aminophenoxy)-7-quinolinic acid Sodium was obtained as the title 1 H-NMR (DMS〇-d6) 5 (ppm): 2·09 (2H tt τ, L &gt; 6·4 Hz) J=6.4

Hz), 2.56 (2H, t, J=6.4 Hz), 3.62 (3H, s) i ^71 , ’，3.71 (3H，s)，4·31 (2H，t，J=6.4 Hz)，6·52 (1H，d，J=5.2 Hz)，6·86 (2H d J=8 8 Hz)，7·22 (2H，d，&gt;8·8 Hz)，7.35 (2H，d，h8.8 Hz)，，7，57 (2H， d，J=8.8 Hz)，7·59 (1H，s)，8.50 (1H，s)，8.72 (1H，山 J=5 2’Hz), 2.56 (2H, t, J=6.4 Hz), 3.62 (3H, s) i ^71 , ',3.71 (3H,s),4·31 (2H,t,J=6.4 Hz),6· 52 (1H,d,J=5.2 Hz),6·86 (2H d J=8 8 Hz), 7·22 (2H,d,&gt;8·8 Hz), 7.35 (2H,d,h8.8 Hz),,7,57 (2H, d, J=8.8 Hz), 7·59 (1H, s), 8.50 (1H, s), 8.72 (1H, mountain J=5 2'

Hz)，8·74 (1H，s)，8·75 (1H，s)。 f施例7 1 N-(4&quot; (6-¾基- 7-(3-曱氧技基丙氧基）-4-峰淋某）氧笨某、 N’“4-甲氫苽某）月尿 將N- (4- ( 6-氰基-7-( 3-曱氧羰基丙氧基π奎琳基）氧苯 基）-N· - (4-甲氧苯基）脉（100 mg)加至甲醇（16 ml)及2N氫氧 化鈉水溶液ml)之混合溶媒中，並於80 °C加熱攪拌35分 鐘。過滤反應液並且加入5N鹽酸水溶液k2 ml。；慮取析出 之固體，用甲醇及乙醚接續洗淨，得到為淡黃色固體之目 的物50 mg。 lH-NMR (DMSO-d6) 5 (ppm): 2.05 (2H, tt, J=6.4 Hz, J=6.4Hz), 8.74 (1H, s), 8.75 (1H, s). fExample 7 1 N-(4&quot; (6-3⁄4基- 7-(3-曱oxy)propoxy)-4-peak leaching) Oxygen, N'"4-methylhydroquinone) Urine will be N-(4-(6-cyano-7-(3-indoxycarbonylpropoxy π-quinolinyl)oxyphenyl)-N-(4-methoxyphenyl) vein (100 mg Adding to a mixed solvent of methanol (16 ml) and 2N aqueous sodium hydroxide solution), and heating and stirring at 80 ° C for 35 minutes. The reaction solution was filtered and k 2 ml of a 5N aqueous hydrochloric acid solution was added; Methanol and diethyl ether were washed successively to give 50 mg of the object as a pale yellow solid. lH-NMR (DMSO-d6) 5 (ppm): 2.05 (2H, tt, J = 6.4 Hz, J = 6.4

Hz), 2.47 (2H, t, 1=6.4 Hz), 3.70 (3H, s), 4.31 (2H, t, J-6.4 Hz), 6.52 (1H, d, J=5.2 Hz), 6.86 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 7.59 (1H, s), 8.50 (1H, s), 8.71 (1H, d, J-5.2 Hz), 8.75 (1H, s)，8.76 (1H，s)。 -193- 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 一 A7 B7 五、發明説明（188) 實施例72 N“4-(6-氰基淼等乙氳基）乙氧基-嘻啉某）氫 笨基）-N’-(4-甲氳茇甚、月尿 以與實施例7同樣之方法，從6-氰基-4-(4-((4-甲氧基苯 胺基）羰基）胺基苯氧基）-7〃奎啉酸鈉，得到標題化合物。 lH-NMR (DMSO-d6)5(ppm): 3.54-3.57 (4H, m), 3.72 (3H, s), 3.87- 3.90 (2H，m), 4.41-4.45 (2H，m)，4·62-4·65 (1H，m), 6.54 (1H, d, J=5.2 Hz), 6.87 (2H, d, J=8.8 Hz), 7.24 (2H? d, J=8.8 Hz), 7.38 (2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz), 7.64 (1H, s), 8.62 (1H, br s), 8.74 (1H, d, J=5.2 Hz), 8.78 (1H，s)，8·87 (1H，br s)。 實施例73 N-(4-( 6-氰基-7-n“二Λ賒某）丙氧基）-4- 4啉氣基）笨 基)甲磺醯篡）笨基）脲 以與實施，7同樣之方法，從N-4-((6-氰基-7-羥基-4-喹 啉基）氧）苯基-N*-(3-(甲磺醯基）苯基）-脲（119 mg，0.25 mmol)，得到為淡褐色結晶之標題化合物（8.8 mg，0.015 mmol，6.0%)。 j-NMR 光譜（DMSO-d6)(5(ppm): 0·95 (6H，t，J=7.2 Hz)， 1.87- 1.95 (2H，m)，2.40-2.70 (6H，m)，3.18(3H，s)，4.29-4.33 (2H, m), 6.51 (1H, d, J=5.2 Hz), 7.25 (2H, d, J=8.8 Hz), 7.49-7.68 (6H, m), 8.16 (1H, br s), 8.71 (1H, d, J=5.2 Hz), 8·75 (1H，s)，9.02 (1H, br s)，9·21 (1H，br s)。 實施例74 -194- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 、 A7 ______B7 五、發明説明（189) 4- ( 6-讯茱-7- (3 - (t嗎一福g林基）丙氣甚4· π奎淋某）氧笑 基）-N’-(3“甲碏醯某）笨某）脲 以與實施例7同樣之方法，從N-4-((6-氰基-7-羥基-4-喹 淋基）氧）苯基-Nf-(3-(甲磺醯基）苯基）脲（119 mg，〇 25 mmol)，得到為淡黃色結晶之標題化合物（81 ^，〇· 135 mmol，53·7%)。 iH-NMR *.(DMSO-d6)5(ppm):1.95-2.04 (2H，m)，2.34-2.60 (6H，m)，3·18 (3H，s)，3·54-3·60 (4H，m)，4.30-4.36 (2H， m)，6·52 (1H，d，J=5.2 Hz)，7·25 (2H，d，J=：8.8 Hz)，7.50-7.68 (6H，m)，8.16 (1H，s)，8.72 (1H，d，J=5.2 Hz)，8.75 (1H，s)， 8·95 (1H，s)，9·15 (1H，s)。 實施例75 N-(4-(6-氰基-7-n-d乙胺基）丙氣笔杳啉氳）笨基v Ν’-笨基脲 以與實施:(fj7同樣之方法，從4-(4-((苯胺羰基）胺基）苯氧 基）-6-氰基-7“奎琳酸鈉（210 mg，0.50 mm〇l)，得到為淡 褐色結晶之標題化合物（70 mg，0.137 mmol，27.5%)。 h-NMR 光譜（DMS〇-d6) 5 (ppm): 0·95 (6H，t，J=7.2 Hz)， 1.85-1.95 (2H，m)，2.40-2.55 (4H，m)，2.60 (2H，t，J=6.8 Hz)， 4.31 (2H，t，J=6.0 Hz)，6.51 (1H，d，J=5.2 Hz)，6.96 (1H，m)， 7.22-7.30 (4H, m), 7.45 (2H, d, J=8.0 Hz), 7.56-7.61 (3H, m), 8.70-8.72 (2H，m)，8.75 (1H, s)，8·84 (1H, s) 〇 實施例76 , -祝基- 7- (3-(4-嗎細g林基）丙系,某）-4 - ?奎g休基）乳尽 -195- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公$) 裝 玎Hz), 2.47 (2H, t, 1=6.4 Hz), 3.70 (3H, s), 4.31 (2H, t, J-6.4 Hz), 6.52 (1H, d, J=5.2 Hz), 6.86 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 7.59 (1H, s) , 8.50 (1H, s), 8.71 (1H, d, J-5.2 Hz), 8.75 (1H, s), 8.76 (1H, s). -193- This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Inventive Note (188) Example 72 N "4-(6-Cyanoquinone et al. Ethyloxy-porphyrin (hydrogen phenyl)-N'-(4-carbocarb, urinary urinary in the same manner as in Example 7, from 6-cyano-4-(4-(( 4-Methoxyanilino)carbonyl)aminophenoxy)-7-indole sodium sulphate gave the title compound. MH-NMR (DMSO-d6) 5 (ppm): 3.54-3.57 (4H, m), 3.72 (3H, s), 3.87- 3.90 (2H, m), 4.41-4.45 (2H, m), 4·62-4·65 (1H, m), 6.54 (1H, d, J=5.2 Hz), 6.87 (2H, d, J=8.8 Hz), 7.24 (2H? d, J=8.8 Hz), 7.38 (2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz), 7.64 ( 1H, s), 8.62 (1H, br s), 8.74 (1H, d, J = 5.2 Hz), 8.78 (1H, s), 8·87 (1H, br s). Example 73 N-(4- (6-Cyano-7-n "dioxa" propoxy)-4- 4 porphyrin) phenyl) sulfonyl) phenyl) urea in the same manner as in the implementation, 7 from N 4-((6-Cyano-7-hydroxy-4-quinolinyl)oxy)phenyl-N*-(3-(methylsulfonyl)phenyl)-urea (119 mg, 0.25 mmol), Obtained as light brown crystal The title compound (8.8 mg, 0.015 mmol, 6.0%). j-NMR spectrum (DMSO-d6) (5 (ppm): 0·95 (6H, t, J = 7.2 Hz), 1.87- 1.95 (2H, m), 2.40-2.70 (6H, m), 3.18 (3H) , s), 4.29-4.33 (2H, m), 6.51 (1H, d, J = 5.2 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.49-7.68 (6H, m), 8.16 (1H, Br s), 8.71 (1H, d, J=5.2 Hz), 8·75 (1H, s), 9.02 (1H, br s), 9·21 (1H, br s). Example 74 -194- Ben The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061, A7 ______B7 V. Invention description (189) 4- (6- 茱-7-(3 - (t?一福g林基) propylene gas 4 π 奎 某 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) (7-hydroxy-4-quinolyl)oxy)phenyl-Nf-(3-(methylsulfonyl)phenyl)urea (119 mg, EtOAc (m. 81 ^, 〇 · 135 mmol, 53.7%). iH-NMR *. (DMSO-d6) 5 (ppm): 1.95-2.04 (2H, m), 2.34-2.60 (6H, m), 3.18 (3H, s), 3·54-3·60 (4H, m), 4.30-4.36 (2H, m), 6.52 (1H, d, J = 5.2 Hz), 7·25 (2H, d, J=: 8.8 Hz), 7.50-7.68 (6H, m) 8.16 (1H, s), 8.72 (1H, d, J = 5.2 Hz), 8.75 (1H, s), 8.95 (1H, s), 9·15 (1H, s). Example 75 N-( 4-(6-Cyano-7-ndethylamino)propanol porphyrin 氲) phenyl v'-stupyl urea in the same manner as (fj7), from 4-(4-((aniline) The title compound (70 mg, 0.137 mmol, 27.5%) was obtained as pale brown crystals. H-NMR spectrum (DMS〇-d6) 5 (ppm): 0·95 (6H, t, J = 7.2 Hz), 1.85-1.95 (2H, m), 2.40-2.55 (4H, m), 2.60 (2H ,t,J=6.8 Hz), 4.31 (2H,t,J=6.0 Hz), 6.51 (1H,d,J=5.2 Hz), 6.96 (1H,m), 7.22-7.30 (4H, m), 7.45 (2H, d, J=8.0 Hz), 7.56-7.61 (3H, m), 8.70-8.72 (2H, m), 8.75 (1H, s), 8.84 (1H, s) 〇 Example 76, - Zhuji - 7- (3-(4-? fine g-lin) C, a) -4 - ? 奎 g 基 ) 乳 195 -195- This paper scale applies to the Chinese National Standard (CNS) A4 specifications (210 X 297 public $) decoration

線 1304061 〜 A7 B7 五、發明説明（19〇) 某）-N、茉基脲 以與實施例7同樣之方法，從4-(4-((苯胺羰基）胺基）苯氧 基）-6-氰基-7-4淋酸鈉（105 mg，0·25 mmol)，得到為淡黃 色結晶之標題化合物（67 mg，0.128 mmol，5 1 ·〇%)。 W-NMR 光譜（〇1^〇-(16)5(?卩111):1.92-2,02 (211，：〇1)，2.35-2.57 (6H, m), 3.55-3.57 (4H, m), 4.30-4.34 (2H, m)5 6.51 (1H, d, J=5.6 Hz), 6.96 (1H, t, J=7.2 Hz), 7.22-7.30 (4H, in), 7.45 (2H, d, J=7.6 Hz), 7.58-7.61 (3H, m), 8.69-8.72 (2H, m), 8.75 (1H，s)，8·83 (1H，s) 〇 實施例77 N-(4-(6-氰基-7-(2-甲氧基乙氣基4-4嗾基）氣笨基 ΠΗ-fdl咮唑-2-基）脲 藉由與實施例11同樣之方法，從N-(4-(6-氰基-7-(2-甲氧 基乙氧基）-4-喹啉基）氧苯基）胺基甲酸苯酯（1〇1 mg，0.222 mmol)得到為白色結晶之標題化合物（71 mg，0· 14 mmol， 64.7%) 〇 、 iH-NMR光譜（DMSO-d6)5(ppm): 3·36 (3Η，s)，3·75-3·79 (2Η， m)，4.40-4.43 (2H，m)，6.54 (1H，d，J=5.2 Hz)，7·04,7·07 (2H， m), 7.26 (2H, d, J=8.8 Hz), 7.34^7.37 (2H, m), 7.62 (1H, s), 7.73 (2H, d, J=8.8 Hz), 8.72 (1H, d, J=5.2 Hz), 8.77 (1H, s)。 實施例78 N- (_4- (6-氰基-7-(2-甲氧基乙氣某4_g争〇故基）氣笨墓Ν’-(2 -酮基-1,2,3,4-四氛-6-口奎g林某） -196- 本紙張尺度適用中國國家禕準(CNS) A4規格(210 X 297公釐） 1304061 A7 ______B7 五、發明説明(^~)~ ' ' — 藉由與實施例11同樣之方法，從N-(4-(6-氰基甲氧 基乙氧基）·4-奎啉基）氧苯基）胺基曱酸苯酯（1〇〇 mg , 〇.22〇 mmol)得到為白色結晶之標題化合物（7〇 mg，〇 134 mm〇1 , 60.9%)。 H-NMR 光譜（〇1\130-&lt;16)(5(??111):2.38-2.43 (21^，111)，2.81-2.85 (2H，m)，3.36 (3H，s)，3.75-3.79 (2H，m)，4·40-4·43 (2H， m), 6.51 (1H, d, J=5.2 Hz), 6.76 (1H, d, J=8.4 Hz), 7.16 (1H, dd, J=2.0, 8.4 Hz), 7.22 (2H, dd, J=8.8 Hz), 7.30 (1H, s), 7.58 (2H，d，J=8.8 Hz)，7·62 (1H，s)，8·52 (1H，s)，8.71 (1H， d，J=5.2 Hz)，8·75 (2H，s)，9.95 (1H，s) 〇 實施例79 N- (A-Ii·：:氰基-7- (2-甲氧基乙氧某）-4- +说基）氣笨基）-N，· (4-乙醯胺笨基）脲 藉由與實施例11同樣之方法，從4-(6-氰基-7-(2-曱氧 基乙氧基）-身-喹啉基）氧苯基）胺基甲酸苯酯（1〇〇 mg，〇.22〇 mmol)得到為白色結晶之標題化合物.、（1〇〇 mg , 〇·ι97 mmol，89·6%) 0 iH-NMR光譜（DMS〇-d6)5(ppm): 2·〇〇 (3H，s), 3·36 (3H，s), 3.76-3.79 (2Η，m)，4·40-4·43 (2Η，m)，6.52 (1Η，d，J=5.2 Hz), 7.23 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.46 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.59 (1H, s), 8.72 (1H, d, J=5.2 Hz), 8.76 (1H, s), 8.77 (1H, s)3 9.80 (1H, s) 0 · 實施例80 -197- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（192 N-(4-M二氰基-7-Γ2-甲氧基乙氫基休基）氣茉某w-(3 -乙醯胺苽某1脹 藉由與實施例11同樣之方法，從N-( 4-(6-氰基-7-( 2-甲氧 基乙氧基）-4-喹啉基）氧苯基）胺基甲酸苯酯（1〇〇 mg，0.220 mmol)得到為白色結晶之標題化合物（95 mg，〇186 mmol， 84·9%)。 W-NMR光 1朁（DMSO-d6)5(ppm): 2·02 (3Η，s)，3.36 (3Η，s)， 3.76-3.79 (2Η, m), 4.40-4.43 (2H, m), 6.52 (1H, d, J=5.6 Hz), 7.15-7.20 (3H, m), 7.23 (2H, d5 J=8.8 Hz), 7.59 (2H, d, J=8.8 Hz), 7.62 (1H, s), 7.76 (1H, s), 8.71-8.76 (4H, m), 9.90 (1H, s) 0 實施例8 1 Μζ·.(4-(6-氰.基-7-苄氧基-4-啐啉基）氧-2H葚） 二氣苯某）脲 使用Ν-(2々4-一氟笨基）-Nf-(2-氟-4-幾苯基）脲（227 mcy , 0· 805 8 mmol)及 4-氯-6-氰基-7-亨氧 口奎嘴、（2 5〇 mg , 0.8482 mmol)，以與實施例86之另一法同樣之方式進行，放冷， 萃取，洗淨後減壓餾去溶媒，將得到之結晶懸浮於乙鞋 中’洗淨後滤取®將其溶解於四氫咬喃，用♦凝膠過據 以及減壓餾去溶媒❶將得到之結晶懸浮於乙趟中，並於、，▲ 淨後濾取，用乙醚洗淨及吸引乾燥後，得到為淡褐色纟士田 ’’0 曰9 之標題化合物（70 mg，0.1295 mmol，16.07%)。 iH-NMR光譜（DMSO-d6)5(ppm): 5·45 (2H，s)，6.63 (1H d J=5.4 Hz), 7·05 (1H，m)，7.15 (1H，m)，7,29,7·46 (5H m) _____-198-Lines 1304061 to A7 B7 V. Description of the Invention (19〇) Some -N, jasmonamide in the same manner as in Example 7 from 4-(4-((phenylaminocarbonyl)amino)phenoxy)-6 The title compound (67 mg, 0.128 mmol, 5 1 · 〇%) was obtained as pale yellow crystals. W-NMR spectrum (〇1^〇-(16)5(?卩111): 1.92-2,02 (211,:〇1), 2.35-2.57 (6H, m), 3.55-3.57 (4H, m) , 4.30-4.34 (2H, m)5 6.51 (1H, d, J=5.6 Hz), 6.96 (1H, t, J=7.2 Hz), 7.22-7.30 (4H, in), 7.45 (2H, d, J =7.6 Hz), 7.58-7.61 (3H, m), 8.69-8.72 (2H, m), 8.75 (1H, s), 8·83 (1H, s) 〇 Example 77 N-(4-(6- Cyano-7-(2-methoxyethyl group 4-4 fluorenyl) oxaphenyl-fdloxazol-2-yl)urea was obtained from N-(4- in the same manner as in Example 11. (6-Cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxyphenyl)carbamic acid phenyl ester (1 〇1 mg, 0.222 mmol) (71 mg, 0·14 mmol, 64.7%) 〇, iH-NMR spectrum (DMSO-d6) 5 (ppm): 3·36 (3Η, s), 3·75-3·79 (2Η, m), 4.40-4.43 (2H,m), 6.54 (1H,d,J=5.2 Hz),7·04,7·07 (2H, m), 7.26 (2H, d, J=8.8 Hz), 7.34^7.37 ( 2H, m), 7.62 (1H, s), 7.73 (2H, d, J = 8.8 Hz), 8.72 (1H, d, J = 5.2 Hz), 8.77 (1H, s). Example 78 N- (_4 - (6-Cyano-7-(2-methoxyethane gas 4_g 〇 〇 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) - 口奎g林) -196- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 ______B7 V. Invention description (^~)~ ' ' - by and with examples 11 In the same manner, from N-(4-(6-cyanomethoxyethoxy)·4-quinolinyloxyphenyl)aminophenyl phthalate (1 〇〇 mg, 〇.22〇) The title compound (7 〇 mg, 〇 134 mm 〇 1, 60.9%) was obtained as white crystals. H-NMR spectrum (〇1\130- &lt;16) (5 (?? 111): 2.38-2.43 ( 21^,111),2.81-2.85 (2H,m), 3.36 (3H,s),3.75-3.79 (2H,m),4·40-4·43 (2H, m), 6.51 (1H, d, J=5.2 Hz), 6.76 (1H, d, J=8.4 Hz), 7.16 (1H, dd, J=2.0, 8.4 Hz), 7.22 (2H, dd, J=8.8 Hz), 7.30 (1H, s) , 7.58 (2H,d,J=8.8 Hz),7·62 (1H,s),8·52 (1H,s),8.71 (1H, d,J=5.2 Hz),8·75 (2H,s ), 9.95 (1H, s) 〇 Example 79 N-(A-Ii·::Cyano-7-(2-methoxyethoxy)-4-yl)yl)-N, (4-Ethylamino-phenyl)urea from 4-(6-cyano-7-(2-decyloxyethoxy)- quinolinyl)oxygen in the same manner as in Example 11. Phenyl)amine Phenyl benzoate (1 〇〇 mg, 〇.22 〇 mmol) gave the title compound as white crystals, (1 〇〇mg, ι·ι97 mmol, 89·6%) 0 iH-NMR spectrum (DMS〇- D6) 5 (ppm): 2·〇〇(3H,s), 3·36 (3H,s), 3.76-3.79 (2Η,m),4·40-4·43 (2Η,m),6.52 ( 1Η, d, J=5.2 Hz), 7.23 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.46 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.59 (1H, s), 8.72 (1H, d, J=5.2 Hz), 8.76 (1H, s), 8.77 (1H, s)3 9.80 ( 1H, s) 0 · Example 80 -197- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of invention (192 N-(4-M dicyano) 7-Γ2-methoxyethylhydrocarbyl) gas-m-w-(3-acetamide) 1 expansion from N-(4-(6-cyano)- in the same manner as in Example 11. Phenyl 7-(2-methoxyethoxy)-4-quinolinyloxyphenyl)carbamate (1 mg, 0.220 mmol) M, 84.9%). W-NMR light 1 朁 (DMSO-d6) 5 (ppm): 2·02 (3Η, s), 3.36 (3Η, s), 3.76-3.79 (2Η, m), 4.40-4.43 (2H, m), 6.52 (1H, d, J=5.6 Hz), 7.15-7.20 (3H, m), 7.23 (2H, d5 J=8.8 Hz), 7.59 (2H, d, J=8.8 Hz), 7.62 (1H, s) , 7.76 (1H, s), 8.71-8.76 (4H, m), 9.90 (1H, s) 0 Example 8 1 Μζ·.(4-(6-Cyano-yl-7-benzyloxy-4-indole)啉-(2々4-monofluorophenyl)-Nf-(2-fluoro-4-phenylphenyl)urea (227 mcy, 0·805 8) Methyl) and 4-chloro-6-cyano-7-henoxy-n-n-n-n-n-n-n, (25 mM mg, 0.8482 mmol), in the same manner as in the other method of Example 86, cooling, extraction, washing After the net, the solvent is distilled off under reduced pressure, and the obtained crystal is suspended in a shoe. After washing, it is filtered and dissolved in tetrahydrocethane. The crystal is obtained by using ♦ gel and distillation under reduced pressure to remove the solvent. The title compound (70 mg, 0.1295 mmol, 16.07%) was obtained as the title compound (70 mg, 0.1295 mmol, 16.07%). . iH-NMR spectrum (DMSO-d6) 5 (ppm): 5·45 (2H, s), 6.63 (1H d J = 5.4 Hz), 7·05 (1H, m), 7.15 (1H, m), 7 ,29,7·46 (5H m) _____-198-

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 s A7 _ B7 五、發明説明（193) 7.54 (2H, d, J=7.6 Hz), 7.71 (1H, s), 8.11 (1H, dt, J=6.0 Hz, 9.2 Hz), 8.27 (1H, d, J=9.2 Hz), 8.74 (1H, d, J=5.4 Hz), 8.77 (1H，s)，8.99 (1H, s), 9.07 (1H，s) 〇 實施例82 N-( 4-(7-(爷氧基）-6-氰基-4-4啉某）氫茇某 基）月尿 藉由與實施例34同樣之方法，從4-(4-胺基苯氧基）-7-(芊 氧基）-6-氰基喹啉（2.61 g，7.10 mmol)及N-(2-噻唑基）胺基 曱酸苯酯（1.88 g，8.54 mmol)，得到為淡褐色結晶之標題 化合物（3.19 g，6.46 mmol，91%)。 iH-NMR光譜（DMS〇-d6)5(ppm): 5.47 (2H，s)，ό.55 (1H，山 J=5.3 Hz), 7.12 (1H, d, J=3.5 Hz), 7.29 (2H, d, J=8.7 Hz)? 7.36-7.58 (6H, m), 7.65 (2H5 d3 J=8.7 Hz), 7.72 (1H, s), 8.74 (1H，d，J=5.3 Hz)，8.80 (1H，s)，9·18 (1H，s)。 實施例83人 氰基基-4-4,林基）氣苯基邊岭基)Jl 將實施例82所得之N-(4-(7-(苄氧基）-6-氰基-4-喹啉基） 氧冬基）-N - (2 -σ塞咬基）踩（3.09 g，7.66 mmol)溶於三氟乙 酸（25 ml)及硫代苯曱醚（4·50 ml，38.3 mmol)中後，於65 °C 攪拌1 5小時。將反應液減壓濃縮，將得到之殘餘物加至5% 碳酸氫鈉水溶液及乙醚中並攪拌，濾取析出之結晶，用水 及乙醚洗淨，然後減壓乾燥。將粗生成物懸浮在己烷-乙酸 乙酯之混合溶媒中並用超音波處理，漆取結晶，用乙醚洗 淨後，在室溫通風乾燥，得到為黃色結晶之標題化合物 -199- I紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)~' ' I3〇4〇61 A7 B7 五、發明説明（ (1.94 g，4·80 mmol，63%) 0 A-NMR 光譜（DMSO-d6)(5(ppm): 6.44 (1H，d，J=5.2 Hz)， 7.12 (1H, d, J=3.7 Hz), 7.28 (2H, d, J=7.8 Hz), 7.39 (1H, d5 J-3.7 Hz), 7.42 (1H, s), 7.64 (2H, d, J=7.8 Hz), 8.65 (1H, d, J=5.2 Hz), 8.68 (1H，s)，9.14 (1H，s)。 f施例84 基- 7- (3-( —乙胺基）丙氧基）·4 - g·蛛氣）笨基）· 以與實施例7同樣之方法，從實施例83得到之N_(4-(6-氰 基-7-羥基-4-喳啉基）氧苯基）-N、（2-噻唑基）脲（1〇1 mg , 0.250 mmol)，得到為無色結晶之標題化合物（26 mg , 0.0503 mmol，20%) 〇 iH-NMR光譜（CDCl3)5(ppm): 1·〇5 (6H，t，J=7.2 Hz)，2.03- 2.12 (2H, m), 2.58 (4H, q, J=7.2 Hz), 2.71 (2H, t, J=7.0 Hz), 4·28 (2H，V、J=6.2 Hz), 6.47 (1H，d，J=5.3 Hz)，6.92 (1H，d， J=3.7 Hz), 7.17 (2H, d, J=8.8 Hz), 7.43 (4H, d, J=3.7 Hz), 7.47 (1H, s), 7.67 (2H, d, J=8.8 Hz), 8.65 (1H, d, J=5.3 Hz), 8,67 (1H，s)。 實施例85 N-(4- ( 6-氰基-7- (3- M-噁福口沐某）S氣某U4- g杏成基）氣笨 基違唑某、4 以與實施例7同樣之方法，從實施例83得到之N- 4- ( 6-氰 基-7-羥基-4-喳啉基）氧苯基噻唑基）脲（丨01 mg , 0.250 mmol)，得到為無色結晶之標題化合物（19 mg , -200- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱) 裝 訂This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 s A7 _ B7 V. Invention description (193) 7.54 (2H, d, J=7.6 Hz), 7.71 (1H, s), 8.11 (1H, d=, J=6.0 Hz, 9.2 Hz), 8.27 (1H, d, J=9.2 Hz), 8.74 (1H, d, J=5.4 Hz), 8.77 (1H, s), 8.99 (1H, s), 9.07 (1H, s) 〇 Example 82 N-(4-(7-(yloxy)-6-cyano-4-4 phenanthyl)hydroquinone) 34, in the same manner, from 4-(4-aminophenoxy)-7-(decyloxy)-6-cyanoquinoline (2.61 g, 7.10 mmol) and N-(2-thiazolyl)amine Phenyl decanoate (1.88 g, 8.54 mmol) gave the title compound (l. iH-NMR spectrum (DMS 〇-d6) 5 (ppm): 5.47 (2H, s), ό.55 (1H, mountain J = 5.3 Hz), 7.12 (1H, d, J = 3.5 Hz), 7.29 (2H , d, J=8.7 Hz)? 7.36-7.58 (6H, m), 7.65 (2H5 d3 J=8.7 Hz), 7.72 (1H, s), 8.74 (1H, d, J=5.3 Hz), 8.80 (1H , s), 9·18 (1H, s). Example 83: Human cyano-4-4, linyl) phenyl phenyl phenyl) Jl. N-(4-(7-(benzyloxy)-6-cyano-4-) obtained in Example 82. Quinolinyl)oxybutyryl)-N-(2- serotonin) tread (3.09 g, 7.66 mmol) dissolved in trifluoroacetic acid (25 ml) and thiophenyl ether (4·50 ml, 38.3 mmol) After the middle, stir at 65 °C for 15 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. The crude product was suspended in a mixed solvent of hexane-ethyl acetate and subjected to ultrasonic treatment, and the crystals were extracted, washed with diethyl ether, and then air-dried at room temperature to obtain the title compound -199-I paper size as yellow crystals. Applicable to China National Standard (CNS) A4 specification (210X 297 mm)~' ' I3〇4〇61 A7 B7 V. Description of invention (1.94 g, 4.80 mmol, 63%) 0 A-NMR spectrum (DMSO- D6) (5 (ppm): 6.44 (1H, d, J = 5.2 Hz), 7.12 (1H, d, J = 3.7 Hz), 7.28 (2H, d, J = 7.8 Hz), 7.39 (1H, d5 J -3.7 Hz), 7.42 (1H, s), 7.64 (2H, d, J=7.8 Hz), 8.65 (1H, d, J=5.2 Hz), 8.68 (1H, s), 9.14 (1H, s). f Example 84 benzyl-7-(3-(-ethylamino)propoxy)·4 - g·spiral)) In the same manner as in Example 7, N_( obtained from Example 83) 4-(6-Cyano-7-hydroxy-4-indolyl)oxyphenyl)-N, (2-thiazolyl)urea (1 〇1 mg, 0.250 mmol) 26 mg , 0.0503 mmol, 20%) 〇iH-NMR spectrum (CDCl3) 5 (ppm): 1·〇5 (6H, t, J=7.2 Hz), 2.03- 2.12 (2H, m), 2.58 (4H, q, J=7.2 Hz), 2.71 (2H, t, J=7.0 Hz ), 4·28 (2H, V, J=6.2 Hz), 6.47 (1H, d, J=5.3 Hz), 6.92 (1H, d, J=3.7 Hz), 7.17 (2H, d, J=8.8 Hz) ), 7.43 (4H, d, J=3.7 Hz), 7.47 (1H, s), 7.67 (2H, d, J=8.8 Hz), 8.65 (1H, d, J=5.3 Hz), 8,67 (1H , s). Example 85 N-(4-(6-Cyano-7-(3-M-Eofukoumu) S gas U4-g apricot base) gas stupid azole, 4 and Example 7 In the same manner, N-4-(6-cyano-7-hydroxy-4-indolyl)oxyphenylthiazolyl)urea (丨01 mg, 0.250 mmol) obtained in Example 83 was obtained as colorless crystals. Title compound (19 mg , -200- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 public) Binding

線 1304061 — A7 B7_____ 五、發明説明（195) 0.0358 mmol，14%) ° iH-NMR光譜（CDC13) 5 (ppm): 2.08-2.16 (2H，m)，2·46·2·52 (4Η, m), 2.62 (2Η, t, J=7.0 Hz), 3.70-3.76 (4H, m), 4.30 (2H, t, 1=6.2 Hz), 6.47 (1H, d, J=5.3 Hz), 6.92 (1H, d, J=3.7 Hz), 7.17 (2H, d, J=8.8 Hz), 7.42 (1H, d, J=3.7 Hz), 7.48 (1H, s), 7.67 (2H, d, J=8.8 Hz), 8.66 (1H, d, J=5.3 Hz), 8.69 (1H, 十 實施例86 氨某-7-芊氣某- 4-4啉基J氧苯基甲氧苯 基）脲 在4-胺基（4-胺基苯氧基）-7-(苄氧基）-6-氰基喹啉（1.0 g) 中，加入甲苯（60 ml)及乙腈（30 ml) ’回流使之溶解後，在 回流下添加異氰酸（4-曱氧基苯）酯（0.53 ml)。在回流下攪 拌1小時後，再加入異氰酸（4-甲氧基苯）酯（0.30 ml)，於回 流下再攪拌、40分鐘，然後回到室溫。濾取析出之結晶，用 甲苯-乙腈=1 : 1混合溶媒洗淨，得到為淡褐色結晶之標題 化合物（0.60 g) ^濾取從洗淨液析出之結晶，得到為淡褐色 結晶之標題化合物（0.20 g)。 iH-NMR 光譜（CDCl3)5(ppm): 3·73 (3H，s)，5·98 (2H，s)， 6.56 (1Η，d，J=5.2 Ηζ)，6·89 (2Η，d，J=9.3 Ηζ)，7.24 (2Η，d， J=9.3 Hz), 7.33-7.65 (9H, m), 7.72 (1H，s)，8.74 (1H，d， J=5.2 Hz)，8.82 (1H，s)，8.89 (1H，br s)，9.19 (1H，br s)。 實施例86-2 _ - 201 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 _B7 五、發明説明（196 ) 基）脲 在 N-4-(^ 本基）-N’-(4-甲氧苯基）腸（4.25 g，16.46 mmol) 中，加入1-甲基吡咯啶酮（3,4 ml)及二異丙基乙胺（3.6 ml， 20.78 mmol)，於130°C加熱攪拌，並使之完全溶解後，加 入4-氯-6-氰基-7-苄氧喹啉（5.10 g，17.32 mmol)，於 130°C 攪拌1·5小時及於150°C攪摔1小時。追加二異丙基乙胺（1·2 ml , 6.93 mmol)並再攪拌1小時。放冷後加入四氫呋喃及乙 酸乙酯’用飽和碳酸氫鈉水溶液及飽和食鹽水接續洗淨， 用無水硫酸鍰乾燥及減恩館去溶媒。將得到之結晶用乙 醚·己烷，乙腈·乙醚·己烷，甲醇及二曱基亞颯·水依 次洗淨。將得到之結晶溶於四氫呋喃，用矽凝膠過濾（矽凝 膠200 cc)，用四氫呋喃3〇〇〇 ml溶離，然後減壓餾去溶媒。 將得到之結晶用乙醚，乙腈，乙醚：乙醇=5 :丨依次洗淨及 吸引乾燥，知·到為褐色結晶之標題化合物㈠7〇 g，7.1 627 mmol，43.5J%)。 實施例87 6- (心（（4·甲t基苯胺革」^基）胺某茇氫菩」· 7·崦说 酸納 在N-(4- ( 6-氰基-7-卞氧基-4-喹啉基）氧苯基）-Ν，·（4-甲 氧苯基）脲（12.2 g)中加入三氟乙酸（122…）及噻唑（11.7 ml)，於50°C攪拌整夜，然後於4〇它攪掉24小時。確認原料 消失後，將反應液系統減壓濃縮，加入四氫呋喃及飽和碳 酸氫鈉水;谷液，濾取析出之黃色結晶反減壓乾燥可得標題 化合物（6·8 g)。進一步於濾液中加入乙醚、濾取析出之黃 ________ - 202 - 本成張尺度適用中國國豕標準(CNS) A4規格（210 X 297公愛） 1304061 〜 A7 _B7 五、發明説明（197 ) ^ 色結晶、減壓乾燥後’得到標題化合物（2. 〇 g)。 iH-NMR 光；if (CDCI3) 5 (ppm): 3·72 (3H，s)，6.56 (1H，d， J=6.1 Hz)，6·88 (2H，d，J=8.7 Hz)，7·23 (2H，d，J=8.7 Hz)， 7·37 (2H，d，J=8.7 Hz)，7·44 (1H，s)，7.60 (2H，d，J=8.7 Hz)， 8.57 (1H，s)，8.67 (1H，d，J=6.1 Hz)，8.70 (1H，s), 8·82 (1H， s)。 實施例88 基-4-(4-((4-乱本胺基）魏基）胺某苯囊某•邊?林酸銷 將4-(4-胺基苯氧基）-7-(宇氧基）· 6-氰基u奎淋（7.776 g， 21.2 mmol)溶於甲苯（400 ml)及乙腈（2 〇〇 mi)之混合溶媒中 後’添加異氰酸（4-氟苯）醋（3.68 ml，3 1 ·7 mmol),並在 12 0 °C加熱回流1小時。將反應液減壓濃縮，將殘餘物懸浮 於四氫呋喃（150 ml)後，添加己烷（150 ml)及以超音波處 理，濾取析出之結晶，減歷r乾燥及得到為淡褐色結晶之义 (4- ( 7-(宇氧·〜基）-6-见基-4-p奎琳基）氧苯基）_ ν’- (4-氟苯基） 脲（9.81 g，19.4 mmol，91.9%)。在氮蒙氣下將其溶於三氟 乙酸（100 ml)及硫代苯甲醚（9.13 nd，77.7 mmol)中，並於 6(TC攪拌12小時。將反應液減壓濃縮，將得到之殘餘物加 至四氫呋喃（50 ml)中後’加入1N氫氧化鈉水溶液（15〇 ml)，再加入水（1 50 ml)並授掉，濾取析出之結晶，用水， 乙醚及乙酸乙酯洗淨，於70°C乾燥，得到為黃色結晶之標 題化合物（3.646 g，8·36 mmol，43.0%)。 陰性 ESI-MS 413 (M-Na)、 ： 實施例89 •203- 本紙張尺度適用中國國家標準(CMS) A4規格(210 X 297公釐) 1304061 A7 _ B7 _ 五、發明説明（198 ) 6-氰某-4-(4-(2 3-二氣苯胺某）蕤某）胺基-3-_氟苯氧基U7-邊啉酸鈉 . 將實施例81得到之7-芊氧基體（1.1 g)，三氟乙酸（10 ml) 與硫代苯甲醚（1 ml)之混合物在油浴中，於63〜67°C加熱攪 拌1 6小時。反應終了後，將反應液濃縮，加入飽和碳酸氫 鈉水溶液，以及濾取析出之固體。將得到之固體用水，乙 醚及乙酸乙酯洗淨，乾燥及定量地得到標題化合物。 lH-NMR (DMSO-d6) 5 (ppm): 6.54 (1H, d, J=5.6 Hz), 7.04-7.10 (1H, m), 7.14-7.17 (1H, m), 7.31-7.36 (1H, m), 7.40 (1H, dd, J=2.8 Hz, J=12 Hz), 7.44 (1H, s), 8.10-8.16 (1H, m), 8.27 (1H, t, J=8.8 Hz), 8.67 (1H, s), 8.68 (1H, d3 J=5.2 Hz), 8·99-9·03 (1H，m)，9.07-9.11 (1H，m) 〇 實施例90 沁（4“6-氨基-7-(2-蒸.乙虽.某）-4-崦啉基）1芡某）-1^-(4^ 氣笨某- 將N-(4-(6-氰基-7-羥基-4-喹啉基）氧苯基）-N’-(4-氟苯 基）月尿（400 mg，0.9166 mmol)溶於二曱基甲酿胺（5·0 ml) 中，加入1-溴-2-氯乙烷（0.12 ml，1.4479 mmol)及碳酸鉀 (200 mg，1.4479 mmol)，以及於55 °C加熱攪拌4小時。放 冷後，加入四氫呋喃及乙酸乙酯，用飽和食鹽水洗淨，用 無水硫酸鎂乾燥及減壓餾去溶媒後，將殘餘物付諸於NH矽 凝膠管柱層析（乙酸乙酯·曱酵系）。將得到之結晶懸浮於 乙醚中，用己烷稀釋，濾取結晶，用己:烷洗淨及吸引乾澡 後得到為淡黃色結晶之標題化合物（33丨mg，〇·6941 -204- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）Line 1304061 — A7 B7_____ V. Description of the invention (195) 0.0358 mmol, 14%) ° iH-NMR spectrum (CDC13) 5 (ppm): 2.08-2.16 (2H, m), 2·46·2·52 (4Η, m), 2.62 (2Η, t, J=7.0 Hz), 3.70-3.76 (4H, m), 4.30 (2H, t, 1=6.2 Hz), 6.47 (1H, d, J=5.3 Hz), 6.92 ( 1H, d, J=3.7 Hz), 7.17 (2H, d, J=8.8 Hz), 7.42 (1H, d, J=3.7 Hz), 7.48 (1H, s), 7.67 (2H, d, J=8.8 Hz), 8.66 (1H, d, J=5.3 Hz), 8.69 (1H, ten example 86 ammonia -7-helium certain - 4-4 phenyl hydroxyphenyl methoxyphenyl) urea in 4- Addition of toluene (60 ml) and acetonitrile (30 ml) to the amine (4-aminophenoxy)-7-(benzyloxy)-6-cyanoquinoline (1.0 g) (4-Methoxybenzene) isocyanate (0.53 ml) was added under reflux. After stirring for 1 hour under reflux, (4-methoxyphenyl)isocyanate (0.30 ml) was further added, and the mixture was further stirred under reflux for 40 minutes, and then returned to room temperature. The precipitated crystals were collected by filtration and purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted (0.20 g). iH-NMR spectrum (CDCl3) 5 (ppm): 3·73 (3H, s), 5·98 (2H, s), 6.56 (1Η, d, J=5.2 Ηζ), 6·89 (2Η, d, J=9.3 Ηζ), 7.24 (2Η, d, J=9.3 Hz), 7.33-7.65 (9H, m), 7.72 (1H, s), 8.74 (1H, d, J=5.2 Hz), 8.82 (1H, s), 8.89 (1H, br s), 9.19 (1H, br s). Example 86-2 _ - 201 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 _B7 V. Invention description (196) Base) Urea in N-4-(^ In the base -N'-(4-methoxyphenyl) intestine (4.25 g, 16.46 mmol), 1-methylpyrrolidone (3,4 ml) and diisopropylethylamine (3.6 ml, 20.78) were added. Ment), after heating and stirring at 130 ° C, and completely dissolved, 4-chloro-6-cyano-7-benzyloxyquinoline (5.10 g, 17.32 mmol) was added and stirred at 130 ° C for 1.5 hours. And stirred at 150 ° C for 1 hour. Diisopropylethylamine (1.2 ml, 6.93 mmol) was added and stirred for an additional hour. After cooling, tetrahydrofuran and ethyl acetate were added, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and evaporated. The obtained crystals were washed successively with diethyl ether·hexane, acetonitrile, diethyl ether·hexane, methanol and dimercaptopurine. The obtained crystals were dissolved in tetrahydrofuran, filtered through a hydrazine gel (200 cc of hydrazine gel), dissolved in 3 liters of tetrahydrofuran, and then the solvent was evaporated under reduced pressure. The crystals obtained were washed with diethyl ether, acetonitrile, diethyl ether:methanol = 5: EtOAc (EtOAc: EtOAc) Example 87 6-(Heart ((4·methyl-t-anilinyl))-) A certain hydrogen hydrazine”······················· -4-Quinolinyl)oxyphenyl)-indole, (4-methoxyphenyl)urea (12.2 g) was added with trifluoroacetic acid (122...) and thiazole (11.7 ml), and stirred at 50 °C. At night, it was stirred for 24 hours at 4 Torr. After confirming the disappearance of the starting materials, the reaction liquid system was concentrated under reduced pressure, and tetrahydrofuran and saturated sodium hydrogencarbonate water were added; the solution was filtered, and the precipitated yellow crystals were dried under reduced pressure to obtain the title. Compound (6·8 g). Further add diethyl ether to the filtrate and filter out the precipitated yellow ________ - 202 - This is a standard for the Chinese National Standard (CNS) A4 specification (210 X 297 public) 1304061 ~ A7 _B7 V. Inventive Note (197) ^ Color crystals, dried under reduced pressure to give the title compound (2. 〇g). iH-NMR light; if (CDCI3) 5 (ppm): 3·72 (3H, s), 6.56 (1H,d, J=6.1 Hz),6·88 (2H,d,J=8.7 Hz), 7·23 (2H,d,J=8.7 Hz), 7·37 (2H,d,J=8.7 Hz),7·44 (1H,s), 7.60 (2H,d,J=8.7 Hz), 8.57 (1H,s), 8.67 (1H,d,J=6.1 H z), 8.70 (1H, s), 8·82 (1H, s). Example 88 -4-(4-((4-)-)------- Acidic acid 4-(4-Aminophenoxy)-7-(decyloxy)·6-cyanoquinone (7.776 g, 21.2 mmol) dissolved in toluene (400 ml) and acetonitrile (2 〇〇) Add the isocyanate (4-fluorobenzene) vinegar (3.68 ml, 3 1 ·7 mmol) in a mixed solvent of mi) and heat to reflux at 120 ° C for 1 hour. After suspending in tetrahydrofuran (150 ml), hexane (150 ml) was added and ultrasonic treatment was carried out, and the precipitated crystals were collected by filtration, and dried by subtraction r to give a pale brown crystal (4-(7-(yu) · ~ base) - 6 - see -4-p- cylinyl) oxyphenyl) _ ν'- (4-fluorophenyl) urea (9.81 g, 19.4 mmol, 91.9%). Under nitrogen It was dissolved in trifluoroacetic acid (100 ml) and thioanisole (9.13 nd, 77.7 mmol), and stirred at 6 (TC for 12 hours). The reaction mixture was concentrated under reduced pressure and the residue was added to tetrahydrofuran ( 50 ml) medium and then 'add 1N aqueous sodium hydroxide solution (15 〇ml), add water (1 50 ml) and give it away, and filter out the precipitated crystals. The extract was washed with water, ethyl acetate and ethyl acetate. Negative ESI-MS 413 (M-Na), : Example 89 • 203- This paper scale applies to Chinese National Standard (CMS) A4 size (210 X 297 mm) 1304061 A7 _ B7 _ V. Invention description (198) 6 -Cyanide-4-(4-(2 3-diphenylaniline) oxime)amino-3-fluorophenoxy U7-sodium porphyrin. The 7-oxime oxime obtained in Example 81 ( 1.1 g), a mixture of trifluoroacetic acid (10 ml) and thioanisole (1 ml) was heated and stirred at 63 to 67 ° C for 16 hours in an oil bath. After the completion of the reaction, the reaction mixture was concentrated, a saturated aqueous sodium hydrogen carbonate solution was added, and the precipitated solid was collected by filtration. The obtained solid was washed with water, ethyl ether and ethyl acetate. lH-NMR (DMSO-d6) 5 (ppm): 6.54 (1H, d, J = 5.6 Hz), 7.04-7.10 (1H, m), 7.14-7.17 (1H, m), 7.31-7.36 (1H, m ), 7.40 (1H, dd, J=2.8 Hz, J=12 Hz), 7.44 (1H, s), 8.10-8.16 (1H, m), 8.27 (1H, t, J=8.8 Hz), 8.67 (1H , s), 8.68 (1H, d3 J=5.2 Hz), 8·99-9·03 (1H, m), 9.07-9.11 (1H, m) 〇Example 90 沁(4"6-Amino-7- (2-Steamed. B. Something) -4-Porphyrinyl)1芡)-1^-(4^ 气笨某- N-(4-(6-Cyano-7-hydroxy-4-) Quinolinyl)oxyphenyl)-N'-(4-fluorophenyl)urea (400 mg, 0.9166 mmol) dissolved in dimercaptoamine (5·0 ml), 1-bromo-2 -chloroethane (0.12 ml, 1.4479 mmol) and potassium carbonate (200 mg, 1.4479 mmol), and heating and stirring at 55 ° C for 4 hours. After cooling, add tetrahydrofuran and ethyl acetate, and wash with saturated brine. After drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, the residue was applied to EtOAc EtOAc EtOAc. , crystallizing by filtration, washing with hexane: alkane and attracting a dry bath to obtain the title of pale yellow crystal (33 Shu mg, square-6941-204- this paper scale applicable Chinese National Standard (CNS) A4 size (210 X 297 mm)

訂Order

線 1304061 - 一 A7 __ ___ B7 一 _ 五、發明説明（199 ) mmol，75.72%) 〇 iH-NMR光譜（DMSO-d6)5(ppm): 4.07 (2H, t，J=5.2 Hz)，4.59 (2H, t, J=5.2 Hz), 6.54 (1H, d, J=5.6 Hz), 7.12 (2H, t, J=9.0 Hz), 7.24 (2H, d, J=9.0 Hz), 7.44-7.48 (2H, m), 7.59 (2H, d, J=9.0 Hz), 7.65 (1H, s), 8.72 (1H, s), 8.73 (1H, d, J=5.6 Hz), 8.78 (1H，s), 8·82 (1H，s)。 f施例9 1 N-(4-L6-氰基氣乙氫某）-4-邊啉基）氣茇某 甲氣笨基）脲 以與實施例90同樣之方法，使用N-( 4-(6-氰基-7-¾基-4-4啉基）氧苯基）-N，-(4-甲氧苯基）脲（500 mg，1.1725 mmol)，得到為黃色結晶之標題化合物（501 mg，1.0247 mmol，87.39%) 〇 1H-NMR 光譜（DMS〇-d6)(5(ppm): 3.70 (3H，s)，4·06 (2H，t， 1=5.0 Hz)5 ί.59 (2H, t, J=5.0 Hz), 6.53 (1H, d, J=5.6 Hz), 6.86 (2H, d, J=9.2 Hz), 7.22 (2H, d, J=9.2^Hz), 7.35 (2H, d, J=9.2 Hz), 7.58 (2H, d, J=9.2 Hz), 7.65 (1H, s), 8.55 (1H, m)5 8.73 (1H, d, J=5.6 Hz), 8·78 (1H，m)，8·88 (1H, s)。 實施例92 氰基-7-(2-氣乙氧签V4杏啉基）氣笨基W-♦ (2,4-二氣笨基）胧 以與實施例90同樣之方法，使用N-(4-(6-氰基-7-羥基-4-口奎淋基）氧苯基）-N’-(2,4-二氟苯基）腺（300 mg，0.6661 mmol)，得到為淡黃色結晶之標題化合物（227 mg，0.4426 -205- _ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（200 ) mmol，66.45%)。 1 H-NMR光譜（DMSO-d6) (5 (ppm): 4·07 (2H，t，J=5.0 Ηζ)，4·59 (2H, t, J=5.0 Hz), 6.64 (1H, d, J=5.4 Hz), 7.06 (1H, m), 7.16 (1H, m), 7.32 (1H, ddd, J=2.8 Hz, 8.8 Hz, 11.6 Hz), 7.41 (1H, dd, J=2.8 Hz, 11.6 Hz), 7.67 (1H, s), 7.93 (1H, s), 8.12 (1H, m), 8.27 (1H5 dt, J=4.0 Hz, 9.2 Hz), 8.76 (1H, d, J=5.4 Hz), δ·77 (1H, s)3 8.97-9.09 (1H, m) .〇 實施例93 氰基- 7-(4-氯丁氣某）-4- 4啉某）氣茉某IN，-Μ- ΐ氧笨某 1服 將Ν-(4-(6-氰基-7-羥基-4-喹啉基）氧苯基）-Ν，-(4-甲氧 基苯基）脲（200 mg)，碳酸鉀（65 mg)及1-溴-4-氯丁烷（81微 升）懸浮於二甲基甲醯胺（3 ml)中並加熱攪拌1小時5〇分 鐘。將反應液注入飽和.食鹽水中及用乙酸乙酯萃取。將有 機層用硫酸-鎂乾燥後，通過NH矽凝膠管柱（富士希利希亞 化學公司）用乙酸乙酯溶離出及將濾液濃嬙。將得到之固體 用乙醚洗淨後，乾燥，得到標題化合物UQ mg ^ lH-NMR (DMSO-d6)(5(ppm): 1.96-2.00 (4H, m), 3.72 (3H, s), 3.77-3.80 (2H5 m), 4.33^4.37 (2H, m), 6.53 (1H, d, J^5.2 Hz)! 6.88 (2H, d, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 7.38 (2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.65 (1H, br s)，8.73 (1H，d，J=5.2 Hz)，8.77 (1H，s), 8 9〇 〇H，心 s)。 實施例94 v 基乳基氣苯基4·Line 1304061 - an A7 __ ___ B7 a _ V. Description of the invention (199 ) mmol, 75.72%) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 4.07 (2H, t, J = 5.2 Hz), 4.59 (2H, t, J=5.2 Hz), 6.54 (1H, d, J=5.6 Hz), 7.12 (2H, t, J=9.0 Hz), 7.24 (2H, d, J=9.0 Hz), 7.44-7.48 (2H, m), 7.59 (2H, d, J=9.0 Hz), 7.65 (1H, s), 8.72 (1H, s), 8.73 (1H, d, J=5.6 Hz), 8.78 (1H, s) , 8·82 (1H, s). f Example 9 1 N-(4-L6-Cyano-hydrogenyl)-4-mercapto-l-yl)methane (a gas-methanol) Urea In the same manner as in Example 90, N-(4- (6-Cyano-7-3-4-yl-4-yl) oxyphenyl)-N,-(4-methoxyphenyl)urea (500 mg, 1.1725 mmol) 501 mg, 1.0247 mmol, 87.39%) 〇1H-NMR spectrum (DMS〇-d6) (5 (ppm): 3.70 (3H, s), 4·06 (2H, t, 1 = 5.0 Hz) 5 ί.59 (2H, t, J=5.0 Hz), 6.53 (1H, d, J=5.6 Hz), 6.86 (2H, d, J=9.2 Hz), 7.22 (2H, d, J=9.2^Hz), 7.35 ( 2H, d, J=9.2 Hz), 7.58 (2H, d, J=9.2 Hz), 7.65 (1H, s), 8.55 (1H, m)5 8.73 (1H, d, J=5.6 Hz), 8· 78 (1H,m),8·88 (1H, s). Example 92 Cyano-7-(2-oxyethoxyxene V4 apricotyl) gas stupid W-♦ (2,4-two gas stupid N-(4-(6-Cyano-7-hydroxy-4-hydroxyl-yl)oxyphenyl)-N'-(2,4-difluoro) was used in the same manner as in Example 90. Phenyl) gland (300 mg, 0.6661 mmol) to give the title compound as pale yellow crystals (227 mg, 0.4426 - 205 - _ The paper size applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 13040 61 A7 B7 V. Description of the invention (200 ) mmol, 66.45%) 1 H-NMR spectrum (DMSO-d6) (5 (ppm): 4·07 (2H, t, J=5.0 Ηζ), 4·59 ( 2H, t, J=5.0 Hz), 6.64 (1H, d, J=5.4 Hz), 7.06 (1H, m), 7.16 (1H, m), 7.32 (1H, ddd, J=2.8 Hz, 8.8 Hz, 11.6 Hz), 7.41 (1H, dd, J=2.8 Hz, 11.6 Hz), 7.67 (1H, s), 7.93 (1H, s), 8.12 (1H, m), 8.27 (1H5 dt, J=4.0 Hz, 9.2 Hz), 8.76 (1H, d, J=5.4 Hz), δ·77 (1H, s)3 8.97-9.09 (1H, m) .〇Example 93 Cyano-7-(4-chlorobutene) )-4- 4 啉 某 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ,-(4-methoxyphenyl)urea (200 mg), potassium carbonate (65 mg) and 1-bromo-4-chlorobutane (81 μL) suspended in dimethylformamide (3 ml) Stir and heat for 1 hour and 5 minutes. The reaction solution was poured into saturated brine and extracted with ethyl acetate. After drying the organic layer with sulfuric acid-magnesium, it was taken out through an NH(R) gel column (Fuji Hilithia Chemical Co., Ltd.) with ethyl acetate and the filtrate was concentrated. The obtained solid was washed with diethyl ether and dried to give the title compound <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 3.80 (2H5 m), 4.33^4.37 (2H, m), 6.53 (1H, d, J^5.2 Hz)! 6.88 (2H, d, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz) , 7.38 (2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.65 (1H, br s), 8.73 (1H,d,J=5.2 Hz ), 8.77 (1H, s), 8 9〇〇H, heart s). Example 94 v-based milk-based gas phenyl 4·

裝 訂Binding

線 -206- 1304061 、- A7 --— _ B7 五、發明説明（2〇1 ) Μ笨某）脲 以與實施.例93同樣之方法，從Ν-(4-(6-氰基-7-羥基-4-喹 琳基）氧苯基）-Ν，-(4-甲氧苯基）脲（500 mg)及1-氣-3-碘丙 境（188微升），得到標題化合物31〇mg。 lH-NMR (DMSO-d6)&lt;5(ppm): 2.28-2.35 (2H, m)5 3.72 (3H, s), 3.86-3.90 (2H, m), 4.41-4.45 (2H, m), 6.54 (1H, d5 J=5.2 Hz), 6.88 (2H, d, J=8.8 Hz), 7.24 (2H, d, J=8.8 Hz), 7.38 (2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 7.65 (1H, s), 8.66 (1H, br s)，8·74 (1H，d，J=5.2 Hz), 8·79 (1H，s)，8·91 (1H, br s)。 實施例95 K4-(7-(苄氧幕」-6-氰基，4-喳啉基）氣笨基甲碏 廑基）笨某）脹 將4-(4-胺基苯氧基）-7-(苄氧基）-6-氰基喹啉（919 mg , 2·5 mmol)溶於二曱基亞颯（1〇 ml)後，加入N-(3-(甲磺醯基） 苯基）胺基冗、酸苯酯（801 mg，2.75 mmol)，並於8 5°C加熱攪 摔2小時。將反應液用乙酸乙酯稀釋後，甩1N氫氧化鈉水溶 液（10 ml) ’水（20 ml X 2)及飽和食鹽水（1〇 ml)洗淨，及用 無水硫酸鈉乾燥。濾除乾燥劑後，將濾液減壓濃縮，將殘 餘物懸浮於乙酸乙酯（30 ml)後，加入己烷（30 ml)並用超音 波處理，濾取析出之結晶，減壓乾燥，得到為淡褐色結晶 之標題化合物（1.43 g，2.5 mmol，定量的）。 • W-NMR光譜（DMS〇-d6) (5 (ppm): 3·18 (3H，s)，5.44 (2H，s)， 6.53 (1H, d, J=5.2 Hz), 7.24 (2H, d, J=8.8 Hz), 7.37 (1H, d, J=8.0 Hz), 7.44 (2H, t, J=7.2 Hz), 7.45-7.69 (8H, m), 8.61 -207- 本紙張尺度適用中國國家標準(CNS) A4規格（210 x 297公釐） 1304061 -- —… A7 B7 五、發明説明（202 ) (1H, s), 8.71 (1H, d, J=5.2 Hz), 8.78 (1H, s), 9.12 (1H, s), 9.31 (1H, s) 〇 實施例96 N-(4-(7-(芊氣基6-氨基-4-喹啉基）氫茉某IN'笨某月尿 使用4-(4-胺基苯氧基）-7-(苄氧基）-6-氰基喳啉（919 mg，2.5 mmol)及異氰酸苯醋（0·298 ml，2.75 mmol),藉由 與實施例10同樣之方法，得到為淡褐色結晶之標題化合物 (1.126 g，2.3 mmol，92·5%)。 iH-NMR光譜(DMSO-d6)(5(ppm): 5·45 (2Η，s)，6·53 (1Η，dd， J=1.6，5.2 Hz)，6·96 (1H，dd，J=6.0，7.2 Hz), 7·23 (2H，d， J=7.6 Hz), 7.27 (2H, dd, J=7.2, 7.6 Hz), 7.37 (1H, d, J=7.2 Hz), 7.42-7.47 (4H, m), 7.54 (2H, d, J=8.0 Hz), 7.60 (2H, dd, J=1.2, 8.8 Hz), 7.70 (1H, s), 8.71 (1H, dd, J=1.6, 5.2 Hz), 8·78 (1H，d，J=1.2 Hz)，8.88 (1H，br s), 9.02 (1H，br s)。 實施例97 人 N-(4-( (6-氰基-7-羥某-4-4啉基）氣）笨表N，-( 3-甲譆醯 基）笨基）脲 將N-(4-(7-(苄氧基）-6-氰基-4啉基）氧苯基）-N，-(3-甲續酿基）苯基）脉（1.43 g，2.5 mmol)在氮蒙氣下溶於三氟 乙酸（10 ml)及硫代苯甲醚（1.1 7 ml，10 mmol)中後，於65 ,°C攪拌19小時。將反應液減壓濃縮，將得到之殘餘物加至 5%碳酸氫鈉水溶液（30 ml)及乙醚（50 ml)中並攪拌，濾取 析出之結晶，用水及乙酸乙酯洗淨，然'後減壓乾燥。分取 濾液之有機層，用飽和食鹽水洗淨及用無水硫酸鈉乾燥 -208- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 、 -..., A7 _____B7 五、發明説明（203 ) 後，減壓濃縮，得到為黃色結晶狀之殘餘物。將其與先前 之結晶合併懸浮於乙酸乙酯（4〇 ml)中並進行超音波處理， 濾取結晶及用乙醚洗靜後，於60°C乾燥，得到為黃色結晶 之標題化合物（862 mg，1.8 mmol，72.7%)。 iH-NMR光譜（DMS〇-d6)5(ppm): 3·18 (3H，s)，ό·43 (1H，d J=5.2 Hz), 7.22-7.25 (3H, m), 7.43 (1H, s), 7.48-7.68 (5H, m)，8·16 (1H，s)，8·63 (1H，d，J=5.2 Hz)，8·67 (1H，s)，9.36 (1H, s), 9.55 (1H, s) 〇 實施例9 8 4-(4-((笨胺基羰基）胺基）笨氣某6-律某-7- +说醉' 藉由與貫施例87同樣之方法’從N-(4-(7-(爷氧基氨 基-4“奎啉基）氧苯基）-Ν·-苯基脲（1·126 g，2.31 mmol)得到 為黃色結晶之標題化合物（8 11 mg，1 ·94 mmol，83 ·8%)。 iH-NMR 光譜（DMSO-d6) 5 (ppm): 6·26 (1H，d，J=5.2 Hz) 6.96 (1H, m), 7.18-7.29 (5H, m), 7.45 (2H, d, J=8.4 Hz), 7·57 (2H，d，J=8.0 Hz)，8.50-8.51 (2H，m)，、8.74 (1H，s)，8.86 (1H，s)。 實施例99 N-(4“6-氰基- 7-(2-甲氣基乙氲某-2-氟茉 基）-Ν’-茉某服 藉由與實施例10同樣之方法，從4-(4-胺基-3-氟苯氧基）_ 6-氰基· 7- (2-甲氧基乙氧基）4淋及異氣酸苯醋’得到標題 化合物。 . 1 H-NMR (DMSO-d6) &lt;5 (ppm): 3.38 (3H, s), 3.78-3.81 (2H, m), -209- __ 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） !3〇4〇61Line -206- 1304061, - A7 --- _ B7 V. Description of the invention (2〇1) Μ 某) urea in the same manner as in Example 93, from Ν-(4-(6-cyano-7) -hydroxy-4-quinolinyloxyphenyl)-indole,-(4-methoxyphenyl)urea (500 mg) and 1-y--3-iodopropyl (188 μL) afforded the title compound 31 〇mg. lH-NMR (DMSO-d6) &lt; 5 (ppm): 2.28-2.35 (2H, m) 5 3.72 (3H, s), 3.86-3.90 (2H, m), 4.41-4.45 (2H, m), 6.54 (1H, d5 J=5.2 Hz), 6.88 (2H, d, J=8.8 Hz), 7.24 (2H, d, J=8.8 Hz), 7.38 (2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 7.65 (1H, s), 8.66 (1H, br s), 8.74 (1H, d, J=5.2 Hz), 8·79 (1H, s), 8.91 ( 1H, br s). Example 95 K4-(7-(benzyloxymethane-6-cyano, 4-carboline) azulylcarbenyl) swells 4-(4-aminophenoxy)- After 7-(benzyloxy)-6-cyanoquinoline (919 mg, 2.5 mmol) was dissolved in dimercaptopurine (1 mL), N-(3-(methylsulfonyl)benzene was added. Amino-based, phenyl ester (801 mg, 2.75 mmol), and stirred at 85 ° C for 2 hours. After the reaction mixture was diluted with ethyl acetate, EtOAc (1 mL) (EtOAc) After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was evaporated to ethyl acetate (30 ml), hexane (30 ml), and the mixture was subjected to ultrasonic treatment, and the crystals were separated by filtration and dried under reduced pressure. The title compound (1.43 g, 2.5 mmol, quantitative) • W-NMR spectrum (DMS〇-d6) (5 (ppm): 3·18 (3H, s), 5.44 (2H, s), 6.53 (1H, d, J = 5.2 Hz), 7.24 (2H, d , J=8.8 Hz), 7.37 (1H, d, J=8.0 Hz), 7.44 (2H, t, J=7.2 Hz), 7.45-7.69 (8H, m), 8.61 -207- This paper size applies to China Standard (CNS) A4 size (210 x 297 mm) 1304061 ---... A7 B7 V. Description of invention (202 ) (1H, s), 8.71 (1H, d, J=5.2 Hz), 8.78 (1H, s ), 9.12 (1H, s), 9.31 (1H, s) 〇 Example 96 N-(4-(7-(indolyl 6-amino-4-quinolinyl)hydrogen imo IN' stupid month urine 4-(4-Aminophenoxy)-7-(benzyloxy)-6-cyanoporphyrin (919 mg, 2.5 mmol) and phenyl isocyanate (0·298 ml, 2.75 mmol), The title compound (1.126 g, 2.3 mmol, 92.5%) was obtained as pale brown crystals. 2Η, s), 6·53 (1Η, dd, J=1.6, 5.2 Hz), 6.96 (1H, dd, J=6.0, 7.2 Hz), 7·23 (2H, d, J=7.6 Hz) , 7.27 (2H, dd, J=7.2, 7.6 Hz), 7.37 (1H, d, J=7.2 Hz), 7.42-7.47 (4H, m), 7.54 (2H, d, J=8.0 Hz), 7.60 ( 2H, dd, J=1.2, 8.8 Hz), 7.70 (1H, s), 8.71 (1H, dd, J=1.6, 5.2 Hz), 8·78 (1H, d, J=1.2 Hz), 8.88 (1H, br s), 9.02 (1H, br s). Example 97 Human N-(4-((6-Cyano-7-hydroxy-4--4-yl)))) N,-(3-methylindolyl)phenyl) N-( 4-(7-(Benzyloxy)-6-cyano-4 phenyl)oxyphenyl)-N,-(3-methylhydro)phenyl) (1.43 g, 2.5 mmol) in Nitrogen After being dissolved in trifluoroacetic acid (10 ml) and thioanisole (1.17 ml, 10 mmol), the mixture was stirred at 65 ° C for 19 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc m. After drying under reduced pressure. The organic layer of the filtrate was separated, washed with saturated brine and dried over anhydrous sodium sulfate - 208 - The paper scale was applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061, -..., A7 _____B7 5. Description of the invention (203), followed by concentration under reduced pressure to give a yellow crystal residue. The title compound (862 mg) was obtained as a yellow crystals. , 1.8 mmol, 72.7%). iH-NMR spectrum (DMS〇-d6) 5 (ppm): 3·18 (3H, s), ό·43 (1H, d J=5.2 Hz), 7.22-7.25 (3H, m), 7.43 (1H, s), 7.48-7.68 (5H, m), 8.16 (1H, s), 8.63 (1H, d, J = 5.2 Hz), 8.67 (1H, s), 9.36 (1H, s) , 9.55 (1H, s) 〇 Example 9 8 4-(4-((thinaminocarbonyl)amino) stupid 6-law -7- + said drunk' by the same as Example 87 Method 'N-(4-(7-(yloxyamino-4" quinolinyl)oxyphenyl)-indole-phenylurea) (1·126 g, 2.31 mmol) (8 11 mg, 1 · 94 mmol, 83 · 8%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 6·26 (1H, d, J = 5.2 Hz) 6.96 (1H, m), 7.18-7.29 (5H, m), 7.45 (2H, d, J=8.4 Hz), 7·57 (2H, d, J=8.0 Hz), 8.50-8.51 (2H, m), 8.74 (1H, s ), 8.86 (1H, s). Example 99 N-(4"6-Cyano- 7-(2-methyl-ethylidene-2-fluoromethyl)-Ν'- Example 10, in the same manner, from 4-(4-amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)4 and isophthalic acid benzene vinegar The title compound was obtained. 1 H-NMR (DMSO-d6) &lt;5 (ppm): 3.38 (3 H, s), 3.78-3.81 (2H, m), -209- __ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) !3〇4〇61

五、發明説明（204 ) 4.42- 4.45 (2H, m), 6.64 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=7.2 Hz), 7.15-7.19 (1H, m), 7.31 (2H, t, J=7.2 Hz), 7.42 (1H, dd, J-2.8 Hz, J=12 Hz), 7.48 (2H, d, J=7.2 Hz), 7.66 (1H, s), 8.28 (1H, t, J=8.8 Hz), 8.72 (1H, br s), 8.76 (1H3 d, J=5.2V. INSTRUCTIONS (204) 4.42- 4.45 (2H, m), 6.64 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=7.2 Hz), 7.15-7.19 (1H, m), 7.31 (2H, t, J=7.2 Hz), 7.42 (1H, dd, J-2.8 Hz, J=12 Hz), 7.48 (2H, d, J=7.2 Hz), 7.66 (1H, s), 8.28 (1H , t, J=8.8 Hz), 8.72 (1H, br s), 8.76 (1H3 d, J=5.2

Hz)，8.78 (1H，s)，9.15 (1H，br s)。 i施例100 氰基- 7-(2-甲氧基乙差^基4嗾某）氳-2-氣笨 基氣笨某 藉由與實施例10同樣之方法，從心胺基-3-氟苯氧基 6-氰基-7-(2-甲氧基乙氧基）喹啉及異氰酸心氟苯酯，得到 標題化合物。 lH-NMR (DMSO-d6) δ (ppm): 3.3 8 (3H, s)3 3.78-3.8 1 (2H5 m), 4.42- 4.45 (2H5 m), 6.64 (1H, d, J=5.2 Hz), 7.12-7.18 (3H, m), 7.42 (1H，dd，J=2.8 Hz，J=12 Hz), 7·46-7·51 (2H，m)，7.65 (1H, s), 8.25 (1H, t, J=9.2 Hz), 8.71 (1H, br s), 8.76 (1H, d, J=5.2 Hz)，8·77 (1H，s)，9.18 (1H，br s)。·、 實施例101 ^1士苯并『(11咪唑-6-基&gt;)-：^，-(4彳6-氰某-7-(2-甲氣基乙 氧基）· 4· 4 g林某）氧苯基）踩（實施例1 〇 A) K1H-苯并f dl咪唑-5-基）-Ν，-(4-Γ6-氰某- 7-(2-甲氣基乙 养基V 4- 4 g林某、氣笨基、脉（實施例1 〇 1 - 藉由與實施例11同樣之方法，從N-(4-(6-氰基-7-(2-甲氧 基乙氧基）-4-口奎琳）氧苯基）胺基曱酸苯g旨（1〇〇 mg，0.220 mmol) ’得到為白色結晶之標題化合物混合物（77.5 mg， -210- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜 A7 _______ B7 五、發明説明（2〇5 ) 0.157 mmol，71.4%)。 上述化合物.（貫施例101 - A)與（實施例101 · B)之混合物 h-NMR光譜（DMS〇-d6)5(ppm): 3.36 (3H，s)，3·76-3·79 (2H， m)，4.40-4.43 (2Η，m)，6·53 (1Η，d，J=5.6 Ηζ)，6.99-7.62 (6Η， m), 7.82 (2/5H, s), 7.91 (3/5H, s), 8.08 (3/5H, s), 8.13 (2/5H, s)，8.59-8.79 (5H，m)，12.26 (3/5H，s)，12.29 (2/5H，s)。 實施例102 甲氫某乙啉基）氫笨某）-N，-(_之-酮基- 23 - 一乳-lH-笨并fdl味峻-5-基）月尿 藉由與實施例11同樣之方法，從N-(4-(6-氰基-7-(2-甲氧 基乙氧基）-4-喹啉基）氧苯基）胺基甲酸苯酯（1〇〇 mg，0.220 mmol)，得到為白色結晶之標題化合物（1〇4·2 mg，0.204 mmol，93.0%)。 iH-NMR光譜(DMSO-d6)5(ppm): 3.36 (3H，s)，3·76-3·79 (2H， m), 4.40-4.4-3 (2H, m), 6.52 (1H, d, J=5.2 Hz), 6.81 (2H, s), 7.22 (2H, d, J=8.0 Hz), 7.31 (1H, s), 7.58 (2H, d, J=8.0 Hz), 7.62 (1H, s), 8.53 (1H, s), 8.71-8.76 (3H, m), 10.41 (1H, s), 10.50 (1H，s) 〇 實施例103 K_4-(6_氰某基乙氣某）-4-4啉某、氣笨基）-Ν’-L1:·酮基-2,3-二新，L3-茉林咩岫-i其）月尿 藉由與實施例11同樣之方法，從Ν_(4-(6-氰基甲氧 基乙氧基）-4-4琳基）氧苯基）胺基甲酸苯酯（1〇〇 mg，0.220 mmol) ’得到為灰白色結晶之標題化合物（1(H ，0.197 _____-211- I紙張尺度適财g S家標準(CNS) A4規g1Q X 297公爱) 1304061 〜 A7 B7 五、發明説明（206 ) mmol，89.9%)。 iH-NMR光譜（DMSO-d6) (5 (ppm): 3·37 (3H，s)，3.76-3.39 (2H， m)，4·40-4·43 (2Η, m)，6·52 (1Η，d，J=5.2 Ηζ)，6.91 (1Η，dd， J=2.0, 8.8 Hz), 7.17 (1H, d, J=8.4 Hz), 7.24 (2H, d, J=8.8 Hz), 7.48 (1H, s), 7.59 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.71-8·77 (3H, m), 8·81 (1H，s), 11.53 (1H，s)。 實施例104 、 4“ 6-氰基-7-( 2-甲氫某乙氳基）-4-4啉某）氫茉基VN1-(2-酮基-2.3-二氫-1.3-笨并呤唑-6-某）脲 藉由與實施例11同樣之方法，從N-(4-(6-氰基-7-(2-曱氧 基乙氧基）-4-喹啉基）氧苯基）胺基甲酸苯酯（1〇〇 mg，0.220 mmol)，得到為灰白色結晶之標題化合物（111 mg，0.217 mmol，98.8%) 〇 j-NMR光譜（DMS〇-d6)5(ppm): 3.37 (3H，s)，3.76-3.79 (2H， m)y 4.40-4.Φ3 (2H, m), 6.52 (1H3 d, J=5.2 Hz), 6.99 (1H, d, J=8.4 Hz), 7.07 (1H, dd, J=2.0, 8.4 Hz), 7.24 (2H, d3 J=8.8 Hz), 7.56-7.63 (4H, m), 8.72 (1H, d, J=5.2 Hz), 8.74 (1H, s)3 8.76 (1H，s)，8.82 (1H，s)，11.46 (1H，s)。 實施例105 N二(,_4二（6-氰曱氫某乙氣某啉基）氣笨某w (2:¾—基氫-1H-5-W 哚某）服 藉由與實施例11同樣之方法，從4-(6-氰基-7-(2-甲氧 基乙氧基）-4-喹啉基）氧苯基）胺基甲酸苯酯（1〇〇 mg，0.220 mmol) ’得到為灰白色結晶之標題化合物（69 mg，〇135 __ _ -212- _ 本紙張尺度適用中國國豕標準(CNS) A4規格（210X297公爱） 1304061 … AT _ B7 五、發明説明（207 ) mmol，61.7%)。 iH-NMR光譜（DMS〇-d6)5(PPm): 3·36 (3H，s)，3·45 (2H，s)， 3.76-3.79 (2Η, s), 4.40-4.43 (2H, m), 6.51 (1H, d, J=5.2 Hz), 6.72 (1H, d, J=8.4 Hz), 7.17 (1H, dd, J=2.〇, 8.4 Hz), 7.22 (2H, d, J=8.8 Hz)5 7.37 (1H, s), 7.58 (2H, d, J=8.8 Hz), 7.62 (1H，s)，8·49 (1H，s)，8.71 (1H, d，J=5,2 Hz)，8.74 (1H，s), 8·75 (1H，s)，10.23 (1H，s)。 實施例106 4“ 6-氨基-7-(3-羥丙氣某）-4-4:琳基）氣茉基 氟笨某1 Μ 藉由與實施例7同樣之方法，從6-氰基-4-(4-((4-氟苯胺 基）羰基）胺基苯氧基）-7-喹啉酸鈉（109 mg，〇·250 mmol)， 得到為淡黃色結晶之標題化合物（64 mg，0.135 mmol， 54.2%)。 W-NMR光譜（DMSO-d6)5(ppm): 1.97 (2H，t，J=6.0 Hz)，3.63 (2H, m)，4·34 (2H，t，J=6.0 Hz)，4·63 (lH/、t，J=5.2 Hz)，6.51 (1H, d, J=5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 7.44-7.47 (2H, m), 7.57-7.60 (3H, m), 8.70-8.75 (3H, m)，8·82 (1H，s)。 實施例107N- (4- ( 6-氰基-7- ( 3-(甲硫基）丙氧基）-4-。奎啤氣）苯基）· n，· (4-氟苽某）脲 藉由與實施例7同樣之方法，從6-氰基-4-(4-((4-氟苯胺 基）羰基）胺基苯氧基）-7-0奎淋酸納（109 mg，0.250 mmol),Hz), 8.78 (1H, s), 9.15 (1H, br s). i Example 100 Cyano- 7-(2-methoxyethyl group 4 嗾) 氲-2- gas base gas by a method similar to that of Example 10, from cardioamine-3- Fluorphenoxy 6-cyano-7-(2-methoxyethoxy)quinoline and fluorophenyl phenyl isocyanate gave the title compound. lH-NMR (DMSO-d6) δ (ppm): 3.3 8 (3H, s)3 3.78-3.8 1 (2H5 m), 4.42- 4.45 (2H5 m), 6.64 (1H, d, J=5.2 Hz), 7.12-7.18 (3H, m), 7.42 (1H, dd, J=2.8 Hz, J=12 Hz), 7·46-7·51 (2H, m), 7.65 (1H, s), 8.25 (1H, t, J=9.2 Hz), 8.71 (1H, br s), 8.76 (1H, d, J=5.2 Hz), 8.77 (1H, s), 9.18 (1H, br s). ·, Example 101 ^1 Benzene "(11 imidazole-6-yl)-: ^, - (4彳6-cyanyl-7-(2-carbamoylethoxy)·4· 4 g林)Oxyphenyl)Step (Example 1 〇A) K1H-benzof dl imidazole-5-yl)-indole,-(4-Γ6-cyanyl- 7-(2-methyl-based) Base V 4- 4 g Lin, gas base, vein (Example 1 〇1 - by the same method as in Example 11, from N-(4-(6-cyano-7-(2-methoxy) (Ethyl ethoxy)-4-hydroxypyridinyloxyphenyl)amino decanoic acid Benzyl ketone (1 〇〇mg, 0.220 mmol) 'A mixture of the title compound obtained as white crystals (77.5 mg, -210- The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ~ A7 _______ B7 V. Description of the invention (2〇5) 0.157 mmol, 71.4%). The above compound. (Case 101-A) (Example 101 · B) mixture h-NMR spectrum (DMS 〇-d6) 5 (ppm): 3.36 (3H, s), 3·76-3·79 (2H, m), 4.40-4.43 (2Η, m),6·53 (1Η,d,J=5.6 Ηζ), 6.99-7.62 (6Η, m), 7.82 (2/5H, s), 7.91 (3/5H, s), 8.08 (3/5H, s), 8.13 (2/5H, s), 8.59-8.79 (5H, m), 12.26 (3/5H, s), 12.29 (2/ 5H, s). Example 102 methyl hydrogen ethionyl) hydrogen benzoate) -N,-(_-keto- 23 - a milk-lH-stupid and fdl miso-5-yl) From the same procedure as in Example 11, phenyl N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxyphenyl)carbamate ( The title compound (1〇4·2 mg, 0.204 mmol, 93.0%) was obtained as white crystals. iH-NMR spectrum (DMSO-d6) 5 (ppm): 3.36 (3H, s ),3·76-3·79 (2H, m), 4.40-4.4-3 (2H, m), 6.52 (1H, d, J=5.2 Hz), 6.81 (2H, s), 7.22 (2H, d , J=8.0 Hz), 7.31 (1H, s), 7.58 (2H, d, J=8.0 Hz), 7.62 (1H, s), 8.53 (1H, s), 8.71-8.76 (3H, m), 10.41 (1H, s), 10.50 (1H, s) 〇 Example 103 K_4-(6-Cyanyl Ethyl)-4-4 porphyrin, succinyl)-Ν'-L1:·keto-2 , 3-dixin, L3-Molybdenum-i) moon urine by the same method as in Example 11, from Ν_(4-(6-cyanomethoxyethoxy)-4-4 lin Phenyl phenyl) phenyl carbamate (1 〇〇 mg, 0.220 mmol) 'The title compound is obtained as an off-white crystal (1 (H, 0.197 _____-211-I paper scale suitable for g S Home Standard (CNS) A4 Regulation g1Q X 297 Public) 1304061 ~ A7 B7 V. Invention Description (206) mmol, 89.9%). iH-NMR spectrum (DMSO-d6) (5 (ppm): 3·37 (3H, s), 3.76-3.39 (2H, m), 4·40-4·43 (2Η, m), 6·52 ( 1Η,d,J=5.2 Ηζ), 6.91 (1Η, dd, J=2.0, 8.8 Hz), 7.17 (1H, d, J=8.4 Hz), 7.24 (2H, d, J=8.8 Hz), 7.48 ( 1H, s), 7.59 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.71-8·77 (3H, m), 8·81 (1H, s), 11.53 (1H, s) Example 104, 4 "6-Cyano-7-(2-methylhydroindolyl)-4-4 oxo) Hydrogen jasmine VN1-(2-keto-2.3-dihydro-1.3-stupid And carbazole-6-)urea was obtained from N-(4-(6-cyanoethoxy)-4-quinolyl) by the same procedure as in Example 11. Phenyl phenyl) phenyl carbamate (1 mg, 0.220 mmol) gave the title compound (111 mg, 0.217 mmol, 98.8%) mp NMR spectrum (DMS 〇-d6) 5 (ppm) ): 3.37 (3H, s), 3.76-3.79 (2H, m)y 4.40-4.Φ3 (2H, m), 6.52 (1H3 d, J=5.2 Hz), 6.99 (1H, d, J=8.4 Hz) ), 7.07 (1H, dd, J=2.0, 8.4 Hz), 7.24 (2H, d3 J=8.8 Hz), 7.56-7.63 (4H, m), 8.72 (1H, d, J=5.2 Hz), 8.74 ( 1H, s)3 8.76 (1H, s), 8.82 (1H, s), 11.46 (1H, s). Example 105 N II (, _4 bis (6-cyanohydrin hydrogen, a certain oxo group) gas stupid w (2:3⁄4 - ylhydro-1H-5-W 哚) by the same method as in Example 11, from 4 -(6-Cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxyphenyl)carbamic acid phenyl ester (1 mg, 0.220 mmol) 'm. Title compound (69 mg, 〇135 __ _ -212- _ This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1304061 ... AT _ B7 V. Invention description (207) mmol, 61.7%). iH-NMR spectrum (DMS〇-d6) 5 (PPm): 3·36 (3H, s), 3·45 (2H, s), 3.76-3.79 (2Η, s), 4.40-4.43 (2H, m) , 6.51 (1H, d, J=5.2 Hz), 6.72 (1H, d, J=8.4 Hz), 7.17 (1H, dd, J=2.〇, 8.4 Hz), 7.22 (2H, d, J=8.8 Hz)5 7.37 (1H, s), 7.58 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8·49 (1H, s), 8.71 (1H, d, J=5, 2 Hz ), 8.74 (1H, s), 8·75 (1H, s), 10.23 (1H, s). Example 106 4 "6-Amino-7-(3-hydroxypropenyl)-4-4: aryl) gas oleylfluorophenoyl 1 Μ From the same procedure as in Example 7, from 6-cyano -4-(4-((4-Fluoroanilinyl)carbonyl)aminophenoxy)-7-quinolinate (109 mg, EtOAc) , 0.135 mmol, 54.2%). W-NMR spectrum (DMSO-d6) 5 (ppm): 1.97 (2H, t, J = 6.0 Hz), 3.63 (2H, m), 4·34 (2H, t, J =6.0 Hz),4·63 (lH/, t, J=5.2 Hz), 6.51 (1H, d, J=5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.23 (2H, d, J = 8.8 Hz), 7.44-7.47 (2H, m), 7.57-7.60 (3H, m), 8.70-8.75 (3H, m), 8.82 (1H, s). Example 107N- (4- 6-Cyano-7-(3-(methylthio)propoxy)-4-. quetiarum)phenyl)·n,·(4-fluoroindole)urea is the same as in Example 7. Method, from 6-cyano-4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-0 quinolate (109 mg, 0.250 mmol),

裝 訂Binding

線 -213- 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 1304061 〜 —.. A 7 _ B7 五、發明説明（208 ) _ 得到為淡褐色結晶之標題化合物（37 mg，0.074 mmol， 29·5%)。 j-NMR 光譜（DMS〇-d6)5(Ppm): 2·08-2·12 (5Η，m)，2·69 (2Η，t，J=7.2 Ηζ)，4.36 (2Η，t，J=6.0 Ηζ)，6.52 (1Η，d，J=5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.23 (2H, d, J-8.8 Hz), 7.44-7·48 (2H，m)，7.57-7.60 (3H，m)，8·71-8·76 (3H，m), 8.82 (1H，s)。 實施例108 N-(4-(6-氰基- 7- (3-(甲石_8產基）N氧基♦喊氧）笨基 N，-(4-氯苽某）月尿 藉由與實施例7同樣之方法，從6-果基-4-( 4-((4-氟苯胺 基）羰基）胺基苯氧基）-7-喹啉酸鈉（1〇9 mg，0·250 mmol)， 得到為淡褐色結晶之標題化合物（70 mg，0· 131 mmol， 52.4%) 〇 iH-NMR光諼(DMS〇-d6)5(ppm): 2·27 (2Η，m)，3·04 (3Η，s)， 3.21-3.37 (2H，m)，4·41 (2H，t，J=6.4 Hz), *6.53 (1H，d，J=5.2 Hz)，7.11(2H，t，J=8.8Hz)，7.23(2H，d，J=8.8Hz)，7.44-7.48 (2H, m), 7.57-7.61 (3H, m), 8.71-8.73 (2H, m), 8.77 (1H，s), 8·82 (1H，s) 〇 實施例109 及-(4-(6-氰基-7-(3“2-酮基四氤-1!1-1-毗咯基」_丙氣某&gt;1-4-喳啉氣）笨基氮茉某）服 藉由與實施例7同樣之方法，從6-氰基-4-(4-((4-氟苯胺 基）藏基）胺基苯氧基）-7-峻琳酸鈉（109 mg，0.250 mmol)， -214- 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 _ B7 五、發明説明（2〇9 ) 得到為淡黃色結晶之標題化合物（11.2 mg，0.021 mmol， 8·3%” 1H-NMR光譜（DMSO-d6)5(ppm): 1·93 (2Η，m)，2·03 (2Η，t， J=6.0 Hz), 2.19 (2H, t, J=8.0 Hz), 3.37-3.42 (4H, m), 4.27 (2H, t, J=6.0 Hz)5 6.51 (1H, d, J=5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 7.44-7.48 (2H, m), 7.55 (1H, s), 7.58 (2H, d, J=8.8 Hz), 8.70-8.73 (2H, m), 8.75 (1H5 s), 8.82 (1H, s)。 實施例110 N-(4“6-氰基- 7-(3-( L3-二酮基- 2,3 -二氫-1H-2-異啕哚基） 丙氣基）-4- 4啉氫）茉某W “ 4-氣笨基）脲 藉由與實施例7同樣之方法，從6-氰基-4-(4-((4-氟苯胺 基）羰基）胺基苯氧基）-7-4啉酸鈉（436 mg，1.00 mmol)， 得到為淡黃色結晶之標題化合物（416 mg，0.692 mmol， 69.2%)。 ' iH-NMR光譜（DMS〇-d6)5(ppm): 2·17 (2H/、t，J=5.6 Hz), 3.84 (2H, t5 J=6.4 Hz), 4.32 (2H3 t, J=6.0 Hz), 6.51 (1H, d, J=5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.23 (2H, d, J=9.2 Hz), 7.44-7.48 (2H, m), 7.52 (1H, s), 7.58 (2H, d, J=8.8 Hz), 7.78-7.84 (4H，m)，8.69-8.73 (3H，m)，8·82 (1H，s) 〇 實施例111 N“3“6-氨基氣-4-((4-氟苯胺某）淼某）胺基笨氣 某7- 4啉某）氫丙某）甲磺醯胺 ，. 藉由與實施例7同樣之方法，從6-氰基-4·(3-氟-4-((4-氟 -215- 本紙乐尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) &quot; &quot; 1304061 A7 B7 五、發明説明（210) 苯胺基）談基）胺基苯氧基）-7-峻淋酸制（114 mg，0.25 mmol)，得到為淡褐色結晶之標題化合物（73 mg，0· 129 mmol，5 1.3%) 〇 j-NMR光譜（DMSO-d6) 5(ppm): 2.02 (2H，t，J=6.4 Hz)，2.91 (3H，s)，3.20 (2H，q，J=6.4 Hz)，4·34 (2H，t，J=6.4 Hz)，6.62 (1H, d, J=5.2 Hz), 7.12-7.38 (4H, m), 7.40 (1H, dd, J=2.8, 11.6 Hz), 7.44-7.48 (2H, m), 7.61 (1H, s), 8.24 (1H, t, J=9.2 Hz), 8.62 (1H, d5 J=2.0 Hz), 8.74 (1H, s), 8.75 (1H, s), 9.09 (1H,十 實施例112 4-(4-((4-氟笨胺基）羰某）胺基苯氫某）-7-(2-甲氫某乙最u 基）-6 - 4：g林# g萏脖 將實施例10所得之N-(4-(6-氰基-7-(2-甲氧基乙氧基）-心 口奎淋基）氧苯基）-Ν·-(4-氟苯基）踩（360 mg，0.762 mmol)溶 於二甲基亞1風（4.5 ml)中，加入5N氫氧化納水溶液（1.5 ml) 並於80 °C攪拌加熱60分鐘。將反應液在涑水浴中冷卻，加 入2N鹽酸（3.75 ml)及中和，再用水（21 ml)稀釋以及濾取析 出的粗結晶。將其懸浮於乙醇（20 ml)中及超音波處理，濾 取結晶後減壓乾燥，得到為灰白色結晶之標題化合物（214 mg，0.436 mmol，57.3%) 〇 j-NMR光譜(DMSO-d6)5(ppm): 3·34 (3H，s)，3.78-3.81 (2H， m), 4.38-4.41 (2H, m), 6.46 (1H, d, J=5.6 Hz), 7.11 (2H, d, J=8.8 Hz), 7.23 (2H, d, J=8.4 Hz), 7.46 (2H, m), 7.54 (1H, s), 7.58 (2H, d, J=8.8 Hz), 7.80 (1H, s), 7.82 (1H, s), 8.64 (1H, -216- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）Line-213- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ~ —.. A 7 _ B7 V. Description of invention (208 ) _ The title compound is obtained as light brown crystal (37 Mg, 0.074 mmol, 29·5%). j-NMR spectrum (DMS〇-d6) 5 (Ppm): 2·08-2·12 (5Η, m), 2·69 (2Η, t, J=7.2 Ηζ), 4.36 (2Η, t, J= 6.0 Ηζ), 6.52 (1Η, d, J=5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.23 (2H, d, J-8.8 Hz), 7.44-7·48 (2H, m) , 7.57-7.60 (3H, m), 8.71-8.76 (3H, m), 8.82 (1H, s). Example 108 N-(4-(6-Cyano-7-(3-(methyl)-8)oxy) 笨 )) N,-(4-chloro 苽) month urine In the same manner as in Example 7, from 6-fruityl-4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-quinoline sodium (1〇9 mg, 0· The title compound (70 mg, 0·131 mmol, 52.4%) was obtained as pale brown crystals. 〇iH-NMR (DMS 〇-d6) 5 (ppm): 2·27 (2 Η, m), 3·04 (3Η, s), 3.21-3.37 (2H, m), 4·41 (2H, t, J = 6.4 Hz), *6.53 (1H, d, J = 5.2 Hz), 7.11 (2H, t , J=8.8Hz), 7.23 (2H, d, J=8.8Hz), 7.44-7.48 (2H, m), 7.57-7.61 (3H, m), 8.71-8.73 (2H, m), 8.77 (1H, s), 8·82 (1H, s) 〇 Example 109 and -(4-(6-cyano-7-(3"2-ketotetradecyl-1!1-1-pyrrolyl)-propyl By a certain method, in the same manner as in Example 7, from a 6-cyano-4-(4-((4-fluoroanilino)) group, a gas was used in the same manner as in Example 7. Aminophenoxy)-7-junolin sodium (109 mg, 0.250 mmol), -214- This paper size applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) 1304061 A7 _ B7 , invention description (2 〇9) The title compound (11.2 mg, 0.021 mmol, 8.3%) was obtained as pale yellow crystals. 1H-NMR spectrum (DMSO-d6) 5 (ppm): 1.93 (2 Η, m), 2·03 ( 2Η, t, J=6.0 Hz), 2.19 (2H, t, J=8.0 Hz), 3.37-3.42 (4H, m), 4.27 (2H, t, J=6.0 Hz)5 6.51 (1H, d, J =5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 7.44-7.48 (2H, m), 7.55 (1H, s), 7.58 (2H, d , J = 8.8 Hz), 8.70-8.73 (2H, m), 8.75 (1H5 s), 8.82 (1H, s). Example 110 N-(4"6-Cyano- 7-(3-( L3- Diketo-2,3-dihydro-1H-2-isoindenyl)propenyl)-4- 4 porphyrin hydrogen) jasmine W "4-indolyl" urea by the same method as in Example 7. Method, from sodium 6-cyano-4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7- phthalate (436 mg, 1.00 mmol), The title compound (416 mg, 0.692 mmol, 69.2%). 'iH-NMR spectrum (DMS〇-d6) 5 (ppm): 2·17 (2H/, t, J=5.6 Hz), 3.84 (2H, t5 J=6.4 Hz), 4.32 (2H3 t, J=6.0 Hz), 6.51 (1H, d, J=5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.23 (2H, d, J=9.2 Hz), 7.44-7.48 (2H, m), 7.52 ( 1H, s), 7.58 (2H, d, J=8.8 Hz), 7.78-7.84 (4H, m), 8.69-8.73 (3H, m), 8.82 (1H, s) 〇 Example 111 N "3 "6-Amino-gas-4-((4-fluoroaniline))) an amine group of a certain 7- 4 phenanthyl) hydrogen propyl sulfonamide, by the same method as in Example 7, From 6-cyano-4(3-fluoro-4-((4-fluoro-215-) This paper is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) &quot;&quot; 1304061 A7 B7 The title compound (73 mg, 0·129 mmol, mp. mp. 5 1.3%) 〇j-NMR spectrum (DMSO-d6) 5 (ppm): 2.02 (2H, t, J = 6.4 Hz), 2.91 (3H, s), 3.20 (2H, q, J = 6.4 Hz), 4·34 (2H, t, J = 6.4 Hz), 6.62 (1H, d, J = 5.2 Hz), 7.12-7.38 (4H, m), 7.40 (1H, dd, J=2.8, 11.6 Hz), 7.44 -7.48 (2H, (m), 7.61 (1H, s) , Tenth Embodiment 112 4-(4-((4-Fluoroamino)carbonyl)aminophenylhydrogen)-7-(2-methylhydrogenylethyl)-6 - 4:g Lin# N-(4-(6-Cyano-7-(2-methoxyethoxy)-heart quinolyl)oxyphenyl)-indole-(4-fluoro) obtained in Example 10 Phenyl) (360 mg, 0.762 mmol) was dissolved in dimethyl nitrobenzene (4.5 ml), 5N aqueous sodium hydroxide (1.5 ml) was added and stirred and stirred at 80 ° C for 60 min. The reaction solution was cooled in a water-cooling bath, and then, 2N hydrochloric acid (3.75 ml) was added and neutralized, and then diluted with water (21 ml) and the precipitated crude crystals were collected by filtration. This was suspended in ethanol (20 ml) and subjected to ultrasonication. 5 (ppm): 3·34 (3H, s), 3.78-3.81 (2H, m), 4.38-4.41 (2H, m), 6.46 (1H, d, J=5.6 Hz), 7.11 (2H, d, J=8.8 Hz), 7.23 (2H, d, J=8.4 Hz), 7.46 (2H, m), 7.54 (1H, s), 7.58 (2H, d, J=8.8 Hz), 7.80 (1H, s) , 7.82 (1H, s), 8.64 (1H, -216- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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1304061 A7 B7 211 五、發明説明（ d，&gt;5.6 Ηζ)，8·75 (1H，s)，8·78 (1H，s)，8·83 (1H，s)。 f施例：m ·1304061 A7 B7 211 V. INSTRUCTIONS (d, &gt; 5.6 Ηζ), 8.75 (1H, s), 8.78 (1H, s), 8. 83 (1H, s). f Example: m ·

Idllz·甲氧某乙氧茱）l基胺某、羰基）胺某 I乳某）-6 -4淋#酿胺 藉由與實施例II2同樣之方法，從實施例12得到之N_(‘ (6-氰基-7-(2-甲氧基乙氧基）-4-喹啉基）氧苯基）-Ν，·（1，3· 嘍唑-2-基）脲（4〇9 mg , 0.886 mmol)得到為灰白色結晶之標 題化合物（181 mg，0·377 mmol，42.6%)。Idllz·methoxy-ethoxylated hydrazinium amide, carbonyl)amine, I, milylamine, -6 -4 leaching, nitrite, N-(' (from N in the same manner as in Example II2) 6-Cyano-7-(2-methoxyethoxy)-4-quinolinyloxyphenyl)-indole, (1,3·oxazol-2-yl)urea (4〇9 mg The title compound (181 mg, 0·377 mmol, 42.6%).

iH-NMR光譜（DMSO-d6)5(PPm): 3·35 (3H，s)，3.78-3.81 (2H 装 m), 4.39-4.42 (2H, m), 6.47 (1H3 d5 J=5.2 Hz), 7.11 (1H, br s), 7.26 (2H, d5 J=8.8 Hz), 7.37 (1H, d, J.3.2 Hz), 7.55 s)，7·62 (2H，d，J=8.8 Hz)，7·80 (1H，s)3 7·82 (1H，s)，8 65’ (1H，d，J=5.2 Hz), 8.78 (1H，s)，9·1〇 (1H，s)。 ’ · 實施例114iH-NMR spectrum (DMSO-d6) 5 (PPm): 3·35 (3H, s), 3.78-3.81 (2H loaded m), 4.39-4.42 (2H, m), 6.47 (1H3 d5 J=5.2 Hz) , 7.11 (1H, br s), 7.26 (2H, d5 J=8.8 Hz), 7.37 (1H, d, J.3.2 Hz), 7.55 s), 7.62 (2H, d, J = 8.8 Hz), 7·80 (1H, s) 3 7·82 (1H, s), 8 65' (1H, d, J = 5.2 Hz), 8.78 (1H, s), 9·1〇 (1H, s). </ RTI> Example 114

生二(4-((茉除卷某）胺某3-氣笨氫 i啉#醯胺 藉由與實施例112同樣之方法，從實施例99得到之 (6-氨基-7-( 2-甲氧基乙氧基）-4-喳啉基）氧氟苯基）、价 苯基脲（106 mg ’ 0.224 mmol)得到為褐色結晶之標題化入 物（21 mg，0.043 mmol，19·1%) 〇 iH-NMR光譜（DMS〇-d6)5(ppm)·· 3·35 (3ίί，s)，3.78-3^ m)，4.39-4.42 (2Η，m)，6·55 (1Η，d，J==5 2 Ηζ)，6·98 (1Η，(6-amino-7-(2-) was obtained from the example 99 in the same manner as in Example 112. Methoxyethoxy)-4-oxalinyl)oxyfluorophenyl), phenylphenylurea (106 mg '0.224 mmol) afforded the title compound as brown crystals (21 mg, 0.043 mmol, 19·1 %) 〇iH-NMR spectrum (DMS〇-d6) 5 (ppm)·· 3·35 (3ίί,s), 3.78-3^ m), 4.39-4.42 (2Η,m),6·55 (1Η, d, J==5 2 Ηζ), 6·98 (1Η,

Uh， J=7.6 Hz)，7·13 (1H，d，J=8.4 Hz)，7.29: (2H，t，j=7 6Uh, J=7.6 Hz), 7·13 (1H, d, J=8.4 Hz), 7.29: (2H, t, j=7 6

Hz)， 7·39 (1H，dd，J=2.4，12·0 Hz)，7.45 (2H，d，J=8.4 Hz)，7 % -217- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 … A7 __B7 I、發明説明（212 ) ^-Hz), 7·39 (1H, dd, J=2.4, 12·0 Hz), 7.45 (2H, d, J=8.4 Hz), 7 % -217- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 ... A7 __B7 I, invention description (212) ^-

(1H，s)，7·82 (2H，br s)，8.25 (1H，m)，8·63 (1H，s)，8 67 (1H d，J=5.2 Ηζ)，8.76 (1Η，s)，9.06 (1Η，s)。 ’ 實施例11 5 4-(4-((4-氟苯胺）,錢）胺基！甲氣基二^如林# 藉由與實施例112同樣之方法，從實施例39得到之N_(4_ (6-氰基-7-甲氧基-4-喹啉基）氧-苯基）_N，_(‘氟苯基）脲 (391 mg，0.913 mmol)得到為灰白色結晶之標題化合物（2()ι mg，0.450 mmol，49.2%)。 1 H-NMR光譜（DMS〇-d6) 5 (ppm): 4·02 (3H，s)，6.53 (1H d J—5.2 Hz)，7.11 (2H，t, J一8.8 Hz)，7·24 (2H，d，J=8.8 Hz) 7.44-7.48 (2H, m), 7.51 (1H, s), 7.59 (2H, d, J=8.8 Hz), 7.75 (1H，s)，7.87 (1H，s)，8·68-8·70 (2H，m)，8.85 (1H，s)，8.95 (1H，s)。 實施例11 6人 4一-ί 4-((環丙胺基）羰基）胺基笨氣基）-7-(大甲氣某乙氧葚、-6-4成藉酿胺 藉由與實施例112同樣之方法，從實施例23得到之N-(4-(6-氰基-7-( 2-曱氧基乙氧基）-4-喹啉基）氧苯基環丙 基踩（150 mg，0.3 58 mmol)得到為淡褐色結晶之標題化合 物（71 mg，0.163 mmol，45.4%) ° iH-NMR 光譜（0乂30-(16)5(??111):0.40-0.44 (211，111)，0.62-0.66 (2H, m), 2.43-2.48 (1H, m), 3.36 (3H, s), 3.80-3.83 (2H, m), 4.40-4.43 (2H, m), 6.43-6.46 (2H, m), 7.18 (2H, d, J=8.8 -218- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）(1H, s), 7·82 (2H, br s), 8.25 (1H, m), 8·63 (1H, s), 8 67 (1H d, J = 5.2 Ηζ), 8.76 (1Η, s) , 9.06 (1Η, s). Example 11 5 4-(4-((4-Fluoroaniline), money) Amino group; Methane group II^如林# By the same method as Example 112, N_(4_ obtained from Example 39. (6-Cyano-7-methoxy-4-quinolinyl)oxy-phenyl)-N,-('fluorophenyl)urea (391 mg, 0.913 mmol). ) ι mg, 0.450 mmol, 49.2%) 1 H-NMR spectrum (DMS 〇-d6) 5 (ppm): 4·02 (3H, s), 6.53 (1H d J-5.2 Hz), 7.11 (2H, t, J 8.8 Hz), 7·24 (2H, d, J = 8.8 Hz) 7.44-7.48 (2H, m), 7.51 (1H, s), 7.59 (2H, d, J=8.8 Hz), 7.75 (1H, s), 7.87 (1H, s), 8.68-8·70 (2H, m), 8.85 (1H, s), 8.95 (1H, s). Example 11 6 people 4 one-ί 4 -((cyclopropylamino)carbonyl)amino group, anthracene)-7- (large methoxy acetophenone, -6-4 hexylamine, obtained from Example 23 in the same manner as in Example 112 N-(4-(6-Cyano-7-(2-decyloxyethoxy)-4-quinolinyl)oxyphenylcyclopropyl tread (150 mg, 0.358 mmol) was obtained as pale brown Crystalline title compound (71 mg, 0.163 mmol, 45.4%) ° iH-NMR spectrum (0乂30-(16)5(??111):0.40-0.44 (211,111), 0.62-0.66 (2H, m), 2.43-2.48 (1H, m), 3.36 (3H, s), 3.80-3.83 (2H, m), 4.40-4.43 (2H, m), 6.43 -6.46 (2H, m), 7.18 (2H, d, J=8.8 -218- This paper size applies to China National Standard (CNS) A4 specification (210 x 297 mm)

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線 1304061 A7 B7 五、發明説明（213)Line 1304061 A7 B7 V. Description of invention (213)

Hz)，7.53-7.67 (3H，m)，7.81 (1H，s), 7.83 (1H，s)，8.46 (1H， s)，8.65 (1H，d，J=5.6 Hz)，8.79 (1H，s)。 實施例117 唑-2-某）Μ 藉由與實施例3 6同樣之方法，從4- (4-胺基苯氧基）氨 基-7-曱氧基4淋（291 mg，1.0 mmol)及2-苯氧基胺甲酿胺 基-1，3-嘍唑（264 mg，1·2 mmol)，得到為白色結晶之標題 化合物（390 mg，0.934 mmol，93.4%)。 iH-NMR光譜（DMS〇-d6)5(ppm): 4·05 (3H，s)，6·52 (1H，d J=5.2 Ηζ)，7.11 (1Η，br)，7·27 (2Η，d，J=8.8 Hz), 7·37 (1Η，d J=3.2 Hz), 7.59 (1H, s), 7.62 (2H, d, J=8.8 Hz), 8.72 (1H, d, J=5.2 Hz)，8.77 (1H，s)，9.12 (1H，s)。 ’ 實施例11 8 甲氧基-4&lt;4-((丄3〇塞唑-2-基胺羞）羰某）胺基茉氫 4 g休#醯胺 ' 藉由與實施例112同樣之方法，從實施例Π7得到之κ ((6 -夜基-7-甲氧基- 4-0奎淋）氧）苯基-Ν·-(1，3-嗟峻-2 -基）踩 (3 54 mg，0.848 mmol)，得到為灰白色結晶之標題化合物 (195 mg，0.448 mmol，52.8%) ° W-NMR光譜（DMS〇-d6)5(ppm): 4,02 (3H，s)，6.47 (1H，d， J=5.2 Hz), 7.10 (1H, br), 7.25 (2H, d, J=8.8 Hz), 7.36 (1H, d J=3.6 Hz), 7.50 (^H, s), 7.62 (2H, d, J=8.8 Hz), 7.73 (1H, s) 7·85 (1H，s)，8·64 (1H，d，J=5.2 Hz), 8.67 (1H，s)，9·45 (1H， -219- 本紙張尺度適用中國國家標準(CNS) A4規格（210 x 297公釐）Hz), 7.53-7.67 (3H, m), 7.81 (1H, s), 7.83 (1H, s), 8.46 (1H, s), 8.65 (1H, d, J = 5.6 Hz), 8.79 (1H, s ). Example 117: oxazol-2-yl) hydrazine was eluted from 4-(4-aminophenoxy)amino-7-decyloxy 4 (291 mg, 1.0 mmol) in the same manner as in Example 36. 2-Phenoxyamine-mercapto-l-indole (264 mg, 1.2 mmol) gave the title compound ( 390 mg, 0.934 iH-NMR spectrum (DMS〇-d6) 5 (ppm): 4·05 (3H, s), 6·52 (1H, d J=5.2 Ηζ), 7.11 (1Η, br), 7·27 (2Η, d, J = 8.8 Hz), 7·37 (1Η, d J=3.2 Hz), 7.59 (1H, s), 7.62 (2H, d, J=8.8 Hz), 8.72 (1H, d, J=5.2 Hz) ), 8.77 (1H, s), 9.12 (1H, s). 'Example 11 8 Methoxy-4&lt;4-((丄3〇 stopper azole-2-ylamine) carbonyl) amide methoxyhydrogen 4 g 休# decylamine' by the same method as in Example 112 , κ ((6-Nyenyl-7-methoxy-4-0 quinone) oxygen) phenyl-Ν·-(1,3-嗟 -2-2 -yl) step (3) obtained from Example Π7 The title compound (195 mg, 0.448 mmol, 52.8%) was obtained as pale white crystals. mp NMR spectrum (DMS 〇-d6) 5 (ppm): 4,02 (3H, s), 6.47 (1H,d, J=5.2 Hz), 7.10 (1H, br), 7.25 (2H, d, J=8.8 Hz), 7.36 (1H, d J=3.6 Hz), 7.50 (^H, s), 7.62 (2H, d, J=8.8 Hz), 7.73 (1H, s) 7·85 (1H, s), 8·64 (1H, d, J=5.2 Hz), 8.67 (1H, s), 9.45 (1H, -219- This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm)

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線 1304061 、Line 1304061,

、 AT ___B7 五、發明説明（214) S) 〇 實施例1 1 9 U4-((2,4-二氟苯胺基）羰基）胺基-3-氯苽1基）-7-甲氧 基-6 - 口杳口林複酿胺 藉由與實施例112同樣之方法，從實施例61得到之N- (4-(6-氰基-7-甲氧基-4-喹啉）氧-2-氟苯基）-N，-(2,4-二氟苯 基）脲（118 mg，0.254 mmol)，得到為淡桃色結晶之標題化 合物（36 mg，0·448 mmol，29.4%)。 iH-NMR光譜（DMS〇-d6)5(ppm): 4·02 (3H，s)，6.56 (1H，d, J=5.2 Hz)，7·06 (1H，m)，7·12 (1H，m)，7·33 (1H，m)，7·39 (1H, dd, 1=2.8, 11.6 Hz), 7.51 (1H, s), 7.73 (1H, s), 7.84 (1H, s)，8·11 (1H，m)，8.25 (1H，t，J=9.2 Hz)，8.65 (1H，s)，8.66 (1H，d，J=5.2 Hz), 8.99 (1H，s)，9.06 (1H，s) 〇 實施例120 氰/棊二甲氧基二生-喳啉）氧）茉某呙其叫 藉由與實施例36同樣之方法，從4〉（仁胺基苯氧基）· 6-氰基-7-甲氧喹淋（381 mg，1.308 mmol)，得到為白色結 晶之標題化合物（293 mg，0.783 mmol，59.8%)。 H-NMR 光讀（DMS〇-d6) 5 (ppm): 0.40-0.44 (2H，m) 〇62 0.67 (2H, m), 2.53-2.58 (1H, m)5 4.07 (3H, m), 6.44 (ih d J=2.0 Hz)，6.51 (1H, d, J=5.6 Hz), 7·19 (2H, d，J=8.8 Hz)’ 7·56 (2H，d，J=8.8 Hz), 7.60 (1H，s)，8·48 (1H，s)，8·73 (1H’ d, J=5.6 Hz), 8·77 (IH, s)。 ： ’ 實施例1 2 1 -220· 1304061 〜 A7 _B7 五、發明説明（215 ) 4-(4-(这丙胺基_)羰基,1胺基墓盖基卜7-甲氩某^縫 藉由與實施例112同樣之方法，從實施例120得到之4-((6-氣基-7-甲氧基-4- p奎淋基）氧）苯基_ ν’-環丙月尿（279 mg，〇·745 mmol)，得到為灰白色結晶之標題化合物（79 mg，0.201 mmol，26.9%)。 4 - NMR 光譜（〇乂3〇-&lt;16)5(?13111):0.40-0.43 (211，111)，0.62-0·64 (2H，m)，2.42-2,45 (1H，m)，4_02 (3H，s)，6.42-6.44 (2H， m), 7.16 (2H, d, J=8.0 Hz), 7.49 (1H, s), 7.53 (2H, d, J=8.0, AT ___B7 V, invention description (214) S) 〇 Example 1 1 9 U4-((2,4-difluoroanilino)carbonyl)amino-3-chloroindole 1 yl)-7-methoxy- 6 - Mouthwash Mouthline N-(4-(6-Cyano-7-methoxy-4-quinoline)oxy-2 obtained in Example 61 in the same manner as in Example 112. -Fluorophenyl)-N,-(2,4-difluorophenyl)urea (118 mg, 0.254 mmol). iH-NMR spectrum (DMS 〇-d6) 5 (ppm): 4·02 (3H, s), 6.56 (1H, d, J = 5.2 Hz), 7·06 (1H, m), 7·12 (1H) ,m),7·33 (1H,m),7·39 (1H, dd, 1=2.8, 11.6 Hz), 7.51 (1H, s), 7.73 (1H, s), 7.84 (1H, s), 8·11 (1H, m), 8.25 (1H, t, J = 9.2 Hz), 8.65 (1H, s), 8.66 (1H, d, J = 5.2 Hz), 8.99 (1H, s), 9.06 (1H , s) 〇 Example 120 cyanide / hydrazine dimethoxy- porphyrin) oxy) 茉 呙 呙 呙 呙 呙 呙 呙 呙 呙 呙 同样 同样 同样 同样 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 The title compound (293 mg, 0.783 mmol, 59.8%) was obtained as white crystals. H-NMR optical reading (DMS〇-d6) 5 (ppm): 0.40-0.44 (2H, m) 〇62 0.67 (2H, m), 2.53-2.58 (1H, m)5 4.07 (3H, m), 6.44 (ih d J=2.0 Hz), 6.51 (1H, d, J=5.6 Hz), 7·19 (2H, d, J=8.8 Hz)' 7·56 (2H, d, J=8.8 Hz), 7.60 (1H, s), 8·48 (1H, s), 8.73 (1H' d, J = 5.6 Hz), 8·77 (IH, s). : ' Example 1 2 1 -220· 1304061 ~ A7 _B7 V. Description of the invention (215) 4-(4-(this propylamino)carbonyl group, 1 amine tomb cover base 7-a argon 4-((6-Gas-7-methoxy-4-p-quinolate)oxy)phenyl_ν'-cyclopropene urinary urethane (279) obtained in the same manner as in Example 112. The title compound (79 mg, 0.201 mmol, 26.9%) was obtained as pale white crystals. 4 - NMR spectrum (〇乂3〇- &lt;16) 5 (?13111): 0.40-0.43 ( 211,111),0.62-0·64 (2H,m),2.42-2,45 (1H,m),4_02 (3H,s),6.42-6.44 (2H, m), 7.16 (2H, d, J =8.0 Hz), 7.49 (1H, s), 7.53 (2H, d, J=8.0

Hz)，7.72 (1H，s)，7.84 (1H，s)，8·45 (1H，s)，8.63 (1H，d， J=5.6 Hz)，8·67 (1H，s) 〇 f施例122 Ν-(4-(5·Λ^·甲基- 4-7H-吡啥并「2,3-dl嘧咬某、氧苯某）' Ν’-ί4-氣笨基）脹 將4-(4-胺^基苯氧基）-5,6-二甲基-711-吡咯并[2,3-(1]嘧啶 於回流下溶於甲苯（0.8 ml)及乙腈（〇·5 mi)中後，加入異氰 酸4-氟苯基醋（7.9 # M)。攪掉1小時，回到室溫後將反應系 統濃縮，將殘餘物加至乙醚中，使其結晶化及濾取。將該 結晶用乙醚洗淨，得到標題化合物（5 mg)。 MS m/z 392(M + H) H-NMR (DMSO-d6) δ (ppm): 2.29 (3H, s), 2.31 (3H, s), 7.00-7.16 (4H, m), 7.38-7.50 (4H, m), 8.10 (1H, s), 8.50 (2H, s)，11.75 (1H, s)。 - 如下述合成中間體。 ___ 221 · 本纸張尺度適用中國國豕標準(CNS) A4規格(21〇x 297公釐） 1304061 A7 B7 五、發明説明（216 製造例122- 1 L(硝基苯氧基）· 5,6-二甲基-7H-吡咯并f 2,3- dl -嘧啶 在 Journal of Medicinal Chemistry, 1996，vol· 39，Nol2, 2285-2292記載之4-氯-5,6-二甲基-7H-吡咯并[2,3-d]-嘧啶 (88 mg)中’加入對-硝基紛（121 mg)，碳酸4甲（133 mg)及 二曱基曱醯胺（1 ml)，並於135- 140°C攪拌72小時。返回室 溫後加入水，用四氫呋喃與乙酸乙，酯之混合溶液萃取，將 有機層用飽和食鹽水洗淨，藉由無水硫酸鈉乾燥後濃縮乾 固。將得到之結晶用乙醚洗淨，得到標題化合物（90 mg)。 MS τη/ζ 285(Μ + Η) !H-NMR (DMS0-d6) (5 (ppm): 2.28 (3H, s), 2.32 (3H, s), 7.50 (2H, d, J=9.5 Hz), 8.20 (1H, s), 8.30 (2H, d, J=9.5 Hz), 11.98 (1H，s) 〇 製造例122-2 1_(胺基笨氧^基）-5,6-二甲某-7^吡咯#「2.3-(11-嘧诖 在藉由上述中間合成法合成之4-(硝基苯氧基）-5,6-二甲 基-7H-吡咯并[2,3-d]-嘧啶（80 mg)中，加入鐵粉（〇.1 g)， 氯化銨（0.2 g)，乙醇（4 ml)及水（1 ml)，並於75- 82 °C授拌 1.5小時。使反應系統回到室溫後，加入四氫呋喃（3 ml)及 乙酸乙酯（3 ml)及經矽藻土過濾，將濾液分液，將有機層 用水及飽和食鹽水依次洗淨，用硫酸鈉乾燥後，減壓濃縮 乾固，用乙醚洗淨，得到標題化合物（22 mg)。 MS m/z 255(M + H) - 1H-NMR (DMS〇-d6) (5 (ppm): 2.27 (3H, s), 2.29 (3H, s), -222- 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（217 ) 4.90-5.00 (2H, m), 6.52-6.88 (4H, m), 8.06 (1H, s), 11.66 (IH’s)。 實施例123 4 V 4“ 3，4-二羥基4唑啉-2-酮-3-基）苯氫某6,7-二甲氫甚 口奎淋 將6,7-二甲氧基-4-(4-(2-胺基苯基）甲胺苯氧基）喹啉（4〇 mg，0.0996 mmol)溶解於二甲基甲醯胺（〇5 ml)中，加入 1，1’-羰基一咪峻（19 mg，0· 1196 mmol)，並於 70 °C 加熱擾 拌8小時。冷卻至室溫後，將反應液用四氫呋喃稀釋，在其 中加入水，用乙酸乙酯萃取，用飽和食鹽水洗淨及用無水 硫酸鎂乾燥後，減壓餾去溶媒。將殘餘物用矽凝膠管柱（乙 酸乙酯-甲醇系）精製，用己烷-乙醚再結晶，得到為無色結 晶之標題化合物（3 mg，0.0070 mmol，7.05%)。 lH-NMR (CDC13) 5 (ppm): 4.06 (6H, s), 4.89 (2H, s), 6.57 (1H，d，J-5·、2 Hz)，6·77 (1H，d，J=7.6 Hz)，6.87 (1H，br s)， 7.03 (1H, t, J=7.6 Hz), 7.14 (1H, d, J=7.6%Hz), 7.23 (3H, m covered by CDC13)，7·44 (1H，s)，7.48 (2H，d，J=8.8 Hz)， 7·55 (1H，s)，8·52 (1H，d，J=5.2 Hz)。 中間體如下述合成。 製造例123-1 6,7-二甲氣基-4-(4-(2-硝基苯基甲亞胺某）苽i葚 將6，7 -二甲乳基- 4-(4 -胺基苯氧基）p奎t/林（5 〇〇 mg，1.6873 mmol)溶於四氫吱喃（64 ml)，加入2 -硝基亨遂（320 mg , 2· 109 1 mmol)及乙酸（〇·58 ml)後，加入三乙酿氧基爛氫化 -223- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜 A7 B7 五、發明説明（218 ) 鈉（720 mg ’ 3.3 746 mmol)，並於室溫攪拌11小時30分鐘。 加入水及飽和碳酸氫鈉水溶液，用乙酸乙酯萃取，用飽和 食鹽水洗淨，及用無水硫酸鎂乾燥後，減壓餾去溶媒。將 得到之結晶用己烷-乙醚洗淨，濾取，用己烷洗淨及在室溫 吸引乾燥後’仔到為）乂兴色結晶之標題化合物（463 mg)。 ^-NMR (CDC13) 5 (ppm): 4.06 (6H, s)5 6.54 (1H, d, J=5.2 Hz), 7.25 (2H, d, J=8.4 Hz), 7.40 (2H, d, J=8.4 Hz), 7.44 (1H, s), 7.57 (1H, s), 7.65 (1H, dd5 J=7.6, 8.0 Hz), 7.77 (1H, dd, J=7.6, 7.6 Hz), 8.10 (1H, d, J=8.0 Hz), 8.33 (1H, d, 1=7,6 Hz)，8·51 (1H，d，J=5.2 Hz)，9·01 (1H，s)。 製造例123-2 6,7-二甲氣基-4-( 4-_( 2二瘦_基笔甲胺某)苯氳某）p杏啉 在6,7-二甲氧基-4-(4-(2-硝基苯基甲亞胺基）苯氧基）喹 啉（200 mg，0.4657 mmol)中加入四氫呋喃（2 ^1)，乙醇（2 ml)及氯仿μ ml)，加熱以使之完全溶解，加入硼氫化鈉 (35 mg，0.9314 mmol)，然後加熱回流w、時3〇分鐘。冷卻 至室溫後’加入水’用乙酸乙酯萃取，用飽和食鹽水洗淨 及用典水硫故鍰乾燥後’減屬:館去溶媒。將殘餘物用NR碎 凝膠管柱（己烷-乙酸乙酯系）精製，得到為黃色油狀物之標 題化合物（151 mg，0.3500 mmol，75 15%)。 ^-NMR (CDCl3)(5(ppm): 4.04 (6H, s), 4.46 (1H, br s), 4.76 (2H, d, J=4.8 Hz), 6.42 (1H, d, J=5.2 Hz), 7.64 (2H, d, J=8.8Hz), 7.72 (1H, s), 7.84 (1H, s), 8.45 (1H, s), 8.63 (1H, d, J = 5.6 Hz), 8.67 (1H, s) 〇f Example 122 Ν-(4-(5·Λ^·Methyl-4-7H-pyridinium and 2,3-dl-pyrimidine, oxybenzene)' Ν'-ί4-gas base) swells 4- (4-Aminophenoxy)-5,6-dimethyl-711-pyrrolo[2,3-(1]pyrimidine dissolved in toluene (0.8 ml) and acetonitrile (〇·5 mi) under reflux After the addition, 4-fluorophenyl vinegar (7.9 #M) was added, and the mixture was stirred for 1 hour. After returning to room temperature, the reaction system was concentrated, and the residue was added to diethyl ether, crystallized and filtered. The crystals were washed with diethyl ether to give the title compound (mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj s), 7.00-7.16 (4H, m), 7.38-7.50 (4H, m), 8.10 (1H, s), 8.50 (2H, s), 11.75 (1H, s) - Synthetic intermediates as described below ___ 221 · This paper size is applicable to China National Standard (CNS) A4 specification (21〇x 297 mm) 1304061 A7 B7 V. Description of invention (216 Manufacturing Example 122-1 L (nitrophenoxy)· 5,6 -Dimethyl-7H-pyrrolof 2,3- dl-pyrimidine in Journal of Medicinal Chemistry, 1996 , vol. 39, Nol 2, 2285-2292, 4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine (88 mg) in the addition of p-nitro- 121 mg), carbonic acid 4 (133 mg) and dimethyl decylamine (1 ml), and stirred at 135-140 ° C for 72 hours. After returning to room temperature, add water, mix with tetrahydrofuran and ethyl acetate, ester The solution was extracted, and the organic layer was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated !H-NMR (DMS0-d6) (5 (ppm): 2.28 (3H, s), 2.32 (3H, s), 7.50 (2H, d, J=9.5 Hz), 8.20 (1H, s), 8.30 (2H, d, J=9.5 Hz), 11.98 (1H, s) 〇Production Example 122-2 1_(Amino phenyloxy)-5,6-dimethyl -7^pyrrole #"2.3-(11 -pyrimidine is added to 4-(nitrophenoxy)-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine (80 mg) synthesized by the above intermediate synthesis method Iron powder (〇.1 g), ammonium chloride (0.2 g), ethanol (4 ml) and water (1 ml) were mixed at 75-82 °C for 1.5 hours. After the reaction system was returned to room temperature, tetrahydrofuran (3 ml) and ethyl acetate (3 ml) were added and filtered through celite, and the filtrate was separated, and the organic layer was washed successively with water and brine. After drying, the title compound (m. MS m/z 255(M + H) - 1H-NMR (DMS〇-d6) (5 (ppm): 2.27 (3H, s), 2.29 (3H, s), -222- This paper size applies to China Standard (CNS) A4 size (210 x 297 mm) 1304061 A7 B7 V. Description of invention (217) 4.90-5.00 (2H, m), 6.52-6.88 (4H, m), 8.06 (1H, s), 11.66 ( IH's). Example 123 4 V 4 "3,4-dihydroxy-4-oxalin-2-one-3-yl)benzene hydrogen 6,7-dimethylhydrogen phenoxy to 6,7-dimethoxy 4-(4-(2-Aminophenyl)methylamine phenoxy)quinoline (4 〇 mg, 0.0996 mmol) was dissolved in dimethylformamide (〇5 ml), and 1,1 was added. '-Carbo-Imi (19 mg, 0·1196 mmol), and stirred at 70 ° C for 8 hours. After cooling to room temperature, the reaction was diluted with tetrahydrofuran, water was added and extracted with ethyl acetate The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated evaporated evaporated. The title compound (3 mg, 0.0070 mmol, 7.05%) mp.: NMR (CD, EtOAc, EtOAc) 57 (1H,d,J-5·, 2 Hz), 6.77 (1H, d, J=7.6 Hz), 6.87 (1H, br s), 7.03 (1H, t, J=7.6 Hz), 7.14 (1H, d, J=7.6% Hz), 7.23 (3H, m covered by CDC13), 7·44 (1H, s), 7.48 (2H, d, J=8.8 Hz), 7·55 (1H, s ), 8·52 (1H, d, J = 5.2 Hz). The intermediate was synthesized as follows. Production Example 123-1 6,7-dimethyll-4-(4-(2-nitrophenyl)胺i葚6,7-dimethyllacyl-4-(4-aminophenoxy)p-r-t-lin (5 〇〇mg, 1.6873 mmol) is dissolved in tetrahydrofuran (64 ml) ), after adding 2-nitroquinone (320 mg, 2.109 1 mmol) and acetic acid (〇·58 ml), adding triethyl ethoxylated hydrogenated-223- this paper scale applies to China National Standard (CNS) A4 size (210 X 297 mm) 1304061 ~ A7 B7 V. Description of the invention (218) Sodium (720 mg '3.3 746 mmol) and stirred at room temperature for 11 hours and 30 minutes. After adding water and a saturated aqueous solution of sodium hydrogencarbonate, the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The crystals obtained were washed with hexane-diethyl ether, filtered, washed with hexanes, and evaporated to dryness. ^-NMR (CDC13) 5 (ppm): 4.06 (6H, s)5 6.54 (1H, d, J=5.2 Hz), 7.25 (2H, d, J=8.4 Hz), 7.40 (2H, d, J= 8.4 Hz), 7.44 (1H, s), 7.57 (1H, s), 7.65 (1H, dd5 J=7.6, 8.0 Hz), 7.77 (1H, dd, J=7.6, 7.6 Hz), 8.10 (1H, d , J=8.0 Hz), 8.33 (1H, d, 1=7,6 Hz), 8·51 (1H, d, J=5.2 Hz), 9·01 (1H, s). Production Example 123-2 6,7-Dimethyl-based-4-(4-_(2二瘦_基笔甲胺) benzoquinone) p-anthryl in 6,7-dimethoxy-4- (4-(2-Nitrophenylmethylimido)phenoxy)quinoline (200 mg, 0.4657 mmol) was added with tetrahydrofuran (2^1), ethanol (2 ml) and chloroform (m) To dissolve completely, sodium borohydride (35 mg, 0.9314 mmol) was added, followed by heating to reflux w for 3 min. After cooling to room temperature, 'water was added', extracted with ethyl acetate, washed with saturated brine and dried with sulphuric acid, and then dried. The residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc ^-NMR (CDCl3) (5 (ppm): 4.04 (6H, s), 4.46 (1H, br s), 4.76 (2H, d, J = 4.8 Hz), 6.42 (1H, d, J = 5.2 Hz) , 7.64 (2H, d, J=8.8

Hz)，6·99 (2H，d，J=8.8 Hz)，7.40 (ih; s)，7.47 (1H，dd， J=7.2，7.2 Hz)，7·57 (1H，s)，7.62 (1H，dd，J=7.2，7.6 Hz), -224- 本纸張尺度適用中國國家標準(CNS) A4規格（21〇x 297公釐） 1304061Hz),6·99 (2H,d,J=8.8 Hz), 7.40 (ih; s), 7.47 (1H, dd, J=7.2, 7.2 Hz), 7·57 (1H, s), 7.62 (1H ,dd,J=7.2,7.6 Hz), -224- This paper size applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1304061

7·71 (1H，d，J=7.6 Ηζ)，8·1〇 (ih5 d，J=7.2 Ηζ)，8·45 (1H，d， J=5.2 Hz) o 製造例123-3 皂二甲氧基二曱胺某）苯氧其、啐咁 將6,7-二甲氧基-4-(4-(2-硝基苯甲胺基）苯氧基）喹啉 (150 mg , 0.35 mmol)溶於乙醇（2 8 ml)及水（〇 7㈤）中，加 入鐵粉（78 mg , 1·4 mmol)及氯化銨（15〇 mg , 2 8 mm〇l), 並加熱回流1小時。冷卻至室溫後，用四氫呋喃及水將反應 液稀釋，並濾去不要物。減壓蒸餾濾液後，將殘餘物用矽 凝膠管柱（乙酸乙酯系）精製，將所得不定形物用己烷及乙 酸乙酯固化，將所得結晶用己烷—乙酸乙酯洗淨，濾取，用 己烷洗淨及在室溫吸引乾燥後，得到為乳白色結晶之標題 化合物（80 mg ’ 0.1993 mmol，56.93%)。 lH-NMR (CDCl3)5(ppm): 3.78 (1H, br s), 4.05 (3H, s), 4.06 (3H，s)，4.15、(2H，br s)，4·26 (2H，s)，6.44 (1H，d，J=5.2 Hz) 6.74-6.81 (4H, m)5 7.06 (2H, d3 J=8.8 Hz)/7.16-7.22 (2H, m) 7·42 (1H, s), 7·60 (1H，s)，8·46 (1H, d, J=5.2 Hz)。 實施例124 苯基说啶-4-基）氧茉某悬m早 將4-(2-苯基吡啶-4-基）氧苯胺（110 mg，〇·42 mM)加至乙 酸乙酯（10 ml)中，於攪摔下加入異氰酸對氟苯基（〇.56 ml，4·9 mM)並攪拌〇·5小時。在反應溶液中加入正己烷（2〇 ml)，於減壓下餾去一部分溶媒，濾取择出之固體，得到為 灰色固體之目的物（98 mg)。 -225 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 13040617·71 (1H, d, J=7.6 Ηζ), 8·1〇 (ih5 d, J=7.2 Ηζ), 8.45 (1H, d, J=5.2 Hz) o Production Example 123-3 Soap Oxydiamine, phenoxyl, ruthenium 6,7-dimethoxy-4-(4-(2-nitrobenzylamino)phenoxy)quinoline (150 mg, 0.35 mmol Soluble in ethanol (28 ml) and water (〇7(5)), add iron powder (78 mg, 1.4 mmol) and ammonium chloride (15 〇mg, 2 8 mm 〇l), and heat to reflux for 1 hour. . After cooling to room temperature, the reaction solution was diluted with tetrahydrofuran and water, and the residue was filtered. After the filtrate was evaporated under reduced pressure, the residue was purified eluting with EtOAc EtOAc EtOAc. The title compound (80 mg '0.1993 mmol, 56.93%) was obtained as crystals eluted eluted elute lH-NMR (CDCl3) 5 (ppm): 3.78 (1H, br s), 4.05 (3H, s), 4.06 (3H, s), 4.15, (2H, br s), 4·26 (2H, s) , 6.44 (1H, d, J = 5.2 Hz) 6.74-6.81 (4H, m)5 7.06 (2H, d3 J=8.8 Hz)/7.16-7.22 (2H, m) 7·42 (1H, s), 7 · 60 (1H, s), 8.46 (1H, d, J = 5.2 Hz). Example 124 Phenylpyridin-4-yl)oxygen methane 4-(2-phenylpyridin-4-yl)oxyaniline (110 mg, 〇·42 mM) was added to ethyl acetate (10) In ml), p-hydroxyphenyl isocyanate (〇.56 ml, 4·9 mM) was added under stirring and stirred for 5 hours. To the reaction solution, n-hexane (2 ml) was added, and a portion of solvent was evaporated under reduced pressure. -225 This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1304061

H-NMR (DMSO-d6)5(Ppm): 6·81 (1H，dd，J=5.6 Hz，J=2.4H-NMR (DMSO-d6) 5 (Ppm): 6·81 (1H, dd, J = 5.6 Hz, J = 2.4

Hz), 7.10-7.20 (4H, m), 7.42-7.52 (6H, m), 7.57 (2H, d, &gt;8.8 Hz)，8·01 (2H，d，J=8.4 Hz)，8·53 (1H，d，J=5.6 Hz)， 8.74 (1H，s)，8.80 (1H，s)。 原料及中間體如下述合成。 製造例124-1 K 2-笨某吡啶-4-某）氫1脖 將4-氯-2 -苯基吡啶1.〇 g (5·5 mM),對硝基酚（i,68 g , 12 mM),修尼驗（一異丙基乙胺）5⑹及卜甲基吨哈唉酮（1 〇 μ) 於160°C攪拌20小時。加入水，用乙酸乙酯萃取以及將有機 層用水洗淨5次將溶媒減|館去，將殘餘物用♦凝膠層析 (己燒：乙酸乙酯=4 : 1)精製，得到為淡黃色固體之4- (4-硝基冬氧基）-2 -冬基说咬4 9 0 m g。 H-NMR (DMSO-d6) 5 (ppm): 7.08-7.14 (1H，m)，7.40-7.53 (5H，m), 7·Τ4 (1H，s)，8.07-8.13 (2H，m)，8,34 (2H，d，J=8.8 Hz), 8·68 (1H，dd，J=5,6 Hz，J=1.2 Hz)。 將4-( 4-硝基苯氧基）-2-苯基p比淀（490 mg)，鐵粉（lg)， 氯化銨（2 g)，乙醇（1〇 ml)，二甲基甲醯胺（10 ml)及水（5 ml)中，並於1〇〇°C攪拌1〇分鐘。經矽藻土過濾，在濾液中 加入水，用乙酸乙酯萃取。將有機層用水洗淨5次後，減壓 餾去溶媒，得到為褐色油狀物之4-(2-苯基吡啶-4-基）氧苯 胺（460 mg) 〇 lH-NMR (DMSO-d6) 5 (ppm): 5.12-5.16 (2H, m), 6.65 (2H, d, J=8.8 Hz), 6.74 (1H, dd, J=5.6 Hz, J=2.4 Hz), 6.89 (2H, d, -226 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 B7 五、發明説明（221) J=8.8 Hz), 7.38 (1H, d, J=2.4 Hz), 7.40-7.52 (3H, m), 7.98 (2H，d，J=8.〇 Hz)，8·48 (1H, d，J=5.6 Hz)。 實施例125 义(4-(3-茉基吡啶-4-基）氣苯某^-(4-氣茉甚&gt;|辉 將4-(3 -苯基吡啶-4-基）氧苯胺（84 mg，0·32 mM)加至乙 酸乙酯（10 ml)中，於攪拌下加入異氰酸對氟苯酯（〇 54 ml ’ 4.7 mM)並揽拌40分鐘。在反應液中加入NH型矽凝 膠，減壓餾去溶媒’以使反應生成物吸著在矽凝膠上。將 该碎k膠鑽入充填有NH型碎凝膠之乾燥管柱中，然後進行 管柱精製（氯仿：甲醇= 10: 1)。在得到之殘餘物中加入乙 酸乙酯及正己烷及減壓餾去溶媒，得到為淡黃色不定形之 目的物（82 mg)。 lH-NMR (DMSO-d6) 5 (ppm): 6.69 (1H, dd, J=5.6 Hz, J=1.6Hz), 7.10-7.20 (4H, m), 7.42-7.52 (6H, m), 7.57 (2H, d, &gt; 8.8 Hz), 8·01 (2H, d, J=8.4 Hz), 8.53 (1H, d, J = 5.6 Hz), 8.74 (1H, s), 8.80 (1H, s). The starting materials and intermediates were synthesized as follows. Production Example 124-1 K 2-Butylpyridin-4-one) Hydrogen 1 neck 4-chloro-2-phenylpyridine 1. 〇g (5·5 mM), p-nitrophenol (i, 68 g , 12 mM), sulphonic acid (monoisopropylethylamine) 5 (6) and methyl ketone (1 〇μ) were stirred at 160 ° C for 20 hours. Water was added, and the organic layer was washed with water for 5 times to remove the solvent, and the residue was purified by hexane chromatography (hexane: ethyl acetate = 4:1). The 4-(4-nitrobutoxy)-2-winter group of the yellow solid was bitten 490 mg. H-NMR (DMSO-d6) 5 (ppm): 7.08-7.14 (1H, m), 7.40-7.53 (5H, m), 7·Τ4 (1H, s), 8.07-8.13 (2H, m), 8 , 34 (2H, d, J = 8.8 Hz), 8·68 (1H, dd, J = 5, 6 Hz, J = 1.2 Hz). 4-(4-Nitrophenoxy)-2-phenyl p-precipitate (490 mg), iron powder (lg), ammonium chloride (2 g), ethanol (1 〇 ml), dimethyl Indoleamine (10 ml) and water (5 ml) were stirred at 1 ° C for 1 min. It was filtered through celite, water was added to filtrate, and ethyl acetate was evaporated. The organic layer was washed with water for 5 times, and then the solvent was evaporated to dryness to give 4-(2-phenylpyridin-4-yl)oxyaniline (460 mg) as a brown oil. 5 (ppm): 5.12-5.16 (2H, m), 6.65 (2H, d, J=8.8 Hz), 6.74 (1H, dd, J=5.6 Hz, J=2.4 Hz), 6.89 (2H, d, -226 This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Invention description (221) J=8.8 Hz), 7.38 (1H, d, J=2.4 Hz), 7.40 -7.52 (3H, m), 7.98 (2H, d, J=8.〇Hz), 8·48 (1H, d, J=5.6 Hz). Example 125 (4-(3-Myrylpyridin-4-yl)-p-benzophenone--(4-qimox&gt;| Hui 4-(3-phenylpyridin-4-yl)oxyaniline ( 84 mg, 0·32 mM) was added to ethyl acetate (10 ml), and p-fluorophenyl isocyanate (〇54 ml '4.7 mM) was added with stirring for 40 minutes. NH was added to the reaction solution. a ruthenium gel, and the solvent is distilled off under reduced pressure to cause the reaction product to be adsorbed on the ruthenium gel. The ruthenium gel is drilled into a dry column packed with NH-type pulverized gel, and then the column is refined ( Chloroform: Methanol = 10: 1) To the residue was added ethyl acetate and n-hexane. 5 (ppm): 6.69 (1H, dd, J=5.6 Hz, J=1.6

Hz)，7.06-7.15 (4H，m)，7.37-7.54 (7H，m)，7·64 (2H，d， J-7.6 Hz), 8^.38 (1H, dd, J=5.6 Hz, J=1.6 Hz), 8.51 (1H, d, J=1.6 Hz), 8.70 (1H, s), 8.75 (1H, s) 〇 、 如下述合成原料及中間體。 製造例125- 1 4- ( 3 -苯基p比咬-4-基）氧笨胺 將4-氯· 3-苯基吡啶（200 mg，1.06 mM)，對硝基酚440 mg(3.18 mM),修尼鹼（iS0pr2EtN ,二異丙基乙胺ml)及 1-甲基吡咯啶酮（2 ml)於1601攪掉2小時。加入水，用乙 酸乙酯萃取以及將溶媒於減壓下餾去。·將殘餘物用矽凝膠 層析（己烷：乙酸乙酯=4 : 1，繼而2 : 1)精製，得到為淡 -227- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 s’ A7 _ B7 五、發明説明（222 ) 黃色油狀物之4- (4-硝基苯氧基）-3 -苯基p比咬（15 0 mg)。 1 H-NMR (C.DCl^ δ (ppm): 6.98 (1H, d, J=5.6 Hz), 7.12 (2.H, d, J=9.2 Hz), 7.37-7.48 (3H, m), 7.50-7.56 (2H, m), 8.24 (2H, d，J=9.3 Hz), 8·55 (1H，d，J=5.6 Hz), 8.71 (1H, s) 〇 將4-( 4-硝基苯氧基）-3-苯基P比症（150 j^g)，鐵粉（300 mg)，氯化銨（600 mg)，乙醇（5 ml)，二甲基甲醯胺（5 ml) 及水（2·5 ml)於100°C攪拌15分鐘。經矽藻土過滤，在遽液 中加入水及用乙酸乙酯萃取《將有機層用水洗淨5次後，減 壓餾去溶媒，得到為黃色油狀物之4- ( 3 -苯基p比淀-4-基）氧 苯胺（84 mg)。 ^-NMR (CDC13) 5 (ppm): 6.65-6.74 (3H, m), 6.88 (2H, d, J=8.8 Hz), 7.36-7.50 (3H, m), 7.64 (2H, d, J=8.8 Hz), 8.34 (1H，dd，J=5.6 Hz，J=0.8 Hz), 8·54 (1H，s)。 實施例126 (i，7-二甲_氧基口奎淋-4-基）氧丙p - N，- (4-氣笨某） 將6,7-二甲氧基-4-(3-胺基丙氧基）4^林15〇1^(0.57 1111^) 及乙酸乙酯（20 ml)於室溫及攪拌下，加入異氰酸4_氣苯酉旨 (0.078 ml，0.68 mM)並再攪拌15分鐘。濾取析出之固體， 得到為白色固體之目的物（92 mg)。 ^-NMR (DMSO-d6) 5 (ppm): 2.03 (2H, tt, J=6.0 Hz, J=6.〇 Hz), 3.36 (2H, t, J=6.0 Hz), 3.89 (3H, s), 3.91 (3H, s), 4.27 (2H, t, J=6.0 Hz), 6.29 (1H, t, J=6.0 Hz), 6.88 (1H, d, J=5.2 Hz), 7.00-7.07 (2H, m), 7.31 (1H, s), 7.34-7.41 (3H, m), 8.47 (1H，s)，8.51 (1H，d，J=5.2 Hz)。 -228- 本紙張尺度適用中國國家標準(CMS) A4規格(210 x 297公釐） 1304061Hz), 7.06-7.15 (4H, m), 7.37-7.54 (7H, m), 7·64 (2H, d, J-7.6 Hz), 8^.38 (1H, dd, J=5.6 Hz, J =1.6 Hz), 8.51 (1H, d, J=1.6 Hz), 8.70 (1H, s), 8.75 (1H, s) 〇, such as the following synthetic raw materials and intermediates. Production Example 125- 1 4-(3-Phenyl p-Butyl-4-yl)oxyantamine 4-Chloro-3-phenylpyridine (200 mg, 1.06 mM), p-nitrophenol 440 mg (3.18 mM) The nicotinic acid (iS0pr2EtN, diisopropylethylamine ml) and 1-methylpyrrolidone (2 ml) were stirred at 1601 for 2 hours. Water was added, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. · Residues were purified by hydrazine gel chromatography (hexane: ethyl acetate = 4:1, then 2:1) to give a pale-227- paper scale applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 s' A7 _ B7 V. Description of the invention (222) 4-(4-Nitrophenoxy)-3-phenyl p-bite (15 0 mg) in yellow oil. 1 H-NMR (C.DCl^ δ (ppm): 6.98 (1H, d, J = 5.6 Hz), 7.12 (2.H, d, J = 9.2 Hz), 7.37-7.48 (3H, m), 7.50 -7.56 (2H, m), 8.24 (2H, d, J=9.3 Hz), 8·55 (1H,d,J=5.6 Hz), 8.71 (1H, s) 4- 4-(4-nitrobenzene Oxy)-3-phenyl P ratio (150 j^g), iron powder (300 mg), ammonium chloride (600 mg), ethanol (5 ml), dimethylformamide (5 ml) and The water (2·5 ml) was stirred at 100 ° C for 15 minutes, filtered through celite, and water was added to the mash and extracted with ethyl acetate. After the organic layer was washed with water for 5 times, the solvent was evaporated under reduced pressure. 4-(3-Phenylpyrimidin-4-yl)oxyaniline (84 mg) was obtained as a yellow oil. NMR (CDC13) 5 (ppm): 6.65-6.74 (3H, m), 6.88 (2H, d, J=8.8 Hz), 7.36-7.50 (3H, m), 7.64 (2H, d, J=8.8 Hz), 8.34 (1H, dd, J=5.6 Hz, J=0.8 Hz), 8 · 54 (1H, s). Example 126 (i,7-dimethyl-oxy-n-hydroxypyran-4-yl)oxypropane p-N,-(4-gaso) 6,7-dimethyl Oxy-4-(3-aminopropoxy) 4^林15〇1^(0.57 1111^) and ethyl acetate (20 ml) were added at room temperature with stirring. Purpose (0.078 ml, 0.68 mM) and stir 1 5 minutes. The precipitated solid was filtered to give crystals (yield: mp. Hz), 3.36 (2H, t, J=6.0 Hz), 3.89 (3H, s), 3.91 (3H, s), 4.27 (2H, t, J=6.0 Hz), 6.29 (1H, t, J=6.0 Hz), 6.88 (1H, d, J=5.2 Hz), 7.00-7.07 (2H, m), 7.31 (1H, s), 7.34-7.41 (3H, m), 8.47 (1H, s), 8.51 (1H ,d,J=5.2 Hz). -228- This paper size applies to Chinese National Standard (CMS) A4 specification (210 x 297 mm) 1304061

如下述合成原料及中間體。 126-1 6,7i·^〒蓋棊二胺某丙氣基）4说 將6,7-—甲氧基-4-羥基喹啉（4.0 g，ΐ9·5 mM)，N-(3-溴 丙基）i太醯亞胺（5·8 g，21·5 mM)，碳酸鉀（5·4 g , 39 mM) 及二甲基甲醯胺（20 ml)於6(TC攪拌1.5小時。在反應液中加 入水，乙酸乙酯及四氫呋喃及萃取。放置一會兒後濾取析 出之固a豆’侍到N-(3-(6,7-二甲氧基P奎林.4-基氧）丙基） 醯亞胺（1·1 g)。 ^-NMR (DMSO-d6) 5 (ppm): 2.22 (2H, tt, J=6.0 Hz, J=6.〇 Hz), 3.82 (3H, s), 3.86 (2H, t, J=6.0 Hz), 3.90 (3H, s), 4.29 (2H, t, J=6.0 Hz), 6.82 (1H, d, J=5.2 Hz), 7.27 (1H, s), 7.31 (1H, s)，7.77-7.84 (4H，m)，8·49 (1H，d，J=5.2 Hz)。 將N-(3-(6,7-二甲氧基喹啉-4-基氧）丙基）醯亞胺（6〇〇 mg，1·53 πτΜ)，月井 1 水合物（300 mg，6.12 mM)，乙醇（5 ml)，曱醇（5 ml)及四氫吱喃（5 ml)於回流·下攪掉2小時。將 溶媒減壓餾去，以及將殘餘物用矽凝膠層析（富士希利希亞 NH型矽凝膠，氯仿：甲醇=20 : 1)精製，得到為褐色油狀 物之目的物（150 mg) β lH-NMR (DMSO-d6) 5(ppm): 1.93 (2H, tt, J=6.0 Hz, J-6.0The starting materials and intermediates are synthesized as follows. 126-1 6,7i·^〒盖棊Diamine a propane group) 4 said 6,7--methoxy-4-hydroxyquinoline (4.0 g, ΐ9·5 mM), N-(3- Bromopropyl)i sulphonimine (5·8 g, 21.5 mM), potassium carbonate (5·4 g, 39 mM) and dimethylformamide (20 ml) were stirred at 6 (TC for 1.5 hours) Water, ethyl acetate and tetrahydrofuran were added to the reaction mixture, and the mixture was extracted for a while, and then the precipitated solid a bean was filtered out to serve N-(3-(6,7-dimethoxyP-quinolin.4-yl). Oxy)propyl) quinone imine (1·1 g). ^-NMR (DMSO-d6) 5 (ppm): 2.22 (2H, tt, J=6.0 Hz, J=6.〇Hz), 3.82 (3H , s), 3.86 (2H, t, J=6.0 Hz), 3.90 (3H, s), 4.29 (2H, t, J=6.0 Hz), 6.82 (1H, d, J=5.2 Hz), 7.27 (1H , s), 7.31 (1H, s), 7.77-7.84 (4H, m), 8.49 (1H, d, J = 5.2 Hz). N-(3-(6,7-dimethoxyquine)啉-4-yloxy)propyl) quinone imine (6 〇〇 mg, 1.53 πτΜ), Moon Well 1 hydrate (300 mg, 6.12 mM), ethanol (5 ml), sterol (5 ml) Tetrahydrofuran (5 ml) was stirred under reflux for 2 hours, the solvent was distilled off under reduced pressure, and the residue was applied to silica gel chromatography (Fuji-Hilichia NH-type gel, chloroform) :Methanol = 20 : 1) Purified to give the title compound as a brown oil (150 mg). &lt;1&gt;H-NMR (DMSO-d6) 5 (ppm): 1.93 (2H, tt, J = 6.0 Hz, J-6.0

Hz)，2.77 (2H，t，J=6.0 Hz)，3·88 (3H，s)，3·91 (3H，s)，4·29 (2H, t, J=6.0 Hz), 6.89 (1H, d, J=5.2 Hz), 7.31 (1H, s), 7.34 (1H, s)，8.51 (1H，d, J=5.2 Hz)。 ， 實施例127 _-229-Hz), 2.77 (2H, t, J = 6.0 Hz), 3·88 (3H, s), 3·91 (3H, s), 4·29 (2H, t, J = 6.0 Hz), 6.89 (1H , d, J = 5.2 Hz), 7.31 (1H, s), 7.34 (1H, s), 8.51 (1H, d, J = 5.2 Hz). , Example 127 _-229-

本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 〜 -.- A7 B7 五、發明説明（224 ) N· 4- ( 6-氰基-7- f Π -甲基六新^比症-3 -基）甲氣某）-4- 口奎味甚） 氧-2-氣苽某VN1&quot;4-氣苯某）胧 將6-氰基-4-(4-(4-氟苯胺羰基）胺基-3-氟苯氧基）喹啉· 7 -醇倒（222 mg)，破酸4甲（162 mg)及3 -氯甲基-1-甲基六氫 吡啶鹽酸鹽（86 mg)懸浮於二甲基甲醯胺（1.7 ml)，於70-80 °C攪拌整夜後，加入水，用四氩呋喃及乙酸乙酯之混合溶 媒萃取，減壓濃縮及將殘餘物用NH矽凝膠（希利希亞化學 公司製）精製。將得到之固體用乙醚洗淨，乾燥及得到標題 化合物（10 mg)。 MS光譜：544 (M+ 1) 1H-NMR光譜：（DMSO-d6)1.30-2.70 (12H，m)，4.17 (2H，d， J=6.7 Hz), 6.61 (1H, d, J=5.0 Hz), 7.06-7.18 (3H, m), 7.36^ 7.50 (3H，m)，7·60 (1H，s)，8.20-8.28 (1H，m)，8·63 (1H，s)， 8·74 (1H，d，J=5.0 Hz)，8·75 (1H，s)，9·10 (1H，s)。 實施例128 ' !^-(3-(5,6-二甲基-4-711-叶1：哈并『2,3-(11喊咬基&gt;)氣笨基）二 ΝΉ-氣茉某 將4-胺基-(3-胺基苯氧基）-5,6-二曱基-711-吡咯并[2,3-(1] 嘧啶（27 mg)於回流下溶於甲苯（1 ml)及乙腈（〇·5 ml)中 後，加入異氰酸4-氟苯基酯（13 ·3 # M)。攪拌1小時，回到 室溫後’；慮取析出之結晶’得到標題化合物（2 6 m g)。 MS(ESI) m/z 392(M+1) lH-NMR (DMSO-d6)(5(ppin): 2.31 (3H, s), 2.46-2.50 (3H, m), 6.78-7.48 (8H, m), 8.14 (1H, s), 8.52 (1H, s), 8.82 (1H, s), -230- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) A7 B7 1304061 五、發明説明（225 ) 11.79 (1H，s)。 如下述合成中間體。 製造例128-1 4-(3-殖j苯氣基）-5,6-二甲基-7H-吡咯#「2.3-dl-嘧生 在 Journal of Medicinal Chemistry，1996，vol· 39，Nol2 2285-2292 έ己載之4-氣-5,6-二甲基-7H-p比哈并[2,3-d]-σ密淀 (177 mg)中加入3-硝基酚（243 mg)，碳酸鉀（268 mg)及二 甲基甲酿胺（2 ml) ’並於120-130C授掉72小時β返回室溫 後加入水，用四氫呋喃與乙酸乙酯之混合溶液萃取，有機 層用飽和食鹽水洗淨，藉由無水硫酸鈉乾燥後濃縮乾固。 將得到之結晶用乙醚洗淨，得到標題化合物（13〇 mg)。 MS(ESI) m/z 285(M+1) lH-NMR (DMS0-d6) δ (ppm): 2.31 (3H, s), 2.46-2.50 (3H, m), 7.70-8.18 (5H，m)，11.89 (1H，s)。 製造例128-爻 4- (―3-胺基笨氣基）-5,6-二甲基-7H- p比洛并T 2·3- dl ·邊症 在藉由上述中間合成法合成之4-( 3-硝基苯氧基）-5,6-二 甲基-7H-吡咯并[2,3-d] -嘧啶（11〇 mg)中，加入鐵粉（0.12 g)，氯化銨（0.24 g)，乙醇（5 ml)及水（1 ml)，並於 80-90°C 攪拌3小時。使反應系統回到室溫後，加入四氫呋喃（3 mi) 及乙酸乙酯（3 ml)及經矽藻土過濾，將濾液用乙酸乙酯分 液，以及將有機層用水及飽和食鹽水依次洗淨。用硫酸鈉 乾燥後，減壓濃縮乾固，用乙醚洗淨，得到標題化合物（37 mg)。 -231 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 ~ -.- A7 B7 V. Description of invention (224) N· 4- (6-Cyano-7- f Π-methyl Six new ^ ratio disease -3 - base) A gas) -4- mouth quetiam even) oxy-2-gas 苽 a VN1 &quot; 4-gas benzene a) 胧 6-cyano-4-(4-( 4-fluoroanilinecarbonyl)amino-3-fluorophenoxy)quinoline·7-ol pour (222 mg), acid-breaking 4A (162 mg) and 3-chloromethyl-1-methylhexahydropyridine The hydrochloride (86 mg) was suspended in dimethylformamide (1.7 ml). After stirring overnight at 70-80 ° C, water was added, and the mixture was extracted with tetrabromofuran and ethyl acetate. The residue was purified by NH(R) gel (manufactured by Hillitech Chemical Co., Ltd.). The obtained solid was washed with diethyl ether and dried and evaporated MS spectrum: 544 (M+ 1) 1H-NMR spectrum: (DMSO-d6) 1.30-2.70 (12H, m), 4.17 (2H, d, J = 6.7 Hz), 6.61 (1H, d, J = 5.0 Hz) , 7.06-7.18 (3H, m), 7.36^ 7.50 (3H,m),7·60 (1H,s),8.20-8.28 (1H,m),8·63 (1H,s), 8·74 ( 1H, d, J = 5.0 Hz), 8·75 (1H, s), 9·10 (1H, s). Example 128 ' !^-(3-(5,6-dimethyl-4-711-leaf 1: ha and "2,3-(11 shouting base)) gas-based base) 4-Amino-(3-aminophenoxy)-5,6-dimercapto-711-pyrrolo[2,3-(1]pyrimidine (27 mg) was dissolved in toluene under reflux (1) After adding ml) and acetonitrile (〇·5 ml), add 4-fluorophenyl isocyanate (13 ·3 # M). Stir for 1 hour, return to room temperature '; consider the precipitated crystal' to get the title Compound (2 6 mg) MS (ESI) m/z 399 (M+1) NMR (DMSO-d6) (5 (pp): 2.31 (3H, s), 2.46-2.50 (3H, m), 6.78-7.48 (8H, m), 8.14 (1H, s), 8.52 (1H, s), 8.82 (1H, s), -230- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297) A7 B7 1304061 V. INSTRUCTIONS (225) 11.79 (1H, s). Synthesis of intermediates as follows. Production example 128-1 4-(3-colonylbenzene)-5,6-dimethyl -7H-pyrrole #"2.3-dl-pyrazine in the Journal of Medicinal Chemistry, 1996, vol. 39, Nol 2 2285-2292 4--loaded 4-gas-5,6-dimethyl-7H-p than Haha 3-Nitrophenol (243 mg), potassium carbonate (268 mg) and dimethyl ketoamine were added to [2,3-d]-σ-dense (177 mg) 2 ml) ', and allowed to return to room temperature at 120-130 C for 72 hours. After returning to room temperature, water was added, and the mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained crystals were washed with diethyl ether to give the title compound (ljjmjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj s), 2.46-2.50 (3H, m), 7.70-8.18 (5H, m), 11.89 (1H, s). Production Example 128-爻4- (3-amino-based stupid)-5,6- Dimethyl-7H-ppirin and T 2·3- dl · edge disease in 4-(3-nitrophenoxy)-5,6-dimethyl-7H- synthesized by the above intermediate synthesis method To pyrrodo[2,3-d]-pyrimidine (11〇mg), iron powder (0.12 g), ammonium chloride (0.24 g), ethanol (5 ml) and water (1 ml) were added, and at 80- Stir at 90 ° C for 3 hours. After the reaction system was returned to room temperature, tetrahydrofuran (3 mi) and ethyl acetate (3 ml) were added and filtered over celite, and the filtrate was partitioned with ethyl acetate, and the organic layer was washed with water and saturated brine. net. The title compound (37 mg) was obtained. -231 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm).

線 1304061 s — A7 ___—__B7 五、發明説明（226 ) lH-NMR (DMSO-d6) (5 (ppm)： 2.27 (3H, s), 2.29 (3H, s), 5.15-5.24 (2H, m), 6.28 (1H, d, J=8.l Hz), 6.32 (1H, s), 6.40 (1H, d, J=8.1 Hz)，7.01 (1H，t，Hz)，8 12 (1H，s)，u 72 (1H，s)。 f施例129 N-6-_(16·，7-二甲.氧基啐啉氣^)·3·吡啶某·Ν，·苇其砷 將6-((6,7-二甲氧基-4-喳啉基）氧卜3-吡啶胺（59 5 mg , 200 mmol)及異氰酸苯 g旨（26.2 mg , 220 mmol)溶於 N，N-二 甲基甲醯胺（1 ml)中，並於室溫攪拌18小時。將反應液用 乙酸乙酯稀釋後，用水及飽和食鹽水洗淨，將有機層用無 水硫酸鎂乾燥，濾除乾燥劑，以及減壓餾去濾液。將得到 之粗製物懸浮於乙酸乙酯中，將其用己烷稀釋，濾取結晶 及用乙酸乙酯洗淨後，藉由通風乾燥得到為無色結晶之標 遞化合物（68 mg，163 mmol，82%)。 H-NMR光 |f(DMSO-d6)5(ppm): 3·90 (3H，s)，3·95 (3H，s)， 6.55 (1Η, d, J=5.2 Hz), 6.96-7.02 (1H, m)3&gt;.26-7.32 (3H, m), 7.40 (1H, s), 7·41 (1H, s), 7·47 (2H, d，J=8.4 Hz), 8·14 (1H, dd, J=2.8, 8.8 Hz), 8.35 (2H, d, 1=2.8 Hz), 8.55 (1H, d, &gt;5·2 Hz)，8·89 (1H，s), 8·99 (1H，s)。 中間體如下述合成。 製造例12H_ U -二甲.I基-4 - (( 5 -硝基-2 -吡啶某、氧）。套,林一 將6,7-二曱氧基-L4-二氫-4-喹啉（4.1Ό g，2〇·〇 mmol)， 2-溴-5-硝基吡啶基（4.46 g，22·0 mmol)及碳酸鉀（5·53 g， __ -232- ___ 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061Line 1304061 s — A7 ___—__B7 V. Description of invention (226) lH-NMR (DMSO-d6) (5 (ppm): 2.27 (3H, s), 2.29 (3H, s), 5.15-5.24 (2H, m ), 6.28 (1H, d, J=8.l Hz), 6.32 (1H, s), 6.40 (1H, d, J=8.1 Hz), 7.01 (1H, t, Hz), 8 12 (1H, s ), u 72 (1H, s). f Example 129 N-6-_(16·,7-dimethyloxoxyporphyrin gas^)·3·pyridine·····苇 砷 arsenic will be 6- ((6,7-Dimethoxy-4-indolyl)oxypyridinium 3-pyridinamine (59 5 mg, 200 mmol) and phenyl isocyanate (26.2 mg, 220 mmol) dissolved in N, N - dimethylformamide (1 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate. The desiccant and the filtrate were evaporated under reduced pressure. The obtained crude product was suspended in ethyl acetate, diluted with hexane, filtered, and washed with ethyl acetate. Standard compound (68 mg, 163 mmol, 82%) H-NMR light |f (DMSO-d6) 5 (ppm): 3·90 (3H, s), 3·95 (3H, s), 6.55 ( 1Η, d, J=5.2 Hz), 6.96-7.02 (1H, m)3&gt ;.26-7.32 (3H, m), 7.40 (1H, s), 7·41 (1H, s), 7·47 (2H, d, J=8.4 Hz), 8·14 (1H, dd, J =2.8, 8.8 Hz), 8.35 (2H, d, 1=2.8 Hz), 8.55 (1H, d, &gt;5·2 Hz), 8·89 (1H, s), 8·99 (1H, s) The intermediate was synthesized as follows. Production Example 12H_U-dimethyl.I-based-4 - ((5-nitro-2-pyridyl, oxy). Set, Linyi 6,7-dimethoxy-L4 -Dihydro-4-quinoline (4.1Ό g, 2〇·〇mmol), 2-bromo-5-nitropyridinyl (4.46 g, 22.0 mmol) and potassium carbonate (5·53 g, __ - 232- ___ This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 1304061

40.0 mmol)加至n，N-二甲基甲醯胺（20 ml)中，並於70。〇加 熱攪拌3小時。將反應液用乙酸乙酯稀釋，並濾去不要物 後’用水及飽和食鹽水洗淨，將有機層用無水硫酸鎂乾燥 後，濾除乾燥劑，及將濾液減壓蒸餾除去。將得到之粗製 生成物進行矽凝膠管柱層析（溶出液：乙酸乙酯系），濃縮 包含目的物之溶出份，使其懸浮於乙酸乙酯中，將其用己 燒稀釋，濾取結晶，及用己烷洗淨後通風乾燥，得到為黃 色結晶之標題化合物（2.23 g，6.81 mmol，34%)。 H-NMR 光 if :(CDC13) 3·95 (3H，s)，4·06 (3H，s)，7.07 (1H， d, J=5.2 Hz), 7.16 (1H, s), 7.26 (1H, d, J=8.8 Hz), 7.49 (1H, s), 8.60 (1H, dd, J=2.8, 8.8 Hz), 8.74 (1H, d, J=5.2 Hz), 9.08 (1H，d，J=2.8 Hz)。 製造例129-2 6:_.(.(6,7-二甲氣某杳啉基）氣毗冷眩 將6,7- —叉氧基-4- (( 5-硝基-2- ρ比咬基）氧），奎〃林（654 mg， 2.00 mmol)，鐵（559 mg，10.0 mmol)及遺化銨（1.07 g， 20·0 mmol)在乙醇（2〇 mi)-水（5 ml)中，於80°C加熱攪掉20 分鐘。反應終了後，將反應混合物經矽藻土過濾，用乙酸 乙酯洗出。將有機層用水及飽和食鹽水洗淨，用硫酸鎂乾 燥後，濾除乾燥劑及將濾液減壓蒸餾。將得到之粗生成物 懸浮於乙酸乙酯中，將其用己烷稀釋，濾取結晶，及用乙 酸乙酯稀釋後，通風乾燥，得到為淡黃色結晶之標題化合 物（380 mg，1.28 mmol，64%)。 j-NMR光譜：（CDC13) 3·73 (2H，s)，4.02 (3H，s)，4·04 (3H， -233- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 x 297公釐) 1304061 〜 A7 ____B7 五、發明説明（228 ) s), 6.61 (1H, d, J=5.2 Hz), 6.96 (1H, d, J=8.8 Hz), 7.18 (1H5 dd, J=2.8，8.8 Hz), 7.41 (1H，s)，7.53 (iH, s)，7·85 (1H，d, J=2.8 Hz)，8·54 (1H，d，J=5.2 Hz)。 實施例130 乒甲氧基-4_呤啉基）氧）-3 -吡啶基-N，- (4-氣笨 基）脲 藉由與實施例129同樣之方法，從異氰酸4_氟苯酯（3〇.i mg ’ 220 mmol)仔到為供色結晶之標題化合物（67 mg，1 54 mmol，77%)。 iH-NMR 光譜：（DMS〇-d6) 3.89 (3H，S)，3.95 (3H，s)，6.79 (1H, d, J—5.0 Hz), 7.11-7.16 (2H, m), 7.29 (1H, d, J=8.6 Hz), 7·39 (1H, s), 7.41 (1H, s), 7.45轉7.51 (2H, m)，8·13 (1H, dd， J=2.6, 8.6 Hz), 8.34 (1H, d3 J=2.6 Hz), 8.55 (1H, d, J=5.0 Hz), 8·93 (1H，s)，8.99 (1H，s) 〇 實施例131、 K- 6- ( 二甲基-4- 口奎淋基）氣）-3-说咬-基-N1 - Π ,3- 口拿岫-2-墓）脲 將實施例129所得之6-((6,7-二曱氧基-4-喹啉基）氧）-3-吡啶胺（89.1 mg，300 mmol)及N-( 2-噻唑基）胺基甲酸苯酯 (79.3 mg，3 60 mmol)在二曱基亞颯（1 ml)中，於85°C 授摔 1 小時。將反應液用乙酸乙酯稀釋後，用水及飽和食鹽水洗 淨，將有機層用無水硫酸鍰乾燥，濾除乾燥劑，及減签館 去)慮液β將仔到之粗生成物懸浮於乙酸乙S旨中，將其用己 烷稀釋，濾取結晶，及用乙酸乙酯稀釋後，通風乾燥，得 -234- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（229 到為供色結晶之標題化合物（88 mg，208 mmol，69%)。 iH-NMR 光譜：（DMSO-d6) 3·89 (3H，s)，3·95 (3H，s)，6.81 (1H，d，J=5.2 Hz)，7.12 (1H，d，J=3.6 Hz)，7.31 (1H，d，J=8.8 Hz), 7.36-7.40 (2H, m), 7.42 (1H, s), 8.18 (1H, dd5 J=2.8, 8.8 Hz), 8.37 (1H, d, J=2.8 Hz), 8.56 (1H, d, J=5.2 Hz), 9.30 (1H，s) 〇 實施例132 4-(-5-((笨胺羰基）胺某v 2-吡啶氳）·7_曱氣基-6-崦啉羧’ 藉由與實施例129同樣之方法，從4-((5-胺基-2-吡啶基） 氧）-7-曱氧基-6-喹啉羧醯胺（55 ·0 mg，177 mmol)得到為無 巴結晶之標題化合物（59 mg，137 mmol，78%)。 iH-NMR 光譜：（DMSO-d6) 4·04 (3H，s)，6.86 (1H，d，J=5.2 Hz), 6.96-7.02 (1H, m), 7.26-7.34 (3H, m), 7.47 (2H, d, J-7.6 Hz), 7.,54 (1H, s), 7.74 (1H, s), 7.86 (1H, s), 8.15 (1H, dd，J=2.8, 8·8 Hz)，8.36 (1H，d，J=2.8 Ηζ)，'8·55 (1H，s)，8.75 (1H，d，J=5.2 Hz), 8·90 (1H，s)，9.01 (1H，s)。 中間體如下述合成。 製造例132-1 7 Έ乳基-心（（5 -石肖基-2-ρ比咬基）氣）-6 -咬琳技酿胺 藉由與實施例129同樣之方法，從W0 98/13350記載之7-甲氧基· 4-嗣基-1，4-二氫-6- 4 σ林幾酷胺經加水分解所衍生 之7-甲氧基-4-酮基-1,4-二羥基-6-喹啉羧醯胺（1.09 g， 5 · 0 0 mm ο 1) ’得到為黃巴結晶之標題化合物（9 3.0 m g，2 7 3 -235- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 裝 訂40.0 mmol) was added to n,N-dimethylformamide (20 ml) at 70. Heat and stir for 3 hours. The reaction mixture was diluted with ethyl acetate, and the residue was filtered, washed with water and brine, and dried over anhydrous magnesium sulfate. The obtained crude product was subjected to hydrazine gel column chromatography (eluent: ethyl acetate), and the fractions containing the desired product were concentrated, suspended in ethyl acetate, diluted with hexane, and filtered. The title compound (2.23 g, 6.81 mmol, 34%). H-NMR light if: (CDC13) 3·95 (3H, s), 4·06 (3H, s), 7.07 (1H, d, J = 5.2 Hz), 7.16 (1H, s), 7.26 (1H, d, J=8.8 Hz), 7.49 (1H, s), 8.60 (1H, dd, J=2.8, 8.8 Hz), 8.74 (1H, d, J=5.2 Hz), 9.08 (1H,d,J=2.8 Hz). Production Example 129-2 6: _. (. (6,7-dimethyl porphyrinyl) gas adjacent to cold glare 6,7---dioxy-4- (( 5-nitro-2- ρ Oxygen), quetiapine (654 mg, 2.00 mmol), iron (559 mg, 10.0 mmol) and ammonium (1.07 g, 20 mmol) in ethanol (2〇mi)-water (5 In ml), the mixture was stirred and heated at 80 ° C for 20 minutes. After the reaction was completed, the reaction mixture was filtered over EtOAc (EtOAc)EtOAc. The desiccant is filtered off and the filtrate is distilled under reduced pressure. The obtained crude product is suspended in ethyl acetate, diluted with hexane, filtered, crystallised, and diluted with ethyl acetate. The title compound (380 mg, 1.28 mmol, 64%) mp.: NMR: (CDC13) 3·73 (2H, s), 4.02 (3H, s), 4·04 (3H, -233- The paper scale applies to the Chinese National Standard (CNS) Α4 specification (210 x 297 mm) 1304061 ~ A7 ____B7 V. Invention description (228) s), 6.61 (1H, d, J=5.2 Hz), 6.96 (1H, d, J=8.8 Hz), 7.18 (1H5 dd, J=2.8, 8.8 Hz), 7.41 (1H, s), 7.53 (i H, s), 7.85 (1H, d, J = 2.8 Hz), 8.54 (1H, d, J = 5.2 Hz). Example 130 phenoxy-4- oxalinyl) oxy)- 3-Pyridyl-N,-(4-carboyl)urea was prepared from the mixture of 4-fluorophenyl isocyanate (3 〇.i mg '220 mmol) in the same manner as in Example 129. The title compound was crystallized (67 mg, 1 54 mmol, 77%). iH-NMR spectrum: (DMS〇-d6) 3.89 (3H, S), 3.95 (3H, s), 6.79 (1H, d, J-5.0 Hz), 7.11-7.16 (2H, m), 7.29 (1H, d, J=8.6 Hz), 7·39 (1H, s), 7.41 (1H, s), 7.45 to 7.51 (2H, m), 8.13 (1H, dd, J=2.6, 8.6 Hz), 8.34 (1H, d3 J=2.6 Hz), 8.55 (1H, d, J=5.0 Hz), 8·93 (1H, s), 8.99 (1H, s) 〇 Example 131, K-6- (dimethyl -4- mouth quinolyl) gas) -3- said bite-based-N1 - Π, 3-mouth 岫 墓 墓 墓 ) 脲 脲 脲 脲 脲 将 将 将 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 实施 6 6 6 4--4-quinolinyloxy)-3-pyridinamine (89.1 mg, 300 mmol) and N-(2-thiazolyl)carboxylate (79.3 mg, 3 60 mmol) in dimercaptopurine In (1 ml), drop at 85 ° C for 1 hour. After diluting the reaction mixture with ethyl acetate, washing with water and saturated brine, drying the organic layer with anhydrous barium sulfate, filtering off the desiccant, and reducing the amount of the solution to suspend the crude product. In the purpose of acetic acid B, it is diluted with hexane, filtered and crystallized, and diluted with ethyl acetate, then ventilated and dried to obtain -234- the paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm). 1304061 A7 B7 V. Inventive Note (229 to the title compound for coloring (88 mg, 208 mmol, 69%). iH-NMR spectrum: (DMSO-d6) 3·89 (3H, s), 3· 95 (3H, s), 6.81 (1H, d, J = 5.2 Hz), 7.12 (1H, d, J = 3.6 Hz), 7.31 (1H, d, J = 8.8 Hz), 7.36-7.40 (2H, m ), 7.42 (1H, s), 8.18 (1H, dd5 J=2.8, 8.8 Hz), 8.37 (1H, d, J=2.8 Hz), 8.56 (1H, d, J=5.2 Hz), 9.30 (1H, s) 〇 Example 132 4-(-5-((stupylcarbonyl)amine) v-pyridinium)·7_fluorenyl-6-carboline carboxylic acid' 4-((5-Amino-2-pyridyl)oxy)-7-decyloxy-6-quinolinecarboxamide (55.0 mg, 177 mmol) gave the title Compound (59 mg, 137 mmol, 78%). iH-NMR spectrum: (DMSO-d6) 4·04 (3H, s), 6.86 (1H, d, J = 5.2 Hz), 6.96-7.02 (1H, m ), 7.26-7.34 (3H, m), 7.47 (2H, d, J-7.6 Hz), 7.,54 (1H, s), 7.74 (1H, s), 7.86 (1H, s), 8.15 (1H , dd, J=2.8, 8·8 Hz), 8.36 (1H, d, J=2.8 Ηζ), '8·55 (1H, s), 8.75 (1H, d, J=5.2 Hz), 8·90 (1H, s), 9.01 (1H, s). The intermediate was synthesized as follows. Production Example 132-1 7 Έ 乳-心 ((5 - 石 肖基-2-ρ比咬) gas)-6 - 咬琳The hydrolyzed amine was hydrolyzed from 7-methoxy-4-indolyl-1,4-dihydro-6- 4 sylinolamine described in WO 98/13350 by the same method as in Example 129. Derivatized 7-methoxy-4-keto-1,4-dihydroxy-6-quinolinecarboxamide (1.09 g, 5 · 0 0 mm ο 1) 'The title compound was obtained as yellow crystals. 3.0 mg, 2 7 3 -235- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) Binding

線 1304061 一 ~ A7 __B7______ 五、發明説明（230 ) mmol，5%)。 W-NMR光譜：（CDC13) 4.15 (3H，s)，5·92 (1H，s)，7·21 (1H， d，J=5.2 Ηζ)，7.35 (1Η，d，J=9.2 Ηζ)，7·63 (1Η，s)，7·79 (1Η， s), 8.62 (1H, dd, J=2.8, 8.8 Hz), 8.94 (1H, d, J=5.2 Hz), 8.96 (1H，s)，9.02 (1H，d，J=5.2 Hz)。 製造例132-2 心(75-脖篡-2-吡啶基）氲T氧幕- 6-p杳啉羧醯胺- 將7-甲氧基- 4-((5-硝基-2-吡啶基）氧）-6-喹啉羧醯胺 (93.0 mg，273 mmol)，鐵粉（76·0 mg，1.36 mmol)及氯化 按（146 mg，2·73 mmol)在乙醇（4 ml)-水（1 ml)中’於80C 加熱攪拌20分鐘。反應終了後，將反應混合物經矽藻土過 濾，用乙酸乙酯-四氫呋喃混合溶媒洗出。將有機層用水及 飽和食鹽水洗淨及用無水硫酸鎂乾燥後，濾除乾燥劑及將 濾液減壓蒸餾。將得到之粗生成物付諸於矽凝膠管柱層析 (溶出液：二酸乙酯：甲醇=20 : 1)，將包含目的物之溶出 份濃縮，然後懸浮於乙酸乙酯中，將其疴己烷稀釋，遽取 結晶，及用己烷洗淨後，通風乾燥，得到為黃色結晶之標 題化合物（61.0 mg，197 mmol，72%)。 lH-NMR 光譜：（DMS〇-d6) 4.03 (3H，s)，6.60 (1H，d, J=5.4Line 1304061 A ~ A7 __B7_________ V. Description of the invention (230) mmol, 5%). W-NMR spectrum: (CDC13) 4.15 (3H, s), 5.92 (1H, s), 7·21 (1H, d, J = 5.2 Ηζ), 7.35 (1Η, d, J=9.2 Ηζ), 7·63 (1Η, s), 7.79 (1Η, s), 8.62 (1H, dd, J=2.8, 8.8 Hz), 8.94 (1H, d, J=5.2 Hz), 8.96 (1H, s) , 9.02 (1H, d, J = 5.2 Hz). Production Example 132-2 Heart (75-neck-2-pyridyl) 氲T-oxygen curtain - 6-p porphyrin carboxy guanamine - 7-methoxy-4-((5-nitro-2-pyridine) Oxy)-6-quinoline carboxamide (93.0 mg, 273 mmol), iron powder (76·0 mg, 1.36 mmol) and chlorinated (146 mg, 2.73 mmol) in ethanol (4 ml) - Stir in water (1 ml) at 80 C for 20 minutes. After the reaction was completed, the reaction mixture was filtered through Celite, and washed with ethyl acetate-THF. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The obtained crude product was subjected to column chromatography on a gel column (eluent: ethyl diacetate: methanol = 20:1), and the fraction containing the desired product was concentrated, and then suspended in ethyl acetate. The title compound (61.0 mg, 197 mmol, 72%) was obtained as yellow crystals. lH-NMR spectrum: (DMS〇-d6) 4.03 (3H, s), 6.60 (1H, d, J=5.4

Hz), 7.04 (1H, d, J=8.4 Hz), 7.18 (1H, dd5 J=2.6, 8.6 Hz), 7·50 (1H，s)，7·68 (1H，d，J=2.6 Hz)，7·73 (1H, s)，7,86 (1H， s)，8.61 (1H，s)，8·67 (1H，d，J=5.4 Hz)。 實施例133 ，· 第‘基-7-((3-甲續酿基)丙乳基林基）氧.2 -举· -236 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) ' ' 1304061Hz), 7.04 (1H, d, J=8.4 Hz), 7.18 (1H, dd5 J=2.6, 8.6 Hz), 7·50 (1H, s), 7·68 (1H, d, J=2.6 Hz) , 7.73 (1H, s), 7, 86 (1H, s), 8.61 (1H, s), 8.67 (1H, d, J = 5.4 Hz). Example 133, · 'K- 7-((3-methyl continuation) propyl lactyl) Oxygen. 2 - Lift · -236 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) ' '1304061

五、發明説明（ A7 B7V. Description of the invention (A7 B7

氣茉某）脲 以與實施例7同樣之方法，從6•氰基·4·{4_[4_氟苯胺羰 基]胺基-3-氟苯氧基}喹啉基醇鈉鹽（1〇〇 mg)得到標^ 化合物67 mg βUrea urea in the same manner as in Example 7, from 6 • cyano·4·{4_[4-fluoroanilinocarbonyl]amino-3-fluorophenoxy}quinolyl alcohol sodium salt (1〇 〇mg) to obtain the standard compound 67 mg β

lH«NMR (DMS〇.d6)&lt;5(ppm)： 2.24-2.32 (2H, m), 3.05 (3H, s) 3.30-3.35 (2H, m), 4.42 (2H, t, J=6 Hz), 6.63 (1H, d, J=5.6 Hz)，7.11-7.15 (3H，m)，7.40 (1H，dd，J=2 8 Hz，J==8 〇 Hz)， 7.44^7.48 (2H, m), 7.63 (1H, s), 8.21-8.26 (1H, m), 8 64 (1H br)，8.75(1H，d，J=5.6Hz)，8.77(1H，s)，91〇(1H，br)。 ’ t施例134lH«NMR (DMS〇.d6)&lt;5(ppm): 2.24-2.32 (2H, m), 3.05 (3H, s) 3.30-3.35 (2H, m), 4.42 (2H, t, J=6 Hz ), 6.63 (1H, d, J=5.6 Hz), 7.11-7.15 (3H, m), 7.40 (1H, dd, J=2 8 Hz, J==8 〇Hz), 7.44^7.48 (2H, m ), 7.63 (1H, s), 8.21-8.26 (1H, m), 8 64 (1H br), 8.75 (1H, d, J = 5.6 Hz), 8.77 (1H, s), 91 〇 (1H, br ). Example 134

以與實施例7同樣之方法，從卜氰基心[心氟苯胺羰 裝 基]胺基-3-氟苯氧基}喹啉-7-醇鈉鹽（1()0 mg)得到標題化 合物30 mg lH-NMR (DMSO-d6) (5(ppm): 2.09 (3H, s), 5.06-2.14 (2H, m), 2.67 (2H，t，J=7.2 Hz)，4.37 (2H，t，J=6 Hz)，6·62 (1H，d， J=5.2 Hz)，7.10-7.15 (3H，m)，7·39 (1H，dd，j=2.8 Hz，J=7.6 Hz)，7.44-7.48 (2H，m)，7.60 (ih，s)，8·21-8·26 (1H，m)，8·65 (1H，br)，8·74 (1H，d，J=5.2 Hz)，8·75 (1H，s)，9·12 (1H，brd， J=3.2 Hz) 〇 實施例135 K.i二(,6-氰基-7-(3-(乙氧屋氣基奎氣氣 笨基氣芙某 -237- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公 訂In the same manner as in Example 7, the title compound was obtained from sodium cyano[CHF carbonyl]amino-3-fluorophenoxy}quinolin-7-ol sodium salt (1 () 0 mg). 30 mg lH-NMR (DMSO-d6) (5 (ppm): 2.09 (3H, s), 5.06-2.14 (2H, m), 2.67 (2H, t, J = 7.2 Hz), 4.37 (2H, t, J=6 Hz),6·62 (1H,d, J=5.2 Hz), 7.10-7.15 (3H,m),7·39 (1H,dd,j=2.8 Hz, J=7.6 Hz),7.44- 7.48 (2H,m), 7.60 (ih,s),8·21-8·26 (1H,m),8·65 (1H,br),8·74 (1H,d,J=5.2 Hz), 8·75 (1H, s), 9·12 (1H, brd, J=3.2 Hz) 〇 Example 135 Ki bis (6-cyano-7-(3-(ethoxy house) Base gas Fu-237- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 public order)

線 1304061 A7 B7Line 1304061 A7 B7

以與實施例7同樣之方法，從6-氰基-4-{4、[4、氣苯胺# 基]胺基-3氟苯氧基}喹啉基-7-醇鈉鹽（1 ·〇 g)得到標題化 合物8 5 0 m g ^ ^-NMR (DMSO-d6) 5 (ppm): 1.17 (3H, t, J-7.2 Hz), 2.05-2.13 (2H，m)，2.53 (2H，t，J=7.2 Hz)，4.07 (2H，q，j=7 2 Hz)， 4.31 (2H, t, J=6.4 Hz), 6.61 (1H, d, J=5.2 Hz), 7.1〇.7&lt;15 (3H m), 7.40 (1H, dd, J=2.8 Hz, J=7.6 Hz), 7.44-7.48 (2H m) 7·60 (1H，s)，8.22-8.27 (1H，m)，8·64 (1H，br)，8.74 (1H, d， J=5.2 Hz), 8.74 (1H，s)，9.10 (1H，br)。 實施例136 N- (4- ( 6-氰基-7-( 3 -讀基丙氧基）-4- 4 g沐基）氩-2-氣笨某）_ 氟笨某 將N-(4-(6-氰基- 7-(3-(乙氧羰基）丙氧基）-4-，奎琳基）氧_ 2-氟苯基）-Ν·-(4-氟苯基）月尿（ 800 mg)溶於曱醇（45 ml)，加 入2N NaOiT水溶液（15 ml)並於80eC加熱揽拌4〇分鐘。反應 終了後’將反應液注入冰水中，用IN HC_1中和以及濾取析 出之固體。將得到之固體水洗，乾燥，得到23〇 mg之標題 化合物。 lH-NMR (DMSO-d6) 5 (ppm): 2.01-2.08 (2H, m), 2.46 (2H, t, J-7.6 Hz)，4.30 (2H，t，J=6.4 Hz)，6·61 (1H，d，J=5.2 Hz)， 7.10-7.15 (3H, m), 7.39 (1H, dd, J=2.8 Hz, J=8.0 Hz), 7.44-7.48 (2H, m), 7.59 (1H, s), 8.21-8.26 (1H, m), 8.66 (1H, br), 8·73 (1H，d，J=5.2 Hz)，8·74 (1H，s)，9.13]1H, br)。 實施例137 -238- 本紙張尺度適用中國國家標準(CNS) A4規格（210X297公爱）In the same manner as in Example 7, a sodium salt of 6-cyano-4-{4, [4, aniline #yl]amino-3fluorophenoxy}quinolinyl-7-ol (1·〇) g) to give the title compound 8 5 0 mg ^^-NMR (DMSO-d6) 5 (ppm): 1.17 (3H, t, J-7.2 Hz), 2.05-2.13 (2H, m), 2.53 (2H, t, J=7.2 Hz), 4.07 (2H, q, j=7 2 Hz), 4.31 (2H, t, J=6.4 Hz), 6.61 (1H, d, J=5.2 Hz), 7.1〇.7&lt;15 ( 3H m), 7.40 (1H, dd, J=2.8 Hz, J=7.6 Hz), 7.44-7.48 (2H m) 7·60 (1H, s), 8.22-8.27 (1H, m), 8·64 ( 1H, br), 8.74 (1H, d, J = 5.2 Hz), 8.74 (1H, s), 9.10 (1H, br). Example 136 N-(4-(6-Cyano-7-(3-(l-propyloxy)-4- 4g)-argon-2-oxo)_Fluorum will be N-(4) -(6-Cyano-7-(3-(ethoxycarbonyl)propoxy)-4-, quinolinyl)oxy-2-fluorophenyl)-indole-(4-fluorophenyl) monthly urine (800 mg) was dissolved in decyl alcohol (45 ml), 2N aqueous NaNiT (15 ml) was added and stirred at 80 ° C for 4 min. After the reaction was completed, the reaction solution was poured into ice water, neutralized with IN HC_1, and the precipitated solid was collected by filtration. The solid obtained was washed with water and dried to give the title compound. lH-NMR (DMSO-d6) 5 (ppm): 2.01-2.08 (2H, m), 2.46 (2H, t, J-7.6 Hz), 4.30 (2H, t, J = 6.4 Hz), 6.61 ( 1H,d,J=5.2 Hz), 7.10-7.15 (3H, m), 7.39 (1H, dd, J=2.8 Hz, J=8.0 Hz), 7.44-7.48 (2H, m), 7.59 (1H, s ), 8.21-8.26 (1H, m), 8.66 (1H, br), 8·73 (1H, d, J = 5.2 Hz), 8.74 (1H, s), 9.13] 1H, br). Example 137 -238- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public)

裝 訂Binding

線 1304061 A7 __ B7 ___ 五、發明説明（233 ) N-(4-(6-氨某-7-(3-((環丙胺基）羰基）而氫某基） i-2-氣苯基氣笨基）脲 將N-(4-(6-氰基- 7-( 3-羧丙氧基）-4-峻啉基）氧-2-氟苯 基）-N’-(4-氟苯基）脲（1〇〇 mg)溶於二甲基甲醯胺（3 ml)， 於冰冷及攪拌下，加入1-乙基-3-(3-二甲胺丙基）羧醯亞胺 (44 mg)及1-羥基-1H-苯并三唑（35 mg)並於室溫攪捽30分 鐘。接下來，加入環丙胺（16微升）並於室溫攪拌18小時。 反應終了後，將反應液注入1N氫氧化鈉水溶液中及用乙酸 乙酯萃取，將得到之有機層用飽和食鹽水洗淨及用硫酸鎂 乾燥。將有機層濃縮，將得到之固體用乙醚及少量乙酸乙 S旨洗淨’得到標題化合物3 8 mg。 !H-NMR (DMSO-d6) (5 (ppm): 0.34-0.38 (2H, m), 0.54-0.59 (2H, m), 1.99-2.06 (2H, m), 2.25 (2H, t, J=7.2 Hz)3 2.56-2.63 (1H, m), 4.27 (2H, t5 J=6.4 Hz), 6.60 (1H, d, J=5.2 Hz), 7.10-7.15 (JH, m), 7.39 (1H, dd, J=2.8 Hz, J=8.0 Hz), 7.44-7.49 (2H, m), 7.59 (1H, s), 7.95 (1H, brd；%J=3.6 Hz), 8.21- S.25 (1H, m), 8.67 (1H, br), 8.73 (1H, d5 J=5.2 Hz), 8.74 (1H, s)，9·15 (1H，br) 〇 裝 訂Line 1304061 A7 __ B7 ___ V. Description of the invention (233) N-(4-(6-Ammonia-7-(3-((cyclopropylamino)carbonyl)))) U-(4-(6-cyano-7-(3-carboxypropoxy)-4-bromo)oxy-2-fluorophenyl)-N'-(4-fluorobenzene Urea (1 mg) was dissolved in dimethylformamide (3 ml), and 1-ethyl-3-(3-dimethylaminopropyl)carboxamide was added under ice-cooling and stirring. 44 mg) and 1-hydroxy-1H-benzotriazole (35 mg) and stirred at room temperature for 30 minutes. Next, cyclopropylamine (16 μL) was added and stirred at room temperature for 18 hours. The reaction mixture was poured into a 1N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. Purification of the title compound 3 8 mg. !H-NMR (DMSO-d6) (5 (ppm): 0.34-0.38 (2H, m), 0.54-0.59 (2H, m), 1.99-2.06 (2H, m), 2.25 (2H, t, J=7.2 Hz)3 2.56-2.63 (1H, m), 4.27 (2H, t5 J=6.4 Hz), 6.60 (1H, d, J=5.2 Hz), 7.10-7.15 (JH, m), 7.39 (1H, dd, J=2.8 Hz, J =8.0 Hz), 7.44-7.49 (2H, m), 7.59 (1H, s), 7.95 (1H, brd;%J=3.6 Hz), 8.21- S.25 (1H, m), 8.67 (1H, br ), 8.73 (1H, d5 J=5.2 Hz), 8.74 (1H, s), 9·15 (1H, br) 〇 binding

線line

二（卜氰基六i.毗啶基）羰基）丙氧奚）·心林基） U-氣笨基氣茇甚、碼 藉由與實施例137同樣之操作，從N-( 4-(6-氰基-7-(3-¾ 丙氧基）-4-喹啉基）氧-2-氟苯基卜N，-(4-·氟笨基）脲（1〇〇 mg) 仔到標題化合物3 3 mg。 -239- 本紙張尺度適;?!巾g g家料(CNS) M規格(_ χ挪公愛) 1304061 A7 B7(N-(4-cyanohexyl)-propionyl)-propionyl)------------ 6-cyano-7-(3-3⁄4 propyloxy)-4-quinolinyloxy-2-fluorophenyl-N,-(4-·fluorophenyl)urea (1〇〇mg) Title compound 3 3 mg. -239- The paper size is suitable;?! towel gg home material (CNS) M specification (_ χ 公公公) 1304061 A7 B7

五、發明説明（234 ) H-NMR (DMS〇-d6) 5 (ppm): 1.38-1.60 (6H，m)，2·〇ι,2·〇9 (2Η，m)，2·53 (2Η，t, J=7.2 Ηζ)，3.39-3.46 (4Η，m)，4·31 (2ΗV. INSTRUCTIONS (234) H-NMR (DMS〇-d6) 5 (ppm): 1.38-1.60 (6H,m),2·〇ι,2·〇9 (2Η,m),2·53 (2Η ,t, J=7.2 Ηζ), 3.39-3.46 (4Η,m),4·31 (2Η

t，J=6.0 Hz)，6.61 (1H，d，J=5.2 Hz)，7·10-7·15 (3H，m)，7 4〇 (1H，dd，J=2.4 Hz，J=8.0 Hz)，7·43-7·49 (2H，m)，7.61 (1H s)，8.20-8.27 (1H，m)，8.70 (1H，br)，8·73 (1H，d，J=5.2 Hz) 8·74 (1H，s)，9.17 (1H，br)。 ’ 實施例139 氣墓 氨基-7-(3·((二甲胺甚、碏 氧-2-氣茉基氣笨某）服 藉由與實施例7同樣之方法，從6-氰基-4-{4-[4-^笨胺 談基]胺基-3 -氣+氧基} ρ奎17林基-7-Sf*納鹽（1〇〇 mg)得到# 題化合物3 5 mg。 1 H-NMR (DMSO-d6) (5 (ppm): 2.19-2.27 (2H，m)，2·80 (6H，s) 3.26-3.31 (2H, m), 4.41 (2H, t, J=6.4 Hz), 6.63 (1H, d, J=5 2 Hz), 7.10-7Π6 (3H, m)5 7.40 (1H, dd, J=2.8 Hz, J-7.6 Hz)t, J=6.0 Hz), 6.61 (1H, d, J=5.2 Hz), 7·10-7·15 (3H, m), 7 4〇 (1H, dd, J=2.4 Hz, J=8.0 Hz ),7·43-7·49 (2H,m), 7.61 (1H s), 8.20-8.27 (1H,m), 8.70 (1H,br),8·73 (1H,d,J=5.2 Hz) 8·74 (1H, s), 9.17 (1H, br). Example 139 A gastrometer amino-7-(3·((dimethylamine, oxime-2-oxymethane)) was obtained from 6-cyano-4 by the same method as in Example 7. -{4-[4-^ 胺 胺 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基H-NMR (DMSO-d6) (5 (ppm): 2.19-2.27 (2H, m), 2·80 (6H, s) 3.26-3.31 (2H, m), 4.41 (2H, t, J = 6.4 Hz ), 6.63 (1H, d, J=5 2 Hz), 7.10-7Π6 (3H, m)5 7.40 (1H, dd, J=2.8 Hz, J-7.6 Hz)

7.44-7.49 (2H，m)，7·61 (1H，s)，8.21-8.27 (、1H，m)，8.68 (1H br), 8·75 (1H，d，J=5.2 Hz)，8·77 (1H，s)，9.15 (1H，br)。 ’ 實施例14 0 Μ- (4- ( 6-氨基-7- ( 3-((環丙胺基）磺醯某）丙氣基八^ 1-2-氟笨某f.芙某）服 藉由與實施例7同樣之方法，從6-氰基-4-{4-[‘氟苯胺 羰基]胺基-3-氟苯氧基} 4:淋-7-醇鈉鹽（100 mg)得到標題 化合物3 1 mg ^ - 丨 H-NMR (DMSO-d6) 5 (ppm): 0.51-0.63 (4H, m)，2,17-2)5 ___ -240- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 、 A7 ____B7 _______ 五、發明説明（235 ) (2H，m)，3·15-3·22 (1H，m)，3.26-3.33 (2H, m)，4·42 (2H，t， J=6.0 Hz)，.6.63 (1H，d，JN5.2 Hz)，7.10-7.16 (3H，m)，7.40 (1H, dd, J=2.8 Hz, J=8.0 Hz), 7.44-7.48 (2H, m), 7.56 (1H, brd, J=2.8 Hz), 7.61 (1H, s), 8.21-8.27 (1H, m), 8.63-8.66 (1H, m), 8.75 (1H, d, J=5.2 Hz), 8.77 (1H, s), 9.11-9.13 (1H, m)。 實施例141 K4- ( 7-字氣某-6-氰基-4-。奎g林基）氧-2-氣笨基）-Ν’ - (2- 口篆 唑基）脲 將Ν-(4-(6-氰基-7-芊氧基-4-喹啉基）氧-2-氟苯基）胺基 甲酸苯酯（6.93 g)及2-胺基噻唑（2.75 g)溶於二甲基甲醯胺 (70 ml)中，在其中加入二異丙基乙胺（4·8 ml) ’並於90°C 加熱攪拌2小時。放冷後，加入水及濾取析出之個體，將其 用乙酸乙酯洗淨，得到為淡褐色結晶之標題化合物5·53 g (產率79%) $ iH-NMR 光譜（DMSO-d6)5(ppm): 5.46 (2注，s)，6.63 (1H，d， J=5.2 Hz), 7.13-7.19 (2H，m)，7,33-7.48 (5H，m)，7.54 (2H，d， J=6.8 Hz), 7.72 (1H, s), 8.21-8.27 (1H, m), 8.73-8.78 (2H, m)。 如下述合成中間體。 製造例141- 1 N-(4-( 6-氨基-7-芸望.某-4-4啉某）氣-2-氟苯基）胺基曱酸 笨酯 : 將製造例8合成之7-芊氧基-6-氰基-4-(3-氟-4-胺基苯氧 -241 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 -- A7 B7 五、發明説明（236 ) 基）α奎琳（9.45 g)溶於二甲基甲酿胺（70 ml)及咕咬（5.9 mi) 以及在氮氣.流下冷卻至0°C。在其中加入氯碳酸苯酯（3.4 ml) 並攪拌2小時。在該反應液中加入水，濾取析出之結晶，將 其在四氫呋喃及甲苯中濕磨，得到為淡褐色結晶之標題化 合物6·93 g (產率56%)。 iH-NMR 光譜（CDCl3)(5(ppm): 5·36 (2H，s)，6·53 (1H，d， J=5.3)，6.98-7.05 (2H，m)，7.17-7.47 (9H，m), 7.51-7.58 (3H， m)，8.67-8.71 (2H，m)。 實施例142 N-f 4-(6-氰某-7-「3-(嗎福啉-4-某）丙氣基1-4^奋嗾 2-氟茉某塞唑基）脲 將Ν-(4-(6-氰基-7-羥基喹啉基）氧-2-氟苯基）-Nf-(2〃塞 唑基）脲（150 mg)溶於二甲基甲醯胺（3 ml)，加入碳酸舒 (150 mg)及1-氯-3-(嗎福琳-4-基）丙燒（70 mg)，並於6〇。〇 加熱攪捽2小、時。放冷後加入水，用乙酸乙酯萃取，將有機 層用飽和食鹽水洗淨後，用無水硫酸鈉乾、燥及減壓餘去溶 媒。將殘餘物用NH矽凝膠層析（乙酸乙酯-甲醇系）精製， 得到標題化合物（20 mg)。 iH-NMR 光譜（〇143〇-(16)5(??111):1.94-2.04 (2}1，111)，2.34-2.52 (6H, m), 3.54-3.61 (4H, m), 4.34 (2H, t, J=6.2 Hz), 6.61 (1H，d，J=5.6 Hz)，7.12-7.20 (2H，m)，7.37-7.47 (2H，m)， 7.61 (1H, s), 8.21-8.27 (1H, m), 8.73-8.76 (2H, m) 中間體如下述合成e - 製造例142- 1 -242- 本纸張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) 1304061 、 、· A7 __________B7 五、發明説明（237 ) 基）脲 將實施例141合成之N-( 4-(7-苄氧基氰基-喹啉基）氧-2-氟苯基）-N’-(2-4 峻基）脉（5.53 g)溶於 TFA(55 ml)，在 其中加入硫代苯甲醚（5·5 ml)，並於7〇 °c加熱攪掉6小時。 將反應溶液冷卻後減壓濃縮，在其中加入碳酸氫鈉水溶液 及甲醇，以及濾取析出之結晶。將其用乙醚洗淨，得到標 題化合物3.63 g (產率80%^ W-NMR 光譜（DMS〇-d6)5(ppm): 6.50 (1H，d，J=5.6 Hz)， 7.12-7.19 (2H, m), 7.35-7.45 (3H, m), 8.19-8.27 (1H, m), 8.61-8.66 (2H，m)。 實施例143 Ν· (4- ( 6-氰基-7- ( 3-(二乙胺基）丙氫基）-4- 4啉基）氣-2-蠢 笨基-ΝΉ-違唑基 將實施例442合成之N-( 4-(6-氰基-7-羥基-4-喹啉基）氧-2-氟苯基）-Ν'-(2-ρ塞咬基）脉（150 mg)溶、於二甲基甲酿胺 (2.5 ml)，加入碳酸鉀（150 mg)及1-氯-3-(二乙胺基）丙烷 (80 mg)並於60°C加熱攪拌2小時。放冷後，加入水並用乙 酸乙酯萃取，將有機層用飽和食鹽水洗淨後，用無水硫酸 鈉乾燥及減壓餾去溶媒。殘餘物藉由NH矽凝膠管柱層析 (乙酸乙酯-甲醇系）精製，得到標題化合物（10 mg)。· iH-NMR 光譜（DMS〇-d6)5(ppm): 0·95 (6H，t，1=7.0 Hz), 1.85-1.96 (2H, m), 2.40-2.65 (6H, m), 4.32 (2H, t, J=6.0 Hz), 6.62 (1H, d, J=5.2 Hz), 7.12-7.20 (2H, m), 7.36-7.48 (2H, m), -243- 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 … A7 ____ B7 五、發明説明（238 ) 7·59 (1H，s)，8.20-8,24 (1H，m)，8·73-8·77 (2H，m)。 實施例144 生丄4-(6-氰基-7-(2-甲氧乙氣某）-4^奎啉基）氣茉某-斤-^ 甲基異啐崦-5-某）月尿 將製造例10合成之4-(4-胺基苯氧基）-6-氰基-7-(2_甲氧 乙氧基）喹啉（100 mg)及N-( 3-甲基異哼唑-5-基）胺基甲酸 苯酯（8 1 mg)加至甲苯（5 ml)中，然後加入二異丙基乙胺 (0.88 ml)並於100°C加熱攪拌2小時。放冷後濾取析出之結 晶，將其用乙酸乙酯及曱苯（1/1)之混合溶媒洗淨，得到標 題化合物（102 mg)。 iH-NMR 光譜（DMS〇-d0)5(ppm): 2·16 (3H，s)，3·36 (3H，s)， 3.76-3.79 (2H, m), 4.40-4.44 (2H, m), 5.95 (1H, s), 6.52 (1H, d, J=5.2 Hz), 7.26 (2¾ d, J=9.2 Hz), 7.58-7.64 (3H, m), 8.71 (1H，d，J=5.2 Hz)，8.76 (1H，s)，9.04 (1H，br s)。 中間體用下述方法合成。 實施例144- 1 ·、 N-(3-甲基異呤唑-5-基）胺墓甲酸茉醅 將從Aldrich公司購入之5-胺基-3-曱基異β号峻（1 g)溶於四 氫呋喃（40 ml)及吡啶（1·5 ml)，於氮氣下冷卻至〇°C後，加 入氯碳酸苯酯（1 ·4 ml)，並於室溫攪拌1.5小時。在其中加 入水及用乙酸乙酯萃取二次，將有機層合併，用水及飽和 食鹽水依次洗淨後用無水硫酸鈉乾燥，並於減壓下濃縮》 將得到之殘餘物從乙酸乙酯及正己燒中'结晶化，得到標題 化合物（45 0 mg，產率20%)。 -244- 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 二—— 、-- A7 . _ B7 五、發明説明（239 ) iH-NMR 光譜（CDCl3)(5(ppm): 2.27 (3H，s)，6.03 (1H，s)， 7.16-7.30 (3H，m)，7·37-7·44 (2H，m)，7.81 (1H，br s) 〇 實施例145 N-( 4-(6-氰基-7-(2-甲氣乙氳基）-4-4啉基）氣茉基 甲基異哼唑-3-基）服 將製造例10合成之4· (4-胺基苯氧基）-6-氰基-7-(2-甲氧 乙氧基）喹啉（100 mg)及N-( 5-甲基異噚唑-3-基）胺基甲酸 苯酯（72 mg)加至甲苯（5 ml)中，然後加入二異丙基乙胺 (0.50 ml)並加熱回流2小時。放冷後濾取析出之結晶，將其 用乙酸乙酯及甲苯（1/1)之混合溶媒洗淨，得到標題化合物 (120 mg)。 j-NMR光譜（DMSO-d0)5(ppm): 2.36 (3H，s)，3·37 (3H，s)， 3.75-3.78 (2H, m), 4.37-4.43 (2H, m), 6.50-6.54 (2H, m)? 7.26 (2H, d, J=8.8 Hz), 7.56-7.63 (3H, m), 8.72 (1H, d, J=5.6 Hz), 8.76 (1&lt;H，s)，8.99 (1H，bi: s)，9.51 (1H，br s) 〇 中間體以下述方法合成β 、 製造例145-丄 5-甲某異呤唑-3-基）胺基曱酸笨酯 將從Aldrich公司購入之3-胺基-5-甲基異呤唑（1.00 g)溶 於四氫吱喃（20 ml)及批这（1.5 ml)，於氮蒙氣下冷卻至(TC 後，加入氯碳酸苯酯（1 ·4 ml)，並於室溫攪摔2小時❶在其 中加入水並用乙酸乙酯萃取2次，將有機層合併，用水及飽 和食鹽水依次洗淨後，用無水硫酸鈉乾燥及於減壓下濃 縮。將得到之殘餘物在乙醚及正己烷中濕磨，得到標題化 -245 - 本紙張尺度適用中準(CNS) Α4規格（210 χ 297公愛） 1304061 、 A7 B7 五、發明説明（240 ) 合物（1·54 g，產率68%)。 1H-NMR 光譜（CDCl3)5(PPm): 2·42 (3H，s)，6·56 (1H，s)， 7.15-7.30 (3Η，m)，7.36-7.43 (2Η，m)，8·18 (1Η，br s) 〇 實施例146 Ν_(4·(6 -亂基_7-(2-甲乳乙氣基）-4-口奎口林基、氧-氣笨某 Ν’- (2 -嗣基-1,2,3,4-四氮-6-冷g林基）月尿 以與實施例25同樣之方法，從N-(4-(6-氰基-7-(2-甲氧乙 氧基）-4-喹啉基）氧-2-氟苯基）胺基甲酸苯酯（65 mg)，得到 標題化合物（64 mg) β W-NMR *，（DMS〇-d6)5(ppm):2.38-2.45 (2H，m)，2.81- 2.90 (2H, m), 3.36 (3H, s), 3.75-3.79 (2H, m), 4.40-4.43 (2H, m), 6.61 (1H, d5 J=5.2), 6.77 (1H, d3 J=8.4 Hz), 7.10-7.18 (2H, m), 7.30 (1H, br s), 7.36-7.42 (1H, m), 7.63 (1H, s), 8.23-8.29 (1H, m), 8.60 (1H, br s), 8.73-8.76 (2H, m), 8.92-8.94 (1H, m7, 9·97 (1H, br s) 〇 實施例147 、 iii 4-(茉胺蒜基）胺基笨氣基）-7-曱氳基-6^杏嗾淼醢眩 將實施例37合成之N-( 4-(6-氰基-7-甲氧基-4-喹啉基）氧 苯基）-N’-苯基脲（100 mg)於80°C溶於二曱基亞鐵（3 ml), 在其中加入5N氫氧化鈉水溶液並加熱攪摔2小時。將反應液 用1N鹽中和後’滤取析出之結晶’用乙醇洗淨，得到標 題化合物（60 mg)。 iH-NMR 光譜（DMS〇-d6)5(PPm): 4.03 (3H，s)，6.56 (1H，d， J=6.0 Ηζ)，ό·96 (1H，t，J=7.6 Ηζ)，7·22-7·30 (4H，m)，7·45 ___ - 246 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A77.44-7.49 (2H,m),7·61 (1H,s), 8.21-8.27 (,1H,m), 8.68 (1H br), 8·75 (1H,d,J=5.2 Hz),8· 77 (1H, s), 9.15 (1H, br). Example 14 0 Μ-(4-(6-Amino-7-(3-((cyclopropylamino))sulfonyl)propane-based VIII- 1-2-fluoro stupid f. Fu) In the same manner as in Example 7, the title was obtained from 6-cyano-4-{4-['fluoroanilinecarbonyl]amino-3-fluorophenoxy} 4: sodium -7-ol sodium salt (100 mg). Compound 3 1 mg ^ - 丨H-NMR (DMSO-d6) 5 (ppm): 0.51-0.63 (4H, m), 2,17-2)5 ___ -240- This paper size applies to the Chinese National Standard (CNS) A4 size (210 x 297 mm) 1304061, A7 ____B7 _______ V. Description of invention (235) (2H, m), 3·15-3·22 (1H, m), 3.26-3.33 (2H, m), 4 · 42 (2H, t, J = 6.0 Hz), .6.63 (1H, d, JN5.2 Hz), 7.10-7.16 (3H, m), 7.40 (1H, dd, J=2.8 Hz, J=8.0 Hz ), 7.44-7.48 (2H, m), 7.56 (1H, brd, J=2.8 Hz), 7.61 (1H, s), 8.21-8.27 (1H, m), 8.63-8.66 (1H, m), 8.75 ( 1H, d, J = 5.2 Hz), 8.77 (1H, s), 9.11-9.13 (1H, m). Example 141 K4-(7-word gas-6-cyano-4-. kulin) Oxy-2-pyrene)-Ν'-(2-oxaxazolyl)urea-(4-(6-cyano-7-decyloxy-4-quinolinyl)oxy-2- Fluorophenyl) phenyl carbamate (6.93 g) and 2- Thiazole (2.75 g) was dissolved in dimethylformamide (70 ml), to which was added diisopropylethylamine (4 · 8 ml) 'and was heated at 90 ° C for 2 hours. After cooling, the mixture was added with water and filtered, and the crystals were evaporated to ethylamine (ethyl acetate). 5 (ppm): 5.46 (2 note, s), 6.63 (1H, d, J = 5.2 Hz), 7.13-7.19 (2H, m), 7, 33-7.48 (5H, m), 7.54 (2H, d , J = 6.8 Hz), 7.72 (1H, s), 8.21-8.27 (1H, m), 8.73-8.78 (2H, m). The intermediate is synthesized as follows. Production Example 141-1 N-(4-(6-Amino-7-Spot. -4-4 phenyl) gas-2-fluorophenyl)amino decanoic acid </RTI> </RTI> </RTI> -decyloxy-6-cyano-4-(3-fluoro-4-aminophenoxy-241 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304061 -- A7 B7 V. INSTRUCTIONS (236) A) acetazone (9.45 g) was dissolved in dimethyl amide (70 ml) and bite (5.9 mi) and cooled to 0 ° C under a stream of nitrogen. Phenyl chlorocarbonate (3.4 ml) was added thereto and stirred for 2 hours. Water was added to the reaction mixture, and the crystals obtained were crystallized from crystals eluted eluted elution elution iH-NMR spectrum (CDCl3) (5 (ppm): 5·36 (2H, s), 6.53 (1H, d, J = 5.3), 6.98-7.05 (2H, m), 7.17-7.47 (9H, m), 7.51-7.58 (3H, m), 8.67-8.71 (2H, m). Example 142 Nf 4-(6-cyanyl-7-"3-(morpholine-4-)propane 1-4^嗾嗾2-Fluoro-methyl-pyrazolyl)urea Ν-(4-(6-Cyano-7-hydroxyquinolinyl)oxy-2-fluorophenyl)-Nf-(2 〃 Azolyl)urea (150 mg) was dissolved in dimethylformamide (3 ml), and carbonated (150 mg) and 1-chloro-3-(moffin-4-yl)propanone (70 mg) were added. And 于 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 The residue was purified by EtOAc EtOAc EtOAc (EtOAc) -2.04 (2}1,111),2.34-2.52 (6H, m), 3.54-3.61 (4H, m), 4.34 (2H, t, J=6.2 Hz), 6.61 (1H,d,J=5.6 Hz ), 7.12-7.20 (2H, m), 7.37-7.47 (2H, m), 7.61 (1H, s), 8.21-8.27 (1H, m), 8.73-8.76 (2H, m) Synthetic e-manufacturing example 142-1-242- This paper scale applies to Chinese National Standard (CNS) A4 specification (210x 297 mm) 1304061, , · A7 __________B7 V. Invention description (237) Base) Urea will be implemented Example 141. Synthesis of N-(4-(7-benzyloxycyano-quinolinyl)oxy-2-fluorophenyl)-N'-(2-4 cyclinyl) vein (5.53 g) was dissolved in TFA ( 55 ml), thioanisole (5. 5 ml) was added thereto, and stirred for 6 hours under heating at 7 ° C. The reaction solution was cooled, concentrated under reduced pressure, and aqueous sodium hydrogencarbonate and methanol were added thereto. The precipitated crystals were collected by chromatography.yield eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted ), 7.12-7.19 (2H, m), 7.35-7.45 (3H, m), 8.19-8.27 (1H, m), 8.61-8.66 (2H, m). Example 143 Ν·(4-(6-Cyano-7-(3-(diethylamino)propylhydro)-4-yl)-4-oxo-2-stactyl-oxime-carbazolyl will be carried out Example 442 Synthesis of N-(4-(6-Cyano-7-hydroxy-4-quinolinyl)oxy-2-fluorophenyl)-indole-(2-oxetyl) pulse (150 mg) Dissolved in dimethyl ketoamine (2.5 ml), added potassium carbonate (150 mg) and 1-chloro-3-(diethylamino)propane (80 mg) and stirred at 60 ° C for 2 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. Purification to give the title compound (10 mg).······································ m), 2.40-2.65 (6H, m), 4.32 (2H, t, J=6.0 Hz), 6.62 (1H, d, J=5.2 Hz), 7.12-7.20 (2H, m), 7.36-7.48 (2H , m), -243- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ... A7 ____ B7 V. Invention description (238) 7·59 (1H, s), 8.20- 8,24 (1H,m),8·73-8·77 (2H,m). Example 144 丄 丄 4-(6-Cyano-7-(2-methoxyethane)-4^ quinolyl) gas jamo-jin-^ methyl isoindole-5-some) monthly urine Production Example 10 Synthesis of 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg) and N-(3-methylisoxazole Phenyl phenyl carbamate (8 1 mg) was added to toluene (5 ml), then diisopropylethylamine (0.88 ml) was added and stirred at 100 ° C for 2 hours. After cooling, the precipitated crystals were collected by filtration and washed with ethyl acetate and ethylbenzene (1/1) to give the title compound (102 mg). iH-NMR spectrum (DMS〇-d0) 5 (ppm): 2·16 (3H, s), 3·36 (3H, s), 3.76-3.79 (2H, m), 4.40-4.44 (2H, m) , 5.95 (1H, s), 6.52 (1H, d, J=5.2 Hz), 7.26 (23⁄4 d, J=9.2 Hz), 7.58-7.64 (3H, m), 8.71 (1H,d,J=5.2 Hz ), 8.76 (1H, s), 9.04 (1H, br s). The intermediate was synthesized by the following method. Example 144- 1 · N-(3-Methylisoxazol-5-yl)amine Tomb formate ruthenium 5-Amino-3-mercaptoiso-beta (1 g) purchased from Aldrich After dissolving in tetrahydrofuran (40 ml) and pyridine (1. 5 ml), EtOAc (EtOAc) Water was added thereto, and the mixture was extracted with ethyl acetate. EtOAc was evaporated, evaporated, evaporated. The crystals were crystallized to give the title compound (45 mg, yield 20%). -244- The paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 II - , - A7 . _ B7 V. Description of invention (239) iH-NMR spectrum (CDCl3) (5 (5 Ppm): 2.27 (3H, s), 6.03 (1H, s), 7.16-7.30 (3H, m), 7·37-7·44 (2H, m), 7.81 (1H, br s) 〇 Example 145 N-(4-(6-Cyano-7-(2-methylethenyl)-4-yl))methanemethylisoxazole-3-yl) · (4-Aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg) and N-(5-methylisoxazol-3-yl)amine Phenyl phenyl benzoate (72 mg) was added to toluene (5 ml), then diisopropylethylamine (0.50 ml) was added and heated to reflux for 2 hr. After cooling, the precipitated crystals were filtered and evaporated. Washing with a mixed solvent of toluene (1/1) gave the title compound (120 mg). j-NMR spectrum (DMSO-d0) 5 (ppm): 2.36 (3H, s), 3·37 (3H, s) , 3.75-3.78 (2H, m), 4.37-4.43 (2H, m), 6.50-6.54 (2H, m)? 7.26 (2H, d, J=8.8 Hz), 7.56-7.63 (3H, m), 8.72 (1H, d, J=5.6 Hz), 8.76 (1&lt;H, s), 8.99 (1H, bi: s), 9.51 (1H, br s) The interstitial was synthesized by the following method, and the 3-amino-5-methylisoxazole purchased from Aldrich Co., Ltd. was produced as a compound of Example 145-丄5-methylisoxazol-3-yl)amino decanoate. 1.00 g) Dissolve in tetrahydrofuran (20 ml) and batch (1.5 ml), cool to (TC, add phenyl chlorocarbonate (1 · 4 ml), and stir at room temperature After 2 hours, water was added thereto, and the mixture was combined with EtOAc. EtOAc (EtOAc m. Wet milling in n-hexane, titled -245 - This paper scale applies to the standard (CNS) Α4 specification (210 297 297 public) 1304061, A7 B7 V. Invention description (240) Compound (1·54 g, produced Rate 68%). 1H-NMR spectrum (CDCl3) 5 (PPm): 2·42 (3H, s), 6.56 (1H, s), 7.15-7.30 (3Η, m), 7.36-7.43 (2Η, m),8·18 (1Η, br s) 〇Example 146 Ν_(4·(6 - 乱基_7-(2-甲乳乙基)-4-口奎口林基,氧-气笨A certain Ν'-(2-mercapto-1,2,3,4-tetrazo-6-cold g-linyl) monthly urine in the same manner as in Example 25. From N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxy-2-fluorophenyl)carbamic acid phenyl ester (65 mg), title Compound (64 mg) β W-NMR *, (DMS〇-d6) 5 (ppm): 2.38-2.45 (2H, m), 2.81- 2.90 (2H, m), 3.36 (3H, s), 3.75-3.79 (2H, m), 4.40-4.43 (2H, m), 6.61 (1H, d5 J=5.2), 6.77 (1H, d3 J=8.4 Hz), 7.10-7.18 (2H, m), 7.30 (1H, br s), 7.36-7.42 (1H, m), 7.63 (1H, s), 8.23-8.29 (1H, m), 8.60 (1H, br s), 8.73-8.76 (2H, m), 8.92-8.94 (1H , m7, 9·97 (1H, br s) 〇 Example 147, iii 4-(Moss algium) amine based stupid base)-7-fluorenyl-6^ apricot glare Example 37 Synthesis of N-(4-(6-cyano-7-methoxy-4-quinolinyl)oxyphenyl)-N'-phenylurea (100 mg) dissolved in dimercapto at 80 ° C Iron (3 ml) was added thereto with a 5 N aqueous sodium hydroxide solution and heated and stirred for 2 hours. The reaction mixture was neutralized with a 1N salt, and the crystals which were collected by filtration were washed with ethanol to give the title compound (60 mg). iH-NMR spectrum (DMS〇-d6) 5 (PPm): 4.03 (3H, s), 6.56 (1H, d, J = 6.0 Ηζ), ό·96 (1H, t, J=7.6 Ηζ), 7· 22-7·30 (4H,m),7·45 ___ - 246 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7

(2H, d, J=7.6 Hz), 7.52 (1H, s), 7.59-7.62 (2H, m)5 7.76 (lH, br s)，7·87.(1Η，br s)，8.69-8·73 (2H, m)，8·76 (1H，br s) 8.90 (1H，br s)。 實施例14丨 基）胺某茉氫墓）-7-( 2-曱氣基乙氣某+ i 叛醯胺 以與實施例147同樣之方法，從實施例65合成之N-(4-(6-氰基-7-(甲氧乙氧基）-4-喹啉基）氧苯基）-N，-苯基脲（95 mg) 合成標題化合物（54 mg) ^ j-NMR 光譜（DMSO-d6)5(ppm): 3.35 (3H，s)，3.75-3.81 (2H， m), 4.37^4.41 (2H, m), 6.46 (1H, d, J=5.2), 6.96 (1H, t, J=7.6), 7.21-7.30 (4H, m), 7.45 (2H, d? J=8.4 Hz), 7.55 (1H, s)，7·59 (2H，d，J=8.8 Hz)，7.81 (1H，br s)，7.82 (1H，br s)， 8.65 (1H，d，J=5.2 Hz)，8.77-8.79 (2H，m)，8.91 (1H，bi: s)。 實施例149 &lt; 4-(4-((2,4-二氣茉某）羰基）胺基-3-氯苽貧某）-7-(2-甲氧1 乙氧基V 6- 4琳#酿胺 以與實施例147同樣之方法，從實施例66合成之N-(4-(6-氰基-7-(2-曱氧乙氧基）-4-喹啉基）氧-2-氟苯基）-比-(2,4-二氟苯基）脲（100 mg)得到標題化合物（35 mg)。 iH-NMR 光譜（DMSO-d6)5(ppm): 3.34 (3H，s)，3.78-3.81 (2H， m), 4.39-4.42 (2H, m), 6.56 (1H, d, J=5.2 Hz), 7.03-7.17 (2H, m), 7.28-7.43 (2H, m), 7.56 (1H, s), 7.81 (2H, br s), 8.08-8.16 (1H, m), 8.28-8.29 (1H, m), 8.67 (1H, d, J=5.2), 8.76 -247 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（242 (1H，s)，9.00:9.09 (2H，m)。 實施例150 id：4-((4-氣苯^基-夂氯芡擎•莘甲氳基 乙氧基）-6- 4 g沐淼醢脸_ 以與貫施例147同樣之方法，從實施例1〇〇合成之N-(4-⑼-氰基^-”-乙氧乙氧基^心喹啉基丨氧^-氟苯基卜^· (4-氟苯基）脲（58 mg)得到標題化合物（25 mg)。 H-NMR光 if (DMSO-d6) 5 (ppm): 3.34 (3H，s), 3.78-3.81 (2H， m), 4.39-4.42 (2H, m), 6.56 (1H, d, J=5.2 Hz), 7.10-7.17 (3H, m), 7.36-7.50 (3H, m)3 7.56 (1H, s), 7.82 (2H, br s), 8.19&gt; 8.26 (1H, m), 8.64-8.69 (2H, m), 8.76 (1H, s), 9.13-9.15 (1H, m) o 實施例1 5 1 U2·甲氧基乙氧某嗱唑-2_基胺基）羰基）胺 基-3-氟苯氧、基）-6-4啦淼碎味 以與實施例U7同樣之方法，從實施例b合成之氺（4-(6-氰基-7-(2-甲氧乙氧基）-4-喹啉基）氧-2_氟苯基）-；^，-(1，3-噻唑-2-基）脲（1〇〇 mg)得到標題化合物（18 mg)。 H-NMR光 if (DMSO-d6) 5 (ppm): 3·34 (3H，s)，3.78-3·81 (2H， m)，4.39-4.42 (2H，m)，6·57 (1H，d，J=5.2 Hz)，7.12-7.19 (2H， m), 7.39 (1H, d, J=3.6 Hz), 7.41-7.46 (1H, m), 7.57 (1H, s), 7.82 (1H, br s)3 8.21-8.25 (1H, m), 8.68 (1H, d, J=5.2 Hz), 8.76 (1H, s), 9.06 (1H, br s) 〇 - 實施例152 -248 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公爱） 1304061 、 Λ7 — _______ Β7 五、發明説明（243 ) — ^ j：_L4-((4-氟苯胺基）羰基）胺基氣茉氲.甲氣基-卜 喹啉#醯胺 以與實施例10同樣之方法，從6-胺甲醯基-(4-(4-胺基-3-氟苯氧基）-7-甲氧喹啉（50 mg)，得到標題化合物（25 mg)。 H-NMR 光譜（DMS〇-d6)5(ppm): 4.02 (3H，s)，6.55 (1H，d J=5.6 Hz), 7.09-7.18 (3H, m), 7.35-7.41 (1H, m), 7.43-7.49 (2H，m)，7.51(lH，S)，7.74(lH，brS)，7.85(lH，brS)，8.18-8·26 (1H，m)，8·61·8·68 (3H，m)，9·09-9·12 (1H，m)。 原料物質用下述方法合成。 製造例152-1 7 -甲氧基-4 -嗣基-1,4 -二氮p套g林-6 -致酸 在製造例24記載之7-曱氧基-4-酮基-1，4-二氫峻琳•甲 腈（2 g)中，加入甘油（20 ml)及KOH(氫氧化鉀，3〇 g),於 1 60 C加熱撥拌3小時，加入水（40 ml)並於80 °C再加熱30分 鐘。放冷後，用2N鹽酸調成酸性，濾取析出之不要物，將 其用水洗淨後減壓乾燥，得到標題化合物（丨.6 。 H-NMR 光譜（DMSO-d^) 5 (ρρτη): 4·87 (3H，s)，6.14 (1H d J=6.0 Ηζ)，7·04 (1H，s)，7·98 (1H，d，J=6.0)，8·40 (1H，s)。 製造例152-2 7-甲氧基_4_氣-口奎口林-6-黢某氟 在7-甲氧基-4-酮基-1，4-二氫4淋-6-幾酸（2·〇 g)中，加 入亞硫醯氯（10 ml)及少量二甲基甲醯胺，並加熱回流2小 時。減壓濃縮後，在甲苯中共沸2次，得到標題化合物（2.7 -249 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 、 A7 _______B7 五、發明説明（244 ) g) 0 iH-NMR 光譜（CDCl3)5(ppm): 4·20 (3H，s)，7·?0-7·90 (1H， m)，8.41 (1Η，s)，8.90-9.00 (2Η，m)。 製造例152-3 甲乳幕-4 -氣-g套g林-6 -義酿胺 將7-甲氧基-4-氯-喹啉-6_羰基氯（2.7 g)溶於四氫呋喃 (150 ml)，然後冷卻至0°C。在其中加入3〇%氨水（5 ml), 並於室溫搅拌30分鐘。加入水並用乙酸乙酯萃取3次後，將 有機層合併，用水及飽和食鹽水接續洗淨，用硫酸鈉乾燥 後減壓乾燥。得到標題化合物（1.35幻。 H-NMR光譜（DMSO-d6) 5 (ppm): 4·〇3 (3H s) 7.56-7.66 (2H， m)，7.79(lH，brs)，7.88(lH，brs)，8.46-8.49 (lH，m)，8·78-8.82 (1H，m) 〇 製造例152-4 酿基&lt;4-(3-氟-4ϋ苯氧甲氣岭喊 以與製造例7同樣之方法，從7-曱氧基-馭氯奎啉羧醯 胺（1·23 g)得到標題化合物（〗丨。 W-NIVIR 光譜（DMSO-d6)5(PPm): 4.03 (3H，s)，6.96 (1H，山 J=5.2 Hz)，7.25-7.30 (lH，m)，7·57 (1H，s)，7.61-7·6ό ΠΗ， m)，7·74 (1Η，br s)，7.84 (1Η，br s)，8·25-8·32 (1Η，πι)，8·49 (1H，s)，8·80 (1H，d，J=5.2 Hz)。(2H, d, J=7.6 Hz), 7.52 (1H, s), 7.59-7.62 (2H, m)5 7.76 (lH, br s),7·87.(1Η,br s),8.69-8· 73 (2H, m), 8.76 (1H, br s) 8.90 (1H, br s). Example 14: Mercapto) An amine methane tomb) - 7-(2-indole-based ethyl group + i retinoic acid N-(4-() synthesized from Example 65 in the same manner as in Example 147 6-Cyano-7-(methoxyethoxy)-4-quinolinyl)oxyphenyl)-N,-phenylurea (95 mg) mp. -d6)5(ppm): 3.35 (3H, s), 3.75-3.81 (2H, m), 4.37^4.41 (2H, m), 6.46 (1H, d, J=5.2), 6.96 (1H, t, J=7.6), 7.21-7.30 (4H, m), 7.45 (2H, d? J=8.4 Hz), 7.55 (1H, s), 7·59 (2H, d, J=8.8 Hz), 7.81 (1H , br s), 7.82 (1H, br s), 8.65 (1H, d, J = 5.2 Hz), 8.77-8.79 (2H, m), 8.91 (1H, bi: s). Example 149 &lt; 4- (4-((2,4-dioxa)carbonyl)amino-3-chloroindole)-7-(2-methoxy 1 ethoxy V 6 - 4 lin # 牛147 In the same manner, the N-(4-(6-cyano-7-(2-oxiranyloxy)-4-quinolinyl)oxy-2-fluorophenyl)-pyrase synthesized from Example 66 -(2,4-difluorophenyl)urea (100 mg) gave the title compound (35 mg). MH-NMR spectrum (DMSO-d6) 5 (ppm): 3.34 (3H, s), 3.78-3.81 (2H , m), 4.39-4.42 (2H, m), 6.56 (1H, d, J=5.2 Hz), 7.03-7.17 (2H, m), 7.28-7.43 (2H, m), 7.56 (1H, s), 7.81 (2H, br s), 8.08-8.16 (1H, m), 8.28- 8.29 (1H, m), 8.67 (1H, d, J=5.2), 8.76 -247 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of invention (242 (1H, s), 9.00: 9.09 (2H, m). Example 150 id: 4-((4-Phenylbenzene-yl-chloropurine 莘 莘 氲 乙 ethoxy)-6- 4 g淼醢面_ In the same manner as in Example 147, N-(4-(9)-cyano-(-)-ethoxyethoxy[inhomoquinolinyl]oxime-fluoride synthesized from Example 1 Phenyl bromide (4-fluorophenyl)urea (58 mg) gave the title compound (25 mg). H-NMR light if (DMSO-d6) 5 (ppm): 3.34 (3H, s), 3.78-3.81 (2H, m), 4.39-4.42 (2H, m), 6.56 (1H, d, J = 5.2 Hz ), 7.10-7.17 (3H, m), 7.36-7.50 (3H, m)3 7.56 (1H, s), 7.82 (2H, br s), 8.19&gt; 8.26 (1H, m), 8.64-8.69 (2H , m), 8.76 (1H, s), 9.13-9.15 (1H, m) o Example 1 5 1 U2·methoxyethoxy a certain carbazole-2-ylamino)carbonyl)amino-3-fluoro Phenyloxy, yl)-6-4 flavonoids The oxime synthesized from Example b (4-(6-cyano-7-(2-methoxyethoxy)-) was synthesized in the same manner as in Example U7. 4-Quinolinyl)oxy-2-fluorophenyl)-;^,-(1,3-thiazol-2-yl)urea (1 mg) gave the title compound (18 mg). H-NMR light if (DMSO-d6) 5 (ppm): 3·34 (3H, s), 3.78-3·81 (2H, m), 4.39-4.42 (2H, m), 6.57 (1H, d, J = 5.2 Hz), 7.12-7.19 (2H, m), 7.39 (1H, d, J = 3.6 Hz), 7.41-7.46 (1H, m), 7.57 (1H, s), 7.82 (1H, br s)3 8.21-8.25 (1H, m), 8.68 (1H, d, J=5.2 Hz), 8.76 (1H, s), 9.06 (1H, br s) 〇 - Example 152 -248 - This paper size applies China National Standard (CNS) A4 Specification (210X297 public) 1304061, Λ7 — _______ Β7 V. Inventions (243) — ^ j:_L4-((4-fluoroanilino)carbonyl)amine-based jasmine. Base-b-quinoline # guanamine in the same manner as in Example 10, from 6-aminoformamido-(4-(4-amino-3-fluorophenoxy)-7-methoxyquinoline (50 The title compound (25 mg) was obtained. H-NMR spectrum (DMS 〇-d6) 5 (ppm): 4.02 (3H, s), 6.55 (1H, d J = 5.6 Hz), 7.09-7.18 (3H, m), 7.35-7.41 (1H, m), 7.43-7.49 (2H, m), 7.51 (lH, S), 7.74 (lH, brS), 7.85 (lH, brS), 8.18-8·26 (1H, m), 8·61·8·68 (3H, m), 9·09-9·12 (1H, m) The starting material was synthesized by the following method. Production Example 152-1 7 -Methoxy-4嗣基- 1,4 -diaza p-g-glin-6-acidic was added to 7-decyloxy-4-keto-1,4-dihydrojunin-carbonitrile (2 g) described in Production Example 24 Glycerin (20 ml) and KOH (potassium hydroxide, 3 〇g), stir for 3 hours at 1200 C, add water (40 ml) and heat for 30 minutes at 80 ° C. After cooling, use 2N hydrochloric acid. After the acidification was carried out, the precipitated residue was filtered, washed with water and then evaporated to dryness to give the title compound ( s. s. H NMR spectrum (DMSO-d^) 5 (ρρτη): 4·87 (3H, s), 6.14 (1H d J=6.0 Ηζ), 7·04 (1H, s), 7·98 (1H, d, J=6.0), 8·40 (1H, s). Manufacturing Example 152-2 7 -Methoxy _4_ gas-mouth quetialine-6-黢 a fluorine in 7-methoxy-4-keto-1,4-dihydro 4 lea-6-acid (2·〇g) Among them, sulfoxide (10 ml) and a small amount of dimethylformamide were added, and the mixture was heated under reflux for 2 hours. After concentration under reduced pressure, azeotrope twice in toluene to give the title compound (2.7 - 249 - the paper size applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304061, A7 _______B7 V. Invention Description (244 g) 0 iH-NMR spectrum (CDCl3) 5 (ppm): 4·20 (3H, s), 7·?0-7·90 (1H, m), 8.41 (1Η, s), 8.90-9.00 ( 2Η, m). Production Example 152-3 Aluminium Curtain-4 - Gas-g Set g Lin-6 - Alkylamine 7-Methoxy-4-chloro-quinoline-6-carbonyl chloride (2.7 g) was dissolved in tetrahydrofuran (150 Ml), then cooled to 0 °C. 3 % ammonia water (5 ml) was added thereto, and stirred at room temperature for 30 minutes. After adding water and extracting with ethyl acetate for 3 times, the organic layers were combined, washed successively with water and saturated brine, dried over sodium sulfate, and evaporated. The title compound was obtained (1.35 phantom. H-NMR spectrum (DMSO-d6) 5 (ppm): 4·〇3 (3H s) 7.56-7.66 (2H, m), 7.79 (lH, brs), 7.88 (lH, brs ), 8.46-8.49 (lH,m),8·78-8.82 (1H,m) 〇Production Example 152-4 Brewing base &lt;4-(3-Fluoro-4-nonylphenoxylated gas ventilated with Manufacturing Example 7 In the same manner, the title compound was obtained from 7-decyloxy-indole chloroquinoline carboxamide (1·23 g). W-NIVIR spectrum (DMSO-d6) 5 (PPm): 4.03 (3H, s ), 6.96 (1H, mountain J=5.2 Hz), 7.25-7.30 (lH,m),7·57 (1H,s), 7.61-7·6ό ΠΗ, m),7·74 (1Η,br s) , 7.84 (1Η, br s), 8·25-8·32 (1Η, πι), 8·49 (1H, s), 8·80 (1H, d, J = 5.2 Hz).

製造例152-S 基-3 -氟苯氣U'··甲氣g夸啉 以與製造例ίο同樣之方法，從6-胺甲醯基·4_(3-氟-4-硝 L ___- 250 - 本紙張尺歧财g @家辟(CNS) A4規格(21Qχ 297公楚) Ϊ304061 A7 B7 五、發明説明（ 245 基苯氧基）-7·甲氧喹啉（1.08 g)得到標題化合物（54〇 mg)。 ^H-NMR 光譜（DMS〇-d6) 5(PPm): 4·〇ι (3H，s)，5 19.5 23 (2H τη), 6.44 (1Η, d, J-5.2), 6.80-6.89 (2H5 m), 7.05-7.10 (1H,m)，7.47 (1H，s)，7.71 (1H，br s)，7·83 (1H，br s)，8.60-8.66 (2H，m)。實施例153Production Example 152-S 3-Benzylbenzene gas U'··Gas g-g-nitroline was obtained in the same manner as in Production Example ί, from 6-aminomethylmercapto-4_(3-fluoro-4-nitrol___- 250 - The paper ruler is ignorant g @家辟(CNS) A4 specification (21Qχ 297 public Chu) Ϊ304061 A7 B7 V. Description of invention (245 phenoxy)-7·methoxyquinoline (1.08 g) to give the title compound (54 〇 mg). ^H-NMR spectrum (DMS〇-d6) 5(PPm): 4·〇ι (3H, s), 5 19.5 23 (2H τη), 6.44 (1Η, d, J-5.2) , 6.80-6.89 (2H5 m), 7.05-7.10 (1H, m), 7.47 (1H, s), 7.71 (1H, br s), 7·83 (1H, br s), 8.60-8.66 (2H, m Example 153

1ι.ί.2,氣-4H.[4-(2-二 底基 基i 甚 &gt;7口 叶卜 a 呼 [2，3 -dp密咬-4-基氣丨笨基）-3-環丙甚日# 將1-{2-氯-4-[6-[4-(2-二乙胺基乙氧基卜苯基卜7-(2_三 曱碎$元乙氧甲基）-7Η-ρ比嘻并[2,3-d]p密咬-4-基氧]•苯某 3-環丙基脲4〇 mg(0.0601 mmol)溶於四氫呋喃i扭卜滴入四 丁基銨氟化物（四氫呋喃1M溶液）〇·5 ml(8.3當量），然後回 流2小時。返回室溫，加入3 ml水，放置3小時，濾取析出 之結晶，用水及乙醚-己烷=1 : 1洗淨及減壓乾躁，得到標 題化合物22^mg。 MS 光譜（ESI) ·· 535 (Μ+1)， 、 H-NMR光諸：（DMS〇-d6) 0.40-0.54 (2H，m)，0.70-0 go (9H m)，1.06 (6H，t，J=7.8 Hz)，2.55-2.70 (5H，m)，2.88 (2H，t J=7.8 Hz)，4.18 (2H，t，J=7.8 Hz)，7·01 (1H，d，J=i 7 Hz) 7·12 (2H，d，J=8.4 Hz)，7.23 (1H，d，J=2.5 Hz)，7.27 (1H，dd， J=8.8 Hz, Jf=2.5 Hz), 7.41 (1H, d? J=2.5 Hz), 7.97 (2H, d, J=8.4 Hz)，8·01 (1H，s)，8·24 (1H，d，J=8.8 Hz)，8.36 (1H，s)， 12.68 (1H，br s)。 : 中間體如下述合成。 251 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 裝 η1ι.ί.2, gas-4H.[4-(2-dibasyl i is very)&gt;7-mouthed ab [2,3 -dp-biti-4-base gas 丨基基)-3-环丙甚日# Will 1-{2-chloro-4-[6-[4-(2-diethylaminoethoxybphenyl) 7-(2_3 曱 $ $元ethoxymethyl) -7Η-ρ is more than [2,3-d]p dimethyl-4-yloxy] benzene 3-cyclopropyl urea 4 〇 mg (0.0601 mmol) dissolved in tetrahydrofuran i twisted into tetrabutyl Ammonium fluoride (tetrahydrofuran 1M solution) 〇·5 ml (8.3 eq.), then refluxed for 2 hours. Return to room temperature, add 3 ml of water, let stand for 3 hours, and remove the crystals by filtration, using water and diethyl ether-hexane = 1 : 1 Washing and drying under reduced pressure to give the title compound: 22 mg. MS Spectrum (ESI) ·· 535 (Μ+1), H-NMR light: (DMS〇-d6) 0.40-0.54 (2H, m ), 0.70-0 go (9H m), 1.06 (6H, t, J = 7.8 Hz), 2.55-2.70 (5H, m), 2.88 (2H, t J = 7.8 Hz), 4.18 (2H, t, J =7.8 Hz),7·01 (1H,d,J=i 7 Hz) 7·12 (2H,d,J=8.4 Hz), 7.23 (1H,d,J=2.5 Hz), 7.27 (1H,dd , J=8.8 Hz, Jf=2.5 Hz), 7.41 (1H, d? J=2.5 Hz), 7.97 (2H, d, J=8.4 Hz), 8·01 (1H, s), 8·24 (1H ,d,J=8.8 Hz), 8.36 (1H, s), 12.68 (1H, br s). : Intermediates are synthesized as follows. 251 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm).

線 1304061 A7 B7 五 、發明説明（ 246〉 1造例153- 1 1胺基-5 - (4-字氧苯基）-1H-叶fc吃-3 -義酸乙酉旨 在2-眯基-乙酸乙酯鹽酸鹽5〇.7 g (Liebigs Ann. chem·， 1895 (1977)記載之公知化合物）中加入乙醇700 ml，並於室 溫攪拌下，加入乙氧化鈉22.3 g (相對於2-眯基-乙酸乙酯 鹽酸鹽，1當量），然後在氮蒙氣下攪拌15分鐘。在其中， 加入 1-(4-卞氧尽基）-2- &gt;臭乙嗣（Journal of HeterocyclicLine 1304061 A7 B7 V. Description of the invention ( 246 > 1 Example 153 - 1 1 Amino-5 - (4-type oxyphenyl)-1H-leaf fc eat-3 - acetyl acetate is intended to be 2-mercapto- Ethyl acetate hydrochloride 5 〇.7 g (known compound described in Liebigs Ann. Chem., 1895 (1977)) was added with 700 ml of ethanol, and stirred at room temperature, sodium sulphate 22.3 g was added (relative to 2 - mercapto-ethyl acetate hydrochloride, 1 equivalent), then stirred under nitrogen atmosphere for 15 minutes, in which 1-(4-indoleoxy)-2- &gt; Heterocyclic

Chemistry vol· 2，310 (1965)，以及 Journal of MedicinalChemistry vol· 2,310 (1965), and Journal of Medicinal

Chemistry vol· 17, 55 ( 1974)記載之公知化合物）49·9 g ,然 後在室溫及氮蒙氣下攪拌3 6小時。加入水及用乙酸乙酯分 液萃取，將有機層用硫酸鈉乾燥後，濃縮乾固，得到標題 化合物5 6.7 g。 ^-NMR 光譜：（DMSO-d6) 1·32 (3H，t，J=7.3 Hz), 4.10 (2H，q J=7.3 Hz), 5.08 (2H, s), 5.62 (2H, s), 6.30 (1H, d, J=2.2 Hz), 6.95 (2H，d，J=7.9 Hz)，7.28-7·47 (7H，m)，10.67 (1H，br s)。 製造例153-2 .、 6-(4-芊氣笨基）-7士吡咯并「2,3-(1卜密啶'4：1^ 在製造例1 53 - 1合成之2-胺基-5 - (4-苄氧苯基）说哈-3 -獲酸乙酯56.7 g中，加入甲酸84 ml，甲酿胺338 ml及二 甲基甲醯胺169 ml ’於140°C攪拌48小時後，放置於室溫24 小時β濾取析出之固體及減壓乾燥後，得到標題化合物41 g ° j-NMR 光譜：（DMS〇-d6) 5.12 (2H，s)5- 6.78 (1H，s)，7.03 (2H, d, J=7.0 Hz), 7.28-7.47 (5H, m), 7.73 (2H, d, J=7.0 Hz), -252 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公爱） 1304061 A7 B7 五、發明説明（247 7.82 (1H，s)，11.80 (1H，br s)，12.20 (1H，br s)。 製造例153-3 氣笨基）-4-氯- 比洛并f2,3-dlp·密症 在製造例153-2合成之6-(4-字氧苯基）-711-7比啥并[2 3(^ 嘧咬-4-醇20 g中，加入氧氯化鱗200 ml及於140°C授掉3小 時後，在室溫下濃縮反應系。在殘餘物中加入水，然後$ 乙酸乙酯-四氫呋喃（5 : 1)混合溶媒分液萃取。將有機層用 水及飽和食鹽水洗淨，用硫酸鈉乾燥及濃縮乾固，得到# 題化合物12 g。 iH-NMR 光譜：（DMSO-d6) 5·18 (2H，s), 6·97 (1H，d, J=24A well-known compound described in Chemistry vol. 17, 55 (1974), 49·9 g, was stirred at room temperature under nitrogen atmosphere for 36 hours. After adding water and extracting with ethyl acetate, the organic layer was dried over sodium sulfate. ^-NMR spectrum: (DMSO-d6) 1·32 (3H, t, J = 7.3 Hz), 4.10 (2H, q J = 7.3 Hz), 5.08 (2H, s), 5.62 (2H, s), 6.30 (1H, d, J = 2.2 Hz), 6.95 (2H, d, J = 7.9 Hz), 7.28-7.47 (7H, m), 10.67 (1H, br s). Production Example 153-2., 6-(4-indole-based)-7-s-pyrrolidene "2,3-(1b-pyridine) 4:1^ 2-amino group synthesized in Production Example 1 53 -1 -5 - (4-Benzyloxyphenyl) Sakha-3 - 56.7 g of ethyl acetate, 84 ml of formic acid, 338 ml of amide and 169 ml of dimethylformamide were stirred at 140 ° C. After a few hours, it was placed at room temperature for 24 hours, and the precipitated solid was filtered and dried under reduced pressure to give the title compound 41 g, j-NMR spectrum: (DMS 〇-d6) 5.12 (2H, s) 5- 6.78 (1H, s), 7.03 (2H, d, J=7.0 Hz), 7.28-7.47 (5H, m), 7.73 (2H, d, J=7.0 Hz), -252 - This paper size applies to the Chinese National Standard (CNS) A4 size (210 x 297 public) 1304061 A7 B7 V. Description of invention (247 7.82 (1H, s), 11.80 (1H, br s), 12.20 (1H, br s). Manufacturing example 153-3 gas base) -4-Chloro-Bilozepine f2,3-dlp·mystosis 6-(4-oxyloxyphenyl)-711-7 synthesized in Preparation Example 153-2 啥[2 3(^ - 20 g of alcohol, after adding 200 ml of oxychlorinated scale and 3 hours at 140 ° C, the reaction system was concentrated at room temperature. Water was added to the residue, then ethyl acetate-tetrahydrofuran (5:1) Mixed solvent separation The organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated to dryness to afford compound 12 g. iH-NMR spectrum: (DMSO-d6) 5·18 (2H, s), 6.97 (1H,d, J=24

Hz), 7.12 (2H, d, J=7.5 Hz), 7.30-7.50 (5H, m), 7.94 (2H, d J=7.5 Hz)，8.70 (1H，s)，12.90 (1H，br s)。 ’ 製造例153-4 6- (4-芊氧苯基）-4-氯-7- (2-三甲碎燒基乙氫曱某） 并「2,341卷碎 在製造例153-3中合成之6-(4-芊氧苯基)、-4-氯-711-吡哈并 [2,3-(1]^密淀2.46 g之二甲基甲酿胺（30 ml)溶液中，加入氣 化鈉（60%分散液，Aldrich)0.381 g (1.3當量）及於室溫攪掉 40分鐘後，加入2-(氯甲氧基）乙基三甲基矽烷丨.68 ml (13 當量）並於室溫授拌整夜，然後加入水2〇 ml及乙酸1 mi，並 用乙酸乙酯-四氫呋喃（5 : 1)混合溶媒分液萃取。將有機層 用硫酸鈉乾燥，濃縮及進行NH矽凝膠管柱層析（乙酸乙 酯），得到標題化合物2.83 g。 : 光譜：（DMS〇-d6) -0.10 (9H，s)，0.84 (2H：，t，J=8.〇 -253 - 本纸張尺度適用中㈣家鮮(CNS) A4規格(210 X 297公爱） &quot; -— 1304061 〜 -… A7 B7 五、發明説明（248 )Hz), 7.12 (2H, d, J=7.5 Hz), 7.30-7.50 (5H, m), 7.94 (2H, d J=7.5 Hz), 8.70 (1H, s), 12.90 (1H, br s). 'Manufacturing Example 153-4 6-(4-Indolylphenyl)-4-chloro-7-(2-trimethylpyridylhydroquinone) and "2,341-volumes were synthesized in Preparation Example 153-3" -(4-oxophenyl), 4-chloro-711-pyhaha[2,3-(1]^-precipitated 2.46 g of dimethylcaraamine (30 ml), added to gasification Add sodium (60% dispersion, Aldrich) 0.381 g (1.3 eq.) and stir at room temperature for 40 minutes, then add 2-(chloromethoxy)ethyltrimethyldecane 丨.68 ml (13 eq.) The mixture was stirred overnight at room temperature, then 2 ml of water and 1 mi of acetic acid were added, and extracted with a mixture of ethyl acetate-tetrahydrofuran (5:1). The organic layer was dried over sodium sulfate, concentrated and evaporated. Column chromatography (ethyl acetate) gave the title compound 2.83 g.: Spectrum: (DMS 〇-d6) -0.10 (9H, s), 0.84 (2H:,t,J=8.〇-253 - paper Zhang scale is applicable (4) Home Fresh (CNS) A4 specification (210 X 297 public) &quot; - 1304041 ~ -... A7 B7 V. Invention description (248)

Hz), 3.62 (2H, t, J=8.0 Hz), 5.20 (2H, s), 5.61 (2H, s), 6.81 (1H, s)5 7.1.9 (2H, d, J=7.7 Hz), 7.33-7.52 (5H, m), 7.88 (2H, d，J=7.7 Hz), 8.70 (1H，s)。 造例 153-5 4-「6-(4-芊氧苯基）-7-(2-三甲矽烷基乙氲甲基）_7只-扑卜洛畔_ f 2.3-dl嘧啶-4-基氳1-2-氣笨胺 在製造例153-4合成之6-(4-芊氧苯基）-4-氯j-(2-三甲碎 烷基乙氧甲基）-7H-吡咯并[2,3-d]嘧啶中加入二曱基亞石風 12 ml，然後於攪拌下加入氫化鈉（60%分散液，Hz), 3.62 (2H, t, J=8.0 Hz), 5.20 (2H, s), 5.61 (2H, s), 6.81 (1H, s)5 7.1.9 (2H, d, J=7.7 Hz), 7.33-7.52 (5H, m), 7.88 (2H, d, J = 7.7 Hz), 8.70 (1H, s). Example 153-5 4-"6-(4-Oxyloxyphenyl)-7-(2-trimethyldecylethylidenemethyl)_7-Pupoline_f 2.3-dl-pyrimidin-4-ylindole 1-(4-Phenyloxyphenyl)-4-chloroj-(2-trimethyl-alkyl ethoxymethyl)-7H-pyrrolo[2] synthesized in Preparation Example 153-4 , 3-d] pyrimidine was added with 12 ml of diterpene sulphur wind, and then sodium hydride (60% dispersion was added with stirring).

Aldrich)141 mg (1·5 當量）及 4-胺基-3-氯酚 5〇7 mg(1.5 當 量），於室溫攪捽10分鐘後，在135- 140t攪拌4小時。之後 回到室溫，加入水及用乙酸乙酯-四氫吱喃（5: 1)混合溶媒 分液萃取。將有機層用硫酸鈉乾燥，濃縮及付諸於NH碎凝 膠管柱層析（己烷-乙酸乙酯），得到標題化合物1,2〇 g。 j-NMR 光 1f:(DMSO-d6) -0·90 (9H，s), 0.85 (2H，t，J=8 〇Aldrich) 141 mg (1.5 eq) and 4-amino-3-chlorophenol 5 〇 7 mg (1.5 eq.), stirred at room temperature for 10 minutes, and stirred at 135-140 Torr for 4 hours. After that, it was returned to room temperature, and water was added thereto and extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (5:1). The organic layer was dried with EtOAc (EtOAc m. j-NMR light 1f: (DMSO-d6) -0·90 (9H, s), 0.85 (2H, t, J=8 〇

Hz), 3.61 (2H, t, J=8.0 Hz), 5.18 (2H, s),%5.34 (2H, s), 5.59 (2H, s), 6.64 (1H, s), 6.85 (1H, d, J=8.0 Hz), 6.95-6.99 (1H rn), 7.15-7.20 (3H, ro), 7.30-7.55 (5H, m), 7.71 (2H d 1=8 0 Hz), 8·41 (1H，d，J=1.4 Hz)。 製造例153-6 6- (4-芊氧苯基）-7- (2-三甲石夕燒基^^甲某）· 7H- 口比 哈并「2,3-dlp密淀-4-基乳1-2 -氯笨某丨-3-環—否基_ 將製造例153-5合成之4-[6-(4-苄氧苯。基三甲碎垸 基乙氧甲基）-7H-吡咯并[2,3-d]嘧啶-4-基氧μ2-氯苯胺334 _ - 254 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱j ---- 1304061 A7 -_ B7 _^_ 五、發明説明（249 ) mg溶於二甲基甲醯胺4 ml，加入吡啶0.066 ml (1·4當量）及 氯碳酸苯酯0.102 ml(1.4當量），及於室溫攪拌2·5小時後， 加入環丙胺0·09 ml(2.2當量）及揽拌整夜。加入水，用乙酸 乙酯分液萃取，將有機層用飽和食鹽水洗淨，用硫酸鈉乾 燥，濃縮及付諸於矽凝膠管柱層析（己烷-乙酸乙酯），得到 標題化合物3 3 0 mg MS 光譜（ESI) : 656 (M+l) , 678(M+23)， iH-NMR光譜：（DMSO-d6) -〇·〇9 (9H，s)，0·40-0·46 (2H，m)， 0.63-0.70 (2Η, m), 0.87 (2H, t, J=7.8 Hz), 2.43-2.62 (1H, m), 3.62 (2H, t5 J=7.8 Hz), 5.20 (2H, s), 5.60 (2H, s), 6.75 (1H, s), 7.15-7.53 (9H, m), 7.73 (2H, d, J=8.6 Hz), 7.94 (1H, s), 7.93 (1H, s), 8.18 (1H, d, J=9.0 Hz), 8.41 (1H, d, J=1.8 Hz) 〇 製造例153-7 氣-4-46-( 4-羥苯基）-7-( 2-三甲矽烷基乙氫甲基 并『2,3-dl嘧啶-4-基氣1-2-苯某丨-3_癀兩葚月释 將製造例153-6合成之1- {4-[6-(4-芊氧苯基）-7-(2-三甲 碎垸基乙氧甲基）-7H- p比洛并[2,3- d]。密淀-4-基氧卜2-氯苯 基}-3 -環丙基脲260 mg溶於乙醇1 〇 ml及四氫啥喃5 ml中， 加入氧化鉑100 mg，以及於室溫及常溫下在氫氣蒙氣中授 拌整夜後，經矽藻土過濾及減壓濃縮。將殘餘物付諸於碎 凝膠管柱層析（己烷-乙酸乙酯），得到標題化合物160〇^。 !H-NMR光譜：（DMSO-d6) -0.09 (9H，s); 0.40-0.46 (2H，m)， 0.63-0.70 (2H，m)，0·86 (2H，t，J=8.1 Hz)，2.53-2.62 (1H，m)， -255 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 、 〜 A7 _____ B7 五、發明説明（250 ) 3.62 (2H, t, J=8.1 Hz), 5.58 (2H, s), 6.67 (1H, s), 6.90 (2H5 d, J=8.2 Hz.), 7.13-7.22 (2H, m), 7.43-7.47 (1H, m), 7.60 (2H, d, J=8.2 Hz), 7.93 (1H, s), 8.17 (1H, d, J=9.1 Hz), 8.40 (1H, s), 9.38 (1H，br s) « 製诰你I 153-8 l-{2-氣-土「hLl-(2-二乙胺基-2-蕤基苯氣基茉基1-7-(2-三甲矽烷基i氧甲基）-7H-吡咯并f2,3-dl嘧啶-4-基氣1-茉某卜3-璦丙基脲 將製造例153-7合成之1- {2-氯-4-[6-(4-羥苯基）-7-(2-三 曱矽烷基乙氧甲基）-7H-吡咯并[2,3-d]嘧啶-4-基氧]-2-苯 基}-3-環丙基脲113 mg溶於二甲基曱醯胺1 mi中，加入2-鼠乙基一乙胺鹽故鹽120 mg(3.5當量）及破酸却138 mg(5當 量），並於80°C揽拌15小時。之後，返回室溫，加入水及用 乙酸乙酯分液萃取。將有機層用硫酸鈉乾燥，濃縮及付諸 於NH矽凝膠管柱層析（己烷-乙酸乙酯），得到標題化合物 40mg 0 、 MS光譜（ESI) : ·665 (M+1), h-NNIR光譜：（DMSO-d6) -0.09 (9H，s)，0.40-0.47 (2H，m), 0.63-0.70 (2H, m), 0.87 (2H, t, J=8.9 Hz), 0.99 (6Ή, t, J=8.0 Hz), 2.52-2.62 (5H, m), 2.80 (2H, t, J=8.0 Hz), 3.62 (2H, t5 J=8.9 Hz), 4.10 (2H, t, J=8.0 Hz), 5.60 (2H, s), 6.72 (1H, s)3 7.08 (2H, d, J=8.1 Hz), 7.17 (1H, d, J=3.2 Hz), 7.21 (1H, dd, J=3.2, 8.4 Hz), 7.46 (1H, d, J=3.2 Hz)； 7.71 (2H, d, J=8.1Hz), 3.61 (2H, t, J=8.0 Hz), 5.18 (2H, s), %5.34 (2H, s), 5.59 (2H, s), 6.64 (1H, s), 6.85 (1H, d, J=8.0 Hz), 6.95-6.99 (1H rn), 7.15-7.20 (3H, ro), 7.30-7.55 (5H, m), 7.71 (2H d 1=8 0 Hz), 8·41 (1H,d , J = 1.4 Hz). Production Example 153-6 6-(4-芊-Oxophenyl)-7- (2-trimethyl sulphide) ^ 7H- 口比哈和"2,3-dlp密-4- Milk 1-2 -Chloro Benzene-3-Cyclo-N-based 4-[6-(4-Benzyloxyphenyl.trimethylammonium ethoxymethyl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yloxy μ2-chloroaniline 334 _ - 254 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 public love j ---- 1304061 A7 - _ B7 _^_ V. Description of the invention (249 ) mg dissolved in 4 ml of dimethylformamide, adding 0.066 ml (1.4 eq) of pyridine and 0.102 ml (1.4 eq) of phenyl chlorocarbonate, and at room temperature After the mixture was stirred for 2 hours, the mixture was stirred with EtOAc (EtOAc). Concentration and column chromatography on silica gel (hexane-ethyl acetate) afforded the title compound 303 (m): ESI (ESI): 656 (M+l), 678 (M+23), iH- NMR spectrum: (DMSO-d6) - 〇·〇9 (9H, s), 0·40-0·46 (2H, m), 0.63-0.70 (2Η, m), 0.87 (2H, t, J=7.8 Hz), 2.43-2.62 (1H, m), 3 .62 (2H, t5 J=7.8 Hz), 5.20 (2H, s), 5.60 (2H, s), 6.75 (1H, s), 7.15-7.53 (9H, m), 7.73 (2H, d, J= 8.6 Hz), 7.94 (1H, s), 7.93 (1H, s), 8.18 (1H, d, J=9.0 Hz), 8.41 (1H, d, J=1.8 Hz) 〇Manufacturing Example 153-7 Gas-4 -46-(4-hydroxyphenyl)-7-(2-trimethylsulfanylethylhydromethyl and 2,3-dl pyrimidin-4-yl gas 1-2-benzene 丨-3_癀 two months The 1-{4-[6-(4-indolylphenyl)-7-(2-trimethylpyridylethoxymethyl)-7H-p-pylorin[2, 3-d]. Methyl 4-methyloxy-2-chlorophenyl}-3-cyclopropylurea 260 mg is dissolved in 1 ml of ethanol and 5 ml of tetrahydrofuran, and platinum oxide 100 mg is added, After being stirred overnight in a hydrogen atmosphere at room temperature and normal temperature, it was filtered through celite and concentrated under reduced pressure. The residue was applied to a gel column chromatography (hexane-ethyl acetate). The title compound is 160〇^. !H-NMR spectrum: (DMSO-d6) -0.09 (9H, s); 0.40-0.46 (2H, m), 0.63-0.70 (2H, m), 0·86 (2H, t, J = 8.1 Hz) , 2.53-2.62 (1H, m), -255 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061, ~ A7 _____ B7 V. Invention description (250) 3.62 (2H, t, J=8.1 Hz), 5.58 (2H, s), 6.67 (1H, s), 6.90 (2H5 d, J=8.2 Hz.), 7.13-7.22 (2H, m), 7.43-7.47 (1H, m ), 7.60 (2H, d, J=8.2 Hz), 7.93 (1H, s), 8.17 (1H, d, J=9.1 Hz), 8.40 (1H, s), 9.38 (1H,br s) « System You I 153-8 l-{2-gas-soil "hLl-(2-diethylamino-2-mercaptophenoxymethyl 1-7-(2-trimethyldecyl i-oxymethyl)-7H -pyrrolo-f2,3-dl-pyrimidin-4-yl gas 1-moumab 3-mercaptopropyl urea 1-{2-chloro-4-[6-(4-hydroxybenzene) synthesized in Production Example 153-7 -7-(2-tridecyl ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-phenyl}-3-cyclopropylurea 113 Mg is dissolved in 1 mi of dimethyl decylamine, adding 2-methyl-2-ethylamine salt, 120 mg (3.5 eq.) and 138 mg (5 eq.) of deacidified acid, and mixing at 80 °C. Hours. After that, return to room temperature and add water and The EtOAc was extracted with EtOAc (EtOAc)EtOAc. 665 (M+1), h-NNIR spectrum: (DMSO-d6) -0.09 (9H, s), 0.40-0.47 (2H, m), 0.63-0.70 (2H, m), 0.87 (2H, t, J =8.9 Hz), 0.99 (6Ή, t, J=8.0 Hz), 2.52-2.62 (5H, m), 2.80 (2H, t, J=8.0 Hz), 3.62 (2H, t5 J=8.9 Hz), 4.10 (2H, t, J=8.0 Hz), 5.60 (2H, s), 6.72 (1H, s)3 7.08 (2H, d, J=8.1 Hz), 7.17 (1H, d, J=3.2 Hz), 7.21 (1H, dd, J=3.2, 8.4 Hz), 7.46 (1H, d, J=3.2 Hz); 7.71 (2H, d, J=8.1

Hz), 7·94 (1H，s)，8.18 (1H，d，J=8.4 Hz), 8.40 (1H，s)。 -256 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 〜 一- A7 B7_______ 五、發明説明（251 ) 實施例15 4 U2 -氯-4- { 1-毗格迄一幕）乙乳基）：+基1二_?衫·吡哈· 斿f2,3-dl嘧啶-4-某氫丨茉基}^-環丙基 藉由與實施例153同樣之方法，從氯-4-[6-[4-(2-吡 咯啶乙氧基）-苯基]-7-(2-三甲矽烷乙氧甲基）-7Η·吡咯并 [2,3-d]嘧啶-4-基氧]-苯基卜3-環丙基脲25 mg得到標題化 合物13 mg。 MS 光譜（ESI) : 533 (M+1)， iH-NMR 光譜：（DMS〇-d6) 〇·4〇-〇·45 (2H，m)，0.60-0.70 (2H， m), 1.65-1.72 (4H, m), 2.47-2.60 (5H, m, covered by DMSO peak), 2.70 (2H, t, J=7.6 Hz), 4.12 (2H, t, J=7.6 Hz), 6.82 (1H, s), 7.02 (2H, d, J=8.5 Hz), 7.13 (1H, d, J=2.6 Hz), 7.17 (1H, dd, J=2.6, 8.5 Hz), 7.41 (1H? d, J=2.6 Hz), 7.87 (2H, d, J=8.5 Hz), 7.91 (1H, s), 8.14 (1H, d, J=8.5 Hz), 8.26 (1H, s), 12.59 (1H，br s)。 製造例154-1 ' 1 - { 2-氩-4-「6-『4- ( 2· Π -毗疼啶基）乙氣基）-苯基]二彡 甲矽烷乙氫甲基吡咯# f2,3-dl嘧啶-4-基氧1苯基1二3二 環丙某胧 藉由與製造例153-8同樣之方法，從製造例153_ 7合成之 1-{2-氯-4-[6-(4-羥苯基）-7-(2-三甲矽烷基乙氧甲基）-7]^ 吡咯并[2,3-d]嘧啶-4-基氧]-2-苯基}-3-環丙基脲86 mg， 1-(2-氯乙基）吡咯啶鹽酸鹽104 mg及碳-·酸鉀126 mg，得到 標題化合物27 mg。 -257 - ___ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061Hz), 7·94 (1H, s), 8.18 (1H, d, J = 8.4 Hz), 8.40 (1H, s). -256 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 ~ A-A7 B7_______ V. Description of invention (251) Example 15 4 U2 - Chloro-4- { 1-Pygge As a result, in the same manner as in Example 153, the same method as in Example 153 was carried out in the same manner as in Example 153. From chloro-4-[6-[4-(2-pyrrolidinylethoxy)-phenyl]-7-(2-trimethyldecaneethoxymethyl)-7Η·pyrrolo[2,3-d]pyrimidine -4-yloxy]-phenyl- 3-cyclopropyl urea 25 mg gave the title compound 13 mg. MS (ESI): 533 (M+1), iH-NMR spectrum: (DMS 〇-d6) 〇·4〇-〇·45 (2H, m), 0.60-0.70 (2H, m), 1.65-1.72 (4H, m), 2.47-2.60 (5H, m, covered by DMSO peak), 2.70 (2H, t, J=7.6 Hz), 4.12 (2H, t, J=7.6 Hz), 6.82 (1H, s) , 7.02 (2H, d, J=8.5 Hz), 7.13 (1H, d, J=2.6 Hz), 7.17 (1H, dd, J=2.6, 8.5 Hz), 7.41 (1H? d, J=2.6 Hz) , 7.87 (2H, d, J=8.5 Hz), 7.91 (1H, s), 8.14 (1H, d, J=8.5 Hz), 8.26 (1H, s), 12.59 (1H, br s). Production Example 154-1 ' 1 - { 2- Argon-4-"6-"4-(2·Π-Pyridinyl)Ethyl)Phenyl] Dimethylhydrazine Ethyl Hydroxypyrrole #f2 3-{2-chloro-4-[4-chloro-4-[[3-chloro-4-[] synthesized from the production example 153-7 by the same method as in Production Example 153-8. 6-(4-Hydroxyphenyl)-7-(2-trimethyldecyl ethoxymethyl)-7]^pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-phenyl}- 3-cyclopropylurea 86 mg, 1-(2-chloroethyl)pyrrolidine hydrochloride 104 mg and potassium-potassium 126 mg, the title compound 27 mg. -257 - ___ This paper size applies to China Standard (CNS) A4 size (210 X 297 mm) 1304061

AT B7 五、發明説明（252 ) MS 光譜（ESI) : 663 (M+1)， ifi-NMR光譜：（DMSO-d6) -0.09 (9H，s)，0·40·0·44 (2H，m)， 0·61-0·69 (2H，m)，0.85 (2H，t，J=8.0 Hz)，1·61-1·76 (4H，m)， 2.44-2.61 (5H, m, covered by DMSO peak), 2.86 (2H, t, J=8.0 Hz), 3.61 (2H, t, J=8.0 Hz), 4.13 (2H, t, J=8.0 Hz), 5.79 (2H，s)，6.72 (1H，s)，7·09 (2H，d，J=8.7 Hz)，7.15 (1H， d, J=8.7 Hz), 7.20 (1H, dd, J=2.5, 8.7 Hz), 7.44 (1H, d, J=2.5 Hz)，7·71 (2H，d，J=8.7 Hz)，7·93 (1H，s)，8.16 (1H，d， J=8.7 Hz), 8·39 (1H，s)。 實施例155 1-(2-氯-4- { 6-Γ4-(2-( 1-g比疼咬基）丙乳基）本基1-7H- ?比♦ # f2.3-dl嘧啶-4-基氣丨茉某V3-環丙某月尿 藉由與實施例153同樣之方法，從1-{2-氯-4·[6-[4-(2-(1-吡咯啶基）丙氧基）苯基]-7-(2-三甲矽烷乙氧曱基）-7Η_ ρ比洛并[2，3 -Ά 密淀-4-基氧]苯基]-3 -環丙基踩28 mg得到標 題化合物11 mg。 ·、 MS 光譜（ESI) : 547 (M+1)， Μ造例155-1 1·{2-氣-4-「6 -「4 -(3-(1-?比疼咬某）丙氣基）笨基1-7-(2-三 甲矽烷乙氧甲基）-7H-吡咯并「2.3-dl嘧啶-4-某氣1笨基卜3-瑷丙基脲 藉由與製造例1 53-8同樣之方法，從製造例1 53-7合成之 1- {2-氯-4-[ 6-(4-羥苯基）-7-( 2-三曱矽烷基乙氧甲基）-7H-吡咯并[2，3-d]嘧啶-4-基氧]-2-苯基卜3 -環丙基脲96 mg， -258 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 一 — 一 A7 ____B7 五、發明説明（253 ) 1-(3-氯丙基）p比洛咬146 mg，礙酸4甲150 mg及礎化卸15 mg ’得到標題化合物2 8 mg。 MS 光譜（ESI) : 677 (M+1)， W-NMR光譜：（DMSO-d6) -0.09 (9H，s)，0.39-0.47 (2H m) 0·63-0·70 (2H，m)，0·87 (2H，t，J=8.0 Hz)，1.63-1.73 (4H，m) 1.88-1.96 (2H, m), 2.40-2.62 (7H, m, covered by DMSO peak), 3.61 (2H, t, J=8.1 Hz), 4.09 (2H, t, J=6.6 Hz), 5.60 (2H，s)，6.72 (1H，s)，7.08 (2H，d，J=8.9 Hz), 7·16 (1H，d， J=2.6 Hz)，7.21 (1H，dd，J=2.4, 8·9 Hz)，7·46 (1H，d，J=2.6 Hz)，7·71 (2H，d，J=8.9 Hz)，7·95 (1H，s)，8.18 (1H，d，J=8.9AT B7 V. Inventive Note (252) MS Spectrum (ESI): 663 (M+1), ifi-NMR spectrum: (DMSO-d6) -0.09 (9H, s), 0·40·0·44 (2H, m), 0·61-0·69 (2H,m), 0.85 (2H,t,J=8.0 Hz),1·61-1·76 (4H,m), 2.44-2.61 (5H, m, covered By DMSO peak), 2.86 (2H, t, J=8.0 Hz), 3.61 (2H, t, J=8.0 Hz), 4.13 (2H, t, J=8.0 Hz), 5.79 (2H, s), 6.72 ( 1H, s), 7·09 (2H, d, J = 8.7 Hz), 7.15 (1H, d, J = 8.7 Hz), 7.20 (1H, dd, J=2.5, 8.7 Hz), 7.44 (1H, d , J=2.5 Hz), 7·71 (2H, d, J=8.7 Hz), 7.93 (1H, s), 8.16 (1H, d, J=8.7 Hz), 8·39 (1H, s) . Example 155 1-(2-Chloro-4-{6-Γ4-(2-(1-g-heavy) propyl)-based group 1-7H-? ratio ♦ #f2.3-dl-pyrimidine- 4-Based gas 丨 某 V V V V V V V V V V V v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v v Propoxy)phenyl]-7-(2-trimethyldecaneethoxy oxyl)-7Η_ ρ piroxi[2,3 -indole -4-yloxy]phenyl]-3 -cyclopropyl 28 mg gave the title compound 11 mg. · MS Spectrum (ESI): 547 (M+1), Μ 155 1-5 1 1 { 2- 「 「 「 「 「 「 「 「 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- ? Bitter bite) Propylene base) Stupid base 1-7-(2-trimethyldecane ethoxymethyl)-7H-pyrrole and "2.3-dl pyrimidine-4-one gas 1 stupid base 3-mercaptopropyl Urea 1-{2-chloro-4-[6-(4-hydroxyphenyl)-7-(2-triterpene) synthesized from Production Example 1 53-7 by the same method as in Production Example 1 53-8矽Alkyl ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-phenyldi-3-cyclopropylurea 96 mg, -258 - This paper size applies to China Standard (CNS) A4 size (210 X 297 mm) 1304061 I—A7 ____B7 V. Description of invention (253) 1-(3-Chloropropyl)p ilo 146 mg, acid 4 A 150 mg and base Chemical 15 mg 'Yield the title compound 2 8 mg. MS Spectrum (ESI): 677 (M+1), W-NMR spectrum: (DMSO-d6) -0.09 (9H, s), 0.39-0.47 (2H m) 0· 63-0·70 (2H,m),0·87 (2H,t,J=8.0 Hz),1.63-1.73 (4H,m) 1.88-1.96 (2H, m), 2.40-2.62 (7H, m, Covered by DMSO peak), 3.61 (2H, t, J=8.1 Hz), 4.09 (2H, t, J=6.6 Hz), 5.60 (2H, s), 6.72 (1H, s), 7.08 (2H, d, J=8.9 Hz), 7·16 (1H,d, J=2.6 Hz), 7.21 (1H, dd, J=2.4, 8·9 Hz), 7·46 (1H, d, J=2.6 Hz), 7·71 (2H,d,J=8.9 Hz), 7.95 (1H, s), 8.18 (1H, d, J=8.9

Hz)，8·40 (1H，s)。 f施例156 1-Π-氯-4-「6-「4-((2ΙΟ-2-# 某-3-二乙胺丙氲某）茇基 &gt; 7H-吡咯并f2,3-dl嘧啶-4-基氣1苽某卜3-環丙某月尿 藉由與宽施例153同樣之方法，從1-{2-氯-4-[6-[4-((2S)-2-羥基-3-二乙胺丙氧基）苯基]-7-·&lt;2-三甲矽烷乙氧 甲基）-7Η-吡咯并[2,3-d]嘧啶-4-基氧]苯基}-3-環丙基脲22 mg，得到標題化合物11 mg。 MS光譜（ESI) : 565 (M+1)， iH-NMR光譜：（DMS〇-d6) 0.40-0.47 (2H，m)，0·63-0·70 (2H， m), 0.96 (6H5 t, J=6.6 Hz), 2.45-2.63 (7H, m, covered by DMSO peak), 3.80-4.10 (3H, m), 6.93 (1H, s), 7.04 (2H, d, J=8.6 Hz), 7.15 (1H, d, J=2.2 Hz), 7.19-(1H, dd, J=2.2, 8.6 Hz), 7.43 (1H, d, J=2.2 Hz), 7.88 (2H, d, J=8.6 Hz), 7.93 (1H, -259 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7五、發明説明（254 ) s)，8.16 (1H，d，J=8.6 Ηζ)，8·28 (1H，s)，12.60 (1H，br s)。 製造例156-1 1-{2-氯-4-【6-「4-((?_^1^」^基二^二乙胺丙氫莘&gt;&gt;苯某1-7_ (2-三曱矽烷乙氣甲基）-7H-吡咯并「2.3-dl嘧篡氧1草 某}-3-環丙基脲 將製造例153-7合成之1- {2-氯-4-[6-(4-羥苯基）-7-(2-三 甲矽烷基乙氧曱基）-7H-吡咯并[2,3-d]嘧啶-4-基氧]-2-苯 基}·_3 -環丙基膽75 mg &gt;谷於一甲基甲酿胺1 ml中，加入對· 甲苯磺酸（2S)-( + )-縮水甘油酯91 mg (3當量）及碳酸鉀92 mg(5當量），並於75t攪拌8小時。之後，返回室溫，將反 應系統過滤’在滤液中加入二乙胺0.1 ml，並於70 °C揽拌8 小時。之後加入水及用乙酸乙酯-四氫吱喃分液萃取。將有 機層濃縮及付諸於NH石夕凝膠管柱層析（己燒-乙酸乙酯）， 得到標題化合物24mg。 MS 光譜（ESJ) : 695 (M+1)， j-NMR光譜：（DMSO-d6) -0.09 (9H，s)，〇、·39-0·47 (2H，m)， 0.63-0.70 (2H, m), 0.86 (2H, t5 J=8.3 Hz), 0.97 (6H, t, J=7.0 Hz), 2.38-2.60 (7H, m), 3.61 (2H, t, J=8.3 Hz), 3.83-4.11 (3H，m)，4.82 (1H，br s)，5.59 (2H，s)，6·73 (1Η，s)，7.08 (2H， d, J=8.5 Hz), 7.18 (1H, d, J=2.7 Hz), 7.21 (1H, dd, J=2.7, 8.5 Hz), 7.45 (1H, d, 1=2.1 Hz), 7.71 (2H, d, J=8.5 Hz), 7.94 (1H, s), 8.18 (1H, d，J=8.5 Hz), 8·40 (1H，s)。 實施例157 : 1-{2-氯-4-『6-『4-((21〇-2-范基：3-二乙脖丙氛某）笨基1-7· -260 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 B7 五、發明説明（255 ) (2.: XJ7·.亨烷乙氧它ϋ-7ίί-生务差「21” p杂々-4·某氳1笨 基卜3-環丙某Μ 藉由與實施例153同樣之方法，從ΐ-{2•氯-4-[6-[4· ((2R) -2-#呈基-3-二乙胺丙氧基）笨基]_7-(2-三甲矽燒乙氧 甲基）-7Η-吡咯并[2,3-d]嘧啶-4-基氧]苯基卜3·環丙基踩22 mg，得到標題化合物11 mg。 MS光譜（ESI) : 565 (M+1)， WNMR光譜：（DMSO-d6) 0.40-0.47 (2H，m)，0.63·0·70 (2H， m)，0.96 (6H，t，J-6.6 Hz)，2.45-2.63 (7H，m，covered by DMS〇 peak)，3.80-4.10 (3H，m)，6·93 (1H，s)，7.04 (2H，d J=8.6 Hz)，7·16 (1H，d，J=2.2 Hz)，7.19 (1H，dd，j=2.2，8.6 Hz)，7.43 (1H，d，J=2.2 Hz), 7.89 (2H，d，J=8.6 Hz)，7.94 (1H， s)，8.16 (1H，d，J=8,6 Hz)，8·28 (1H，s)，12.60 (1H，br s)。 製造例157-1 1二f 4- ((2R) - 2-羥基-乙胺丙氳篡、苯芊 麥烷乙氧甲基）-7H-吡咯连丄2,3_ dl嘧啶-4·其^^ 基} _ 3 ·玉哀丙基脉 藉由與製造例153-9同樣之方法，並使用對-甲苯續酸 (2R)-縮水甘油酯1 54 mg，硬酸却1 55 mg及二乙胺〇 15 ml，從1-{ 2-氯-4-[6-(4-羥苯基）-7-(2-三甲矽烷乙氧甲 基）-7H-吡咯并[2,3-d]嘧啶-4-基氧]-2-苯基卜3 -環丙i踩 127 mg得到標題化合物62 mg。 MS 光譜（ESI) : 695 (M+ 1)， ^•NMR光 if :(DMS〇-d6) -0·09 (9H，s)，0.39-0.47 (2H m) -261 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐)Hz), 8·40 (1H, s). fExample 156 1-Π-chloro-4-"6-"4-((2ΙΟ-2-# -3-ethylethyl propyl hydrazide) sulfhydryl] 7H-pyrrolof2,3-dl pyrimidine -4-Base gas 1 苽 卜 3- 环 环 3- 某 某 某 某 某 某 某 某 某 某 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- Hydroxy-3-diethylaminepropoxy)phenyl]-7-·&lt;2-trimethyldecaneethoxymethyl)-7Η-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 0·63-0·70 (2H, m), 0.96 (6H5 t, J=6.6 Hz), 2.45-2.63 (7H, m, covered by DMSO peak), 3.80-4.10 (3H, m), 6.93 (1H , s), 7.04 (2H, d, J=8.6 Hz), 7.15 (1H, d, J=2.2 Hz), 7.19-(1H, dd, J=2.2, 8.6 Hz), 7.43 (1H, d, J =2.2 Hz), 7.88 (2H, d, J=8.6 Hz), 7.93 (1H, -259 - This paper size applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) 1304061 A7 B7 V. Description of invention (254) s), 8.16 (1H, d, J = 8.6 Ηζ), 8·28 (1H, s), 12.60 (1H, br s). Manufacturing Example 156-1 1-{2-Chloro-4-[ 6-"4-((?_^1^"^基二^diethylaminepropanehydroquinone&gt;&gt;Benzene 1-7_(2-trioxaneethylmethyl)-7H-pyrrole and "2.3-dl-pyrimidinium 1 grass"-3-cyclopropylurea 1-1/2 of the synthesis example 153-7 Chloro-4-[6-(4-hydroxyphenyl)-7-(2-trimethyldecyl ethoxycarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2- Phenyl}·_3 -cyclopropyl biliary 75 mg &gt; glutamic acid in 1 ml of monomethyl amide, and added p-toluenesulfonic acid (2S)-( + )-glycidyl ester 91 mg (3 equivalents) Potassium carbonate 92 mg (5 eq.) and stirred at 75t for 8 hours. After that, return to room temperature and filter the reaction system. Add 0.1 ml of diethylamine to the filtrate and mix at 70 ° C for 8 hours. The extract was extracted with ethyl acetate-tetrahydromethane. MS spectroscopy (ESJ): 695 (M+1), j-NMR spectrum: (DMSO-d6) -0.09 (9H, s), 〇, · 39-0·47 (2H, m), 0.63-0.70 (2H , m), 0.86 (2H, t5 J=8.3 Hz), 0.97 (6H, t, J=7.0 Hz), 2.38-2.60 (7H, m), 3.61 (2H, t, J=8.3 Hz), 3.83- 4.11 (3H, m), 4.82 (1H, br s), 5.59 (2H, s), 6.73 (1Η, s), 7.08 (2H, d, J = 8.5 Hz), 7.18 (1H, d, J =2.7 Hz), 7.21 (1H, dd, J=2.7, 8.5 Hz), 7.45 (1H, d, 1=2.1 Hz), 7.71 (2H, d, J=8.5 Hz), 7.94 (1H, s), 8.18 (1H, d, J = 8.5 Hz), 8·40 (1H, s). Example 157: 1-{2-Chloro-4-"6-"4-((21〇-2-Fanyl: 3-di-Ben-Cycle) Stupid Base 1-7·-260 - Paper Size Applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Invention description (255) (2.: XJ7·.Heptane ethoxylated ί-7ίί-Life difference "21" p 々-4·氲1笨基基卜3-Cyclopropene 藉 By the same method as Example 153, from ΐ-{2•chloro-4-[6-[4· ((2R) -2-# Benzyl-3-diethylaminepropoxy)phenyl]]7-(2-trimethylhydrazine ethoxymethyl)-7Η-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl 3·Cyclopropyl tread 22 mg to give the title compound 11 mg. MS spectrum (ESI): 565 (M+1), WNMR spectrum: (DMSO-d6) 0.40-0.47 (2H, m), 0.63·0·70 (2H, m), 0.96 (6H, t, J-6.6 Hz), 2.45-2.63 (7H, m, covered by DMS〇peak), 3.80-4.10 (3H, m), 6.93 (1H, s) , 7.04 (2H, d J=8.6 Hz), 7·16 (1H, d, J=2.2 Hz), 7.19 (1H, dd, j=2.2, 8.6 Hz), 7.43 (1H, d, J=2.2 Hz) ), 7.89 (2H,d,J=8.6 Hz), 7.94 (1H, s), 8.16 (1H,d,J=8,6 Hz),8·28 (1H,s),12.60 (1H,br s Manufacturing Example 157-1 1 f 4- ((2R)-2-hydroxy-ethylamine propyl hydrazine, benzoquinone ethoxymethyl)-7H-pyrrole hydrazine 2,3_ dl pyrimidine-4·其^^ 基} _ 3 ·Jade The propyl propyl group was obtained by the same method as in Production Example 153-9, and using p-toluene acid (2R)-glycidyl ester 1 54 mg, hard acid but 1 55 mg and diethylamine hydrazine 15 ml, from 1 -{ 2-chloro-4-[6-(4-hydroxyphenyl)-7-(2-trimethyldecaneethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy] -2-Phenyl 3-cyclopropane i stepped on 127 mg to give the title compound 62 mg. MS Spectrum (ESI): 695 (M+ 1), NMR light: (DMS 〇-d6) -0·09 (9H ,s),0.39-0.47 (2H m) -261 - This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm)

裝 η 線 1304061 A7 B7 五、發明説明（256 ) 0.63-0.70 (2H, in), 0.86 (2H, t3 J=8.3 Hz), 0.97 (6H, t, J=7.0 Hz)，2.38-2.60 (7H，m，covered by DMS〇 peak)，3·61 (2H，t， J=8.3 Hz), 3.83-4.11 (3H, m), 4.82 (1H, br s), 5.60 (2H, s), 6·73 (1H，s)，7.09 (2H，d，J=8.5 Hz)，7.16 (1H，d，J=2.7 Hz)， 7.20 (1H5 dd, J=2.7, 8.5 Hz)? 7.45 (1H, d, J=2.7 Hz), 7.71 (2H，d，J=8.5 Hz)，7·94 (1H，s)，8.18 (1H，d，J=8.5 Hz)，8.40 (1H，s)。 實施侈 1^111^4-{6-『4-((23&gt;&gt;-2-藉基-3-毗咯啶丙氣基&gt;&gt;笨基卜 111^^并[2,3-(11嘧啶-4-某氛！芡基）-3-環丙基脲 藉由與實施例153同樣之方法，從l-{2-氯-4-[6-[4-(2-羥 基吡咯啶丙氧基）苯基]_7-(2·三甲矽烷乙氧甲基）-7H-ρ比洛并[2,3- d]續淀-4-基氧]苯基} - 3 -環丙基踩30 mg，得到 標題化合物14 mg。 MS 光譜（ESj) : 563 (M+1), lH-NMR光譜：（DMSO-d6) 0.40-0.47 (2H, m)，0.60-0.70 (2H， m)，1.62-1.74 (4H，m)，2.40-2.70 (7H，m，covered by DMS〇 peak)，3.88-4.10 (3H，m)，4·92 (1H，br s)，6.94 (1H，s)，7·04 (2H3 d, J=8.6 Hz), 7.15 (1H, d, J=2.4 Hz), 7.20 (1H? dd5 J=2.4, 8·6 Hz)，7·44 (1H，d，J=2.4 Hz)，7.88 (2H，d，J=8.6 Hz)，7·94 (1H，s)，8.16 (1H，d，J=8.6 Hz)，8.28 (1H，s)，12.60 (1H，br s) 〇 製造例158- 1 1_-{2-氣-4-「6-「4-(25)-2-範某-3-毗略啶雨氫某）笨基1-7- -262 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（257 ) 〔2-三甲矽烷乙氣甲基）-7H-毗咯并f2,3-dl嘧啶朴 基卜3-環丙.基脲 藉由與製造例153-9同樣之方法，並使用對-甲笨續酸 (2 S) - (+)-縮水甘油g旨9 8 mg，破酸_99 mg及p比啥咬 m卜從1-{2-氯-4-[ 6-(4-羥苯基）-7-(2-三曱矽烷乙氧甲 基）-7H-吡咯并[2,3_d]嘧啶-4-基氧]-2-苯基}-3-環丙基腺 81 mg得到標題化合物30 mg。 MS 光譜（ESI) : 693 (M+l)， iH-NMR光譜：（DMSO-d6) -〇·〇9 (9Η，s)，0.40-0.46 (2Η，m)， 0.62-0.70 (2H，m)，0·87 (2H，t，J=8.4 Hz)，1.62-1.72 (4H，m)， 2.40-2.68 (7H，m，covered by DMSO peak)，3·62 (2H，t， J=8.4 Hz)，3·90-4·10 (3H，m)，4·92 (1H，br s)，5·60 (2H，s)， 6.72 (1H，s)，7.10 (2H，d，J=8.8 Hz), 7·10 (1H，d，J=2.4 Hz)， 7.21 (1H, dd, J=2.4, 8.8 Hz), 7.46 (1H, d5 J=2.4 Hz), 7.71 (2H，d，J=8j Hz)，7·95 (1H，s)，8.18 (1H，d，J=8.8 Hz)，8.41 (1H，S)。 .、 實施例159 1-(2-氣-4- { 6-「4-((2R)-2-蕤某-3-毗呔哇丙氩基）苽某1-ΙΗ-吨咯并f 2,3-dl嘧啶-4-某氧}苯葚V3-瑷丙基脲 藉由與實施例153同樣之方法，從卜{2-氯-4-[6-[4-(2-羥 基-3-吡咯啶丙氧基）苯基卜7-(2-三甲矽烷乙氧曱基）-7H-17比洛并[2,3- d]喊淀-4 -基氧]苯基卜3 -環丙基脉70 mg，得到 標題化合物24mg° MS 光譜（ESI) : 563 (M+1), ___- 263 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公愛）Install η line 1304061 A7 B7 V. Description of invention (256 ) 0.63-0.70 (2H, in), 0.86 (2H, t3 J=8.3 Hz), 0.97 (6H, t, J=7.0 Hz), 2.38-2.60 (7H ,m,covered by DMS〇peak),3·61 (2H,t, J=8.3 Hz), 3.83-4.11 (3H, m), 4.82 (1H, br s), 5.60 (2H, s), 6· 73 (1H, s), 7.09 (2H, d, J = 8.5 Hz), 7.16 (1H, d, J = 2.7 Hz), 7.20 (1H5 dd, J=2.7, 8.5 Hz)? 7.45 (1H, d, J = 2.7 Hz), 7.71 (2H, d, J = 8.5 Hz), 7·94 (1H, s), 8.18 (1H, d, J = 8.5 Hz), 8.40 (1H, s). Execution 1^111^4-{6-『4-((23&gt;&gt;-2-boryl-3-pyrrolidinyl)&gt;&gt; stupid base 111^^ and [2,3- (11-pyrimidin-4-one: mercapto)-3-cyclopropylurea in the same manner as in Example 153, from 1-{2-chloro-4-[6-[4-(2-hydroxypyrrole) Pyridyloxy)phenyl]_7-(2·trimethyldecaneethoxymethyl)-7H-ρpiro[2,3-d]precipitate-4-yloxy]phenyl}-3-cyclopropane The title compound was obtained by the step of 30 mg. MS spectrum (ESj): 563 (M+1), lH-NMR spectrum: (DMSO-d6) 0.40-0.47 (2H, m), 0.60-0.70 (2H, m ), 1.62-1.74 (4H, m), 2.40-2.70 (7H, m, covered by DMS〇peak), 3.88-4.10 (3H, m), 4.92 (1H, br s), 6.94 (1H, s ), 7·04 (2H3 d, J=8.6 Hz), 7.15 (1H, d, J=2.4 Hz), 7.20 (1H? dd5 J=2.4, 8·6 Hz), 7·44 (1H, d, J = 2.4 Hz), 7.88 (2H, d, J = 8.6 Hz), 7.94 (1H, s), 8.16 (1H, d, J = 8.6 Hz), 8.28 (1H, s), 12.60 (1H, Br s) 〇 Manufacture Example 158- 1 1_-{2-Qi-4-"6-"4-(25)-2-Fan-3-Oralidine Rain Hydrogen) Stupid 1-7--262 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of the Invention (257) [2-Trimethyldecane Ethylmethyl)-7H-Pyro-f2,3-dl-pyrimidinylpyridyl 3-cyclopropylidene The same method as in Production Example 153-9 And use p-formaldehyde (2 S) - (+)-glycidol g to 9 8 mg, acid-breaking _99 mg and p-bite m b from 1-{2-chloro-4-[ 6 -(4-hydroxyphenyl)-7-(2-trioxaneethoxymethyl)-7H-pyrrolo[2,3_d]pyrimidin-4-yloxy]-2-phenyl}-3-cyclopropane 81 mg of the base gland gave the title compound 30 mg. MS Spectrum (ESI): 693 (M+l), iH-NMR spectrum: (DMSO-d6) - 〇·〇9 (9Η, s), 0.40-0.46 (2Η, m), 0.62-0.70 (2H, m), 0·87 (2H, t, J = 8.4 Hz), 1.62-1.72 (4H, m), 2.40-2.68 (7H, m, covered by DMSO peak), 3 ·62 (2H, t, J=8.4 Hz), 3·90-4·10 (3H, m), 4·92 (1H, br s), 5·60 (2H, s), 6.72 (1H, s ), 7.10 (2H, d, J = 8.8 Hz), 7·10 (1H, d, J = 2.4 Hz), 7.21 (1H, dd, J=2.4, 8.8 Hz), 7.46 (1H, d5 J=2.4 Hz), 7.71 (2H, d, J=8j Hz), 7.95 (1H, s), 8.18 (1H, d, J = 8.8 Hz), 8.41 (1H, S). Example 159 1-(2-Ga-4-{6-"4-((2R)-2-蕤)-3-pyroxypropargyl) 苽1-ΙΗ-吨-r-f 2 , 3-dl pyrimidine-4-oxo}benzoquinone V3-mercaptopropyl urea by the same method as Example 153, from {2-chloro-4-[6-[4-(2-hydroxy-3) -pyrrolidylpropoxy)phenyl 7-(2-trimethyldecaneethoxycarbonyl)-7H-17piro[2,3-d]-salt-4-yloxy]phenyl- 3-ring Propyl pulse 70 mg, the title compound 24mg ° MS spectrum (ESI): 563 (M+1), ___- 263 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 public)

裝 訂Binding

線 1304061 A7 ___ B7 五、發明説明（258 )&quot; ：Line 1304061 A7 ___ B7 V. Description of invention (258 )&quot; :

iH-NMR光譜：（DMSO-d6) 0.40-0.47 (2H，m)，0·60-0·70 (2H， m), 1.73-1.87 (4H, m), 2.49-2.60 (7H, m, covered by DMSO peak)，3.94-4.19 (3H，m)，4·92 (1H，br s)，6.94 (1H，d，&gt;1.2 Hz)，7.06 (2H，d，Hz)，7.15-7.22 (2H，m)，7.43 (1H，d， J=2.4 Hz)，7.91 (2H，d，J=8.6 Hz)，7.96 (1H，s)，8.17 (1H，d， J=8.6 Hz)，8·29 (1H，s)，12.61 (ih，br s)。 製造例159- 1 1!_11:.氯-4-『6-『4-〇^!1)-2-後羞二3_吡咯啶丙氫某）笨基1_7· 一甲歹垸乙氧甲..基并「23-di嘧啶基氣1茇 基卜3-環丙某月晨 藉由與製造例153-9同樣之方法，並使用對-甲苯磺酸 (211)-(-)-縮水甘油酯155 11^，碳酸鉀156 11^及吡咯啶〇.13 m卜從1·{ 2-氯-4-[6-(4-羥苯基）_7-(2_三甲矽烷乙氧曱 基）-7H-吡咯并[2,3-d]嘧啶-4-基氧]苯基卜3-環丙基脲128 mg得到標@匕合物72 mg。 MS 光譜（ESI) ·· 693 (M+1)， ·、 W-NMR光譜：（DMSO-d6) -0.09 (9H，s)，0.40-0.46 (2H，m)， 0.60-0.70 (2H? m), 0.87 (2H, t, J=8.4 Hz), 1.62-1.72 (4H, m), 2.40-2.68 (7H, m, covered by DMSO peak), 3.61 (2H, t, J=8.4 Hz)5 3.90-4.10 (3H5 m)5 4.92 (1H, br s), 5.60 (2H, s), 6.72 (1H, s), 7.09 (2H, d, J=8.8 Hz), 7.16 (1H, d, J=2.4 Hz)5 7.20 (1H, dd, J=2.4, 8.8 Hz), 7.45 (1H, d3 J=2.4 Hz), 7.71 (2H, d, J=8.8 Hz), 7.95 (1H5 s), 8.18 (1H, d, J=8.8 Hz), 8.40 (1H, s) 〇 -264 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 裝 訂iH-NMR spectrum: (DMSO-d6) 0.40-0.47 (2H, m), 0·60-0·70 (2H, m), 1.73-1.87 (4H, m), 2.49-2.60 (7H, m, covered By DMSO peak), 3.94-4.19 (3H, m), 4.92 (1H, br s), 6.94 (1H, d, &gt; 1.2 Hz), 7.06 (2H, d, Hz), 7.15-7.22 (2H , m), 7.43 (1H, d, J = 2.4 Hz), 7.91 (2H, d, J = 8.6 Hz), 7.96 (1H, s), 8.17 (1H, d, J = 8.6 Hz), 8.29 (1H, s), 12.61 (ih, br s). Production Example 159- 1 1!_11:. Chlorine-4-"6-"4-〇^!1)-2- After Shame 2_Pyrrolidine Propyl Hydrogen) Stupid Base 1_7· One Acetone Ethoxy .. and "23-dipyrimidinyl gas 1 茇 卜 3- 3-cyclopropyl amide one month by the same method as in Production Example 153-9, and using p-toluenesulfonic acid (211)-(-)-shrinkage Glyceride 155 11^, potassium carbonate 156 11^ and pyrrolidine 〇.13 m from 1·{2-chloro-4-[6-(4-hydroxyphenyl)-7-(2-trimethyldecane ethoxylated) -7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl-3-cyclopropylurea 128 mg gives the standard @匕合72 mg. MS Spectrum (ESI) ·· 693 (M +1), · W-NMR spectrum: (DMSO-d6) -0.09 (9H, s), 0.40-0.46 (2H, m), 0.60-0.70 (2H? m), 0.87 (2H, t, J= 8.4 Hz), 1.62-1.72 (4H, m), 2.40-2.68 (7H, m, covered by DMSO peak), 3.61 (2H, t, J=8.4 Hz)5 3.90-4.10 (3H5 m)5 4.92 (1H , br s), 5.60 (2H, s), 6.72 (1H, s), 7.09 (2H, d, J=8.8 Hz), 7.16 (1H, d, J=2.4 Hz) 5 7.20 (1H, dd, J =2.4, 8.8 Hz), 7.45 (1H, d3 J=2.4 Hz), 7.71 (2H, d, J=8.8 Hz), 7.95 (1H5 s), 8.18 (1H, d, J=8.8 Hz), 8.40 ( 1H, s) 〇-264 - This paper scale applies to Chinese national standards (CN S) A4 size (210X297 mm) binding

線 1304061 A7Line 1304061 A7

笨某）-3-璦雨甚月尿 藉由與實施例I53同樣之方法，從丨_{2-氯-4-[6·[4·(2·二 乙胺丙氧基）苯基]-7-(2-三甲矽烷乙氧甲基）_7Η_吡咯并 [2,3 d]密淀-4-基氧]冬基卜3 -環丙基脉17 mg，得到標題化 合物2 mg。 MS 光譜（ESI) : 549 (M+1)， 製造例160-1 1114-(4-胺某二^氯笨氣基&gt;)-7“2_三曱矽忮乙氣甲某&gt;&gt;_71^ 扯洛并f 2,3-dl命鳴&gt;6-某1驗 將製造例153-5合成之4-[ 6-(4-苄氧苯基）-7-(2-三甲矽烷 基乙氧甲基）-711-吡洛并[2,3-〇1]嘧啶-4-基氧]-2-氯苯胺255 mg溶於乙醇10 ml及四氫呋喃3 〇1中，加入氧化鉑1〇〇 mg， 以及於室溫常溫下在氫氣蒙氣中攪掉終夜後，經矽藻土 過濾及將濾液減壓濃縮。將殘餘物付諸衿矽凝膠管柱層析 (己烷-乙酸乙酯），得到標題化合物丨05 mg。 iH-NMR 光譜：（DMSO-d6) -〇·〇9 (9H，s)，0.83 (2H，t，J=7.8 Hz), 3.52 (2H, t5 J=7.8 Hz), 5.33 (2H, s)5 5.54 (2H5 s), 6.55 (1H，s)，6.83 (1H，d，J=8.8 Hz)，6.88 (2H，d，J=8.8 Hz)，6.94 (1H，dd，J=2.4, 8.8 Hz)，7.17 (1H，d，J=2.4 Hz)，7·58 (2H，d， J=8.8 Hz)，8.35 (1H，s)，9.84 (1H，br s) 〇 造例 160-2 2-氯-4- [ 6-〖4_- (3-一乙胺基丙氣某）苯某卜7 _ί2·三甲矽烷某 -265 - 本紙張尺度適用中國國豕標準(CNS) Α4規格(210 X 297公袭) 1304061 一 一- A7 ____ B7___ i明説明（260 ) ^' 乙氣曱某V7H-吡咯并f2,3-dl嘧啶-4-某氣1笨胺 將製造例160- 1合成之4-[4-(4-胺基-3-氯苯氧基）-7-(2-三甲矽烷乙氧甲基）-7H-吡咯并[2,3-d]嘧啶·6-基]酚47 mg 溶於二甲基曱醯胺〇·5 ml中，加入（3 -氯丙基）二乙胺鹽酸鹽 56mg(3.1當量）及碳酸鉀94mg(7當量），並於80°C攪拌24小 時。之後，返回室溫，加入水及用乙酸乙酯-四氫呋喃之 5 : 1混合溶液分液萃取。將有機層用硫酸鈉乾燥，濃縮及 付諸於NH矽凝膠管柱層析（己烷-乙酸乙酯），得到標題化 合物49 mg。 MS 光譜（ESI) : 596 (M+1)， 製造例160-3 1-{2-氯-4-[6-「4-(3-二乙胺丙氣基）笨基1-7-(2-三甲矽烷 I氧甲基V7H-吡咯并f2,3-dl嘧啶-4-基氣1苯某丨-3-瑗丙某 败 將製造例丄60-2合成之2-氯-4-[6-[4-(3-二乙胺基丙氧基） 苯基]-7-( 2-三甲矽烷基乙氧曱基）-7H-吡硌并[2,3-引嘧啶-4-基氧]苯胺溶於二曱基亞礙〇.6 ml中，加入環丙基胺基甲 酸苯酯23 mg，並於80°C攪捽1.5小時。然後加入環丙基胺 基甲酸苯酯75 mg，並於100°C攪拌5小時後，再加入相同試 藥70 mg，攪拌整夜。回到室溫後，加入水及用乙酸乙酯· 四氫呋喃之5 : 1混合溶液分液萃取。將有機層用硫酸鈉乾 燥，濃縮及付諸於NH矽凝膠管柱層析（己烷-乙酸乙酯）， 得到標題化合物18 mg。 二 MS光譜（ESI) : 679 (M+ 1)， -266 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061笨{)2-瑷4-[6·[4·(2·diethylaminepropoxy)phenyl]] -7-(2-Trimethyldecaneethoxymethyl)_7Η-pyrrolo[2,3 d]Methoxy-4-yloxy]dongjib 3-cyclopropyl pulse 17 mg gave the title compound 2 mg. MS spectrum (ESI): 549 (M+1), Production Example 160-1 1114-(4-amine 2 chlorobenzene) -7 "2_三曱矽忮乙甲甲>&gt;;_71^ 脱洛和f 2,3-dl 命鸣&gt;6-一一验 will produce the synthesis of 15-35-(4-benzyloxyphenyl)-7-(2-trimethyldecane Ethyl ethoxymethyl)-711-pyrrolo[2,3-〇1]pyrimidin-4-yloxy]-2-chloroaniline 255 mg is dissolved in 10 ml of ethanol and tetrahydrofuran 3 〇1, and platinum oxide 1 is added. 〇〇mg, and after stirring overnight at room temperature in a hydrogen atmosphere, filtered through diatomaceous earth and concentrated under reduced pressure. The residue was applied to a gel column chromatography (hexane-acetic acid) Ethyl ester) gave the title compound 丨05 mg. iH-NMR spectrum: (DMSO-d6) - 〇·〇9 (9H, s), 0.83 (2H, t, J = 7.8 Hz), 3.52 (2H, t5 J =7.8 Hz), 5.33 (2H, s)5 5.54 (2H5 s), 6.55 (1H, s), 6.83 (1H,d,J=8.8 Hz), 6.88 (2H,d,J=8.8 Hz), 6.94 (1H, dd, J=2.4, 8.8 Hz), 7.17 (1H, d, J=2.4 Hz), 7·58 (2H, d, J=8.8 Hz), 8.35 (1H, s), 9.84 (1H, Br s) 〇例160-2 2-Chloro-4-[6-[4_-(3-Ethylaminopropene) Benzene 7 _ί2·Trimethyl hydrazine某-265 - This paper size applies to China National Standard (CNS) Α4 specification (210 X 297 public attack) 1304061 One-A7 ____ B7___ i Ming description (260) ^' 乙气曱V7H-pyrrole and f2,3 -dl-pyrimidine-4-one gas 1 stearamine 4-[4-(4-Amino-3-chlorophenoxy)-7-(2-trimethyldecaneethoxymethyl) synthesized in Example 160-1 -7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol 47 mg is dissolved in dimethylammonium oxime·5 ml, and (3-chloropropyl)diethylamine hydrochloride 56 mg is added. (3.1 equivalents) and potassium carbonate 94 mg (7 equivalents), and stirred at 80 ° C for 24 hours. Thereafter, return to room temperature, add water and extract with a 5:1 mixed solution of ethyl acetate-tetrahydrofuran. The title compound (49 mg) was obtained from mjjjjjjjjjjjjjjjjj 3 1-{2-Chloro-4-[6-"4-(3-diethylamine-propenyl)phenyl 1-7-(2-trimethyldecane-I-oxymethyl-V7H-pyrrolo-f2,3-dl Pyrimidine-4-yl gas 1 benzene, a certain 丨-3-瑗-propyl, will produce 2-chloro-4-[6-[4-(3-diethylaminopropoxy)benzene synthesized by 丄60-2 Base]-7-( 2-38 Alkyl ethoxylated)-7H-pyrido[2,3-pyrimidin-4-yloxy]phenylamine is dissolved in dimercaptopurine. 6 ml, and phenyl cyclopropylcarbamate is added. Mg, and stirred at 80 ° C for 1.5 hours. Then, 75 mg of phenylcyclopropylcarbamate was added, and after stirring at 100 ° C for 5 hours, 70 mg of the same test drug was added, and the mixture was stirred overnight. After returning to room temperature, water was added and the mixture was extracted with a 5:1 mixed solution of ethyl acetate·tetrahydrofuran. The organic layer was dried (MgSO4), evaporated Two MS spectra (ESI): 679 (M+ 1), -266 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061

實施例161 izl,4-氣苯基上丄-μ-(6二苯嘧冷-4_其 硫）遠唑-5-基脲 在4-(5-硝基4唑-2-基硫）_6-苽甚7口〇«々“ ; 奉暴-7H-吡咯并[2,3-d]嘧 啶中，加入鐵粉323 11^，乙醇191^1芬|&gt;，^ 。 畔ml及水2.4 ml，於80C攪 拌1〇分鐘，回到室溫後，加入碳酸却7 5 ml，經梦蕩土過 濾，在濾液中加入乙酸乙酯及水，以分液萃取。將有機層 用飽和食鹽水洗淨，用無水硫酸鈉乾燥，經綿栓過濾及&amp; 縮乾固，得到310 mg之固體。將該固體於回流下溶於四氫 咬喃10 ml，甲苯10 ml及乙腈10ml ’加入異氰酸扣氟苯酿 0.1 ml，並攪拌2小時。返回室溫及濃縮反應系，然後付諸 於碎k膠管柱層析及乾燥’得到標題化合物3 3 mg。 iH-NMR光譜：（DMS〇-d6) 6·71 (1H，s)，7·ι2 (2H，m)，7 36、Example 161 izl, 4-phenylphenyl-hydrazine-μ-(6 diphenylsulfanol-4_sulfate) farazol-5-ylurea in 4-(5-nitro-4-oxazol-2-ylsulfonate) _6-苽更七口〇«々"; In the violent -7H-pyrrolo[2,3-d]pyrimidine, add iron powder 323 11^, ethanol 191^1fen|&gt;,^. 2.4 ml, stir at 80 ° for 1 hr, return to room temperature, add 7 5 ml of carbonic acid, filter through the dream soil, add ethyl acetate and water to the filtrate, and extract by liquid separation. The organic layer is saturated with salt. Washed with water, dried over anhydrous sodium sulfate, filtered through a pad of Celite, and dried to give a solid of 310 mg. The solid was dissolved in 10 ml of tetrahydrotetramethane, 10 ml of toluene and 10 ml of acetonitrile. 0.1 ml of isocyanic acid fluorobenzene was stirred and stirred for 2 hours. The reaction mixture was returned to room temperature and concentrated, and then applied to a sep. k. column chromatography and dried to give the title compound 3 3 mg. iH-NMR spectrum: (DMS 〇-d6) 6·71 (1H, s), 7·ι2 (2H, m), 7 36,

7·52 (5H，m)，7.62 (1H，s)，7.92 (2H，d，&gt;8·1 Ηζ)，8·55 (1H s)，9·12 (1H乂 s)，10.24 (1H，s)，12.82 (1H，br s)。 中間體如下述合成。 _7·52 (5H,m), 7.62 (1H,s), 7.92 (2H,d,&gt;8·1 Ηζ),8·55 (1H s),9·12 (1H乂s),10.24 (1H , s), 12.82 (1H, br s). The intermediate was synthesized as follows. _

N 製造例16 1 - 1 6-笨某-7H-吡咯并f2,3-dl嘧啶-4-硫_ 在 WO 97/02266，PCT/EP96/02728 記載之 6-苯基-7H·% 咯并[2,3-d]嘧啶-4-醇2.45 g中，加入五硫化磷6.19 g，雙 酸氫鈉6.24 g及二甘醇甲醚25 ml，及於8CTC攪拌1小時後， 再加入五硫化磷3 g及碳酸氫鈉3 g並攪捽1小時。之後，再 加入五硫化磷3 g及碳酸氫鈉3 g並攪掉1:小時。回到室溫， 加入水及攪拌10分鐘，濾取析出之結晶及用水洗及乾燥， 267 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱)N. Production Example 16 1 - 1 6-Stupid-7H-pyrrolof2,3-dl-pyrimidine-4-sulfo- 6-phenyl-7H·% in WO 97/02266, PCT/EP96/02728 [2,3-d]pyrimidine-4-ol 2.45 g, adding 6.19 g of phosphorus pentasulfide, 6.24 g of sodium dihydrogenate and 25 ml of diethylene glycol methyl ether, and stirring at 8 CTC for 1 hour, then adding five-sulfide 3 g of phosphorus and 3 g of sodium hydrogencarbonate were stirred for 1 hour. Thereafter, 3 g of phosphorus pentasulfide and 3 g of sodium hydrogencarbonate were added and stirred for 1 hour. Return to room temperature, add water and stir for 10 minutes, filter out the precipitated crystals and wash with water and dry, 267 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public)

裴 訂 線 !304061 一 ‘ A7 ----__ B7_ 五、發明説明（262 ) 得到標題化合物2.5 g。 iH-NMR光譜：（DMS〇-d6) 7.03 (1H，d，J=2.1 Ηζ)，7·32 (1H，t， J=7.9 Hz), 7.43 (2H, t, J = 7.9 Hz), 7.88 (2H, d, J=7.9 Hz), 8·05 (1H，s)，12.68 (1H，br s)，13.36 (1H，br s)。 製造例161-2 1^卜硝基嗥吐-2-基硫）-6-苯某-711-毗咯#「2,3-(11嘧啶 在6-苯基-7H-吡咯并[2,3-d]嘧啶-4-硫醇中加入2-溴-5-硝基嘍唑1·06 g及二甲基曱醯胺15 ml並於室溫攪拌3小時 後，加入吡啶0.45 ml及攪拌整夜。加入水，濾取析出之結 晶，風乾及減壓乾燥得到標題化合物丨2〇 g。 H-NMR 光 if :(DMSO-d6) 7.26 (1H，J=2.4 Hz)，7.36-7.54 (3H，m)，8·01 (2H，d，J=7.8 Hz)，8·90 (1H，s)，8·94 (1H，s)5 13·11 (1H，br s)。 5 實施例162 1^[5-(6-苯朞-7：»-吡咯112^3-糾嘧啶-4-其硫卜3-4唑-2二 基脲 - 在5-(6-苯基- 7H-吡咯并[2,3-d]嘧啶-4-基硫）-2-硫苯胺 354 mg中，加入2-嘍唑基胺基甲酸苯酯265 mg及二甲基亞 石風10 ml並於80 C攪掉2小時。加入乙酸乙酯及水，分液萃 取，濃縮有機層，付諸於矽凝膠管柱層析及乾燥，將得到 之固體用乙醚洗淨，得到標題化合物丨7〇 mg。 h-NMR光瑨：（DMSO.d6) 6·55 (1H，br s)，6·94 (1H，d，J=4.2 Hz)，7.05(lH，d，J=l.9Hz)，7.26(lH，-d，J=4.2Hz)，7.28-7·50 (4H’ m)’ 7·82-7·90 (3H，m)，8.49 (1H，s)，10.42 (1H，br -268 - 本紙張尺度適用中國國家標準(CNS) A4規公爱) ----订 set line !304061 a ‘ A7 ----__ B7_ 5, invention description (262) to get the title compound 2.5 g. iH-NMR spectrum: (DMS 〇-d6) 7.03 (1H, d, J = 2.1 Ηζ), 7·32 (1H, t, J = 7.9 Hz), 7.43 (2H, t, J = 7.9 Hz), 7.88 (2H, d, J=7.9 Hz), 8·05 (1H, s), 12.68 (1H, br s), 13.36 (1H, br s). Production Example 161-2 1 卜 nitropyrid-2-ylthio)-6-benzene-711-pyrrole #"2,3-(11-pyrimidine in 6-phenyl-7H-pyrrolo[2, 3-d]pyrimidine-4-thiol was added with 2-bromo-5-nitrocarbazole 1·06 g and dimethyl decylamine 15 ml and stirred at room temperature for 3 hours, then pyridine 0.45 ml was added and stirred. After adding water, the precipitated crystals were filtered, dried and dried under reduced pressure to give the title compound 丨2 〇g. H-NMR light if: (DMSO-d6) 7.26 (1H, J=2.4 Hz), 7.36-7.54 ( 3H,m),8·01 (2H,d,J=7.8 Hz), 8·90 (1H, s), 8.94 (1H, s) 5 13·11 (1H, br s). 162 1^[5-(6-Phenyl-7:»-pyrrole 112^3-pyrimidine-4-thiophene 3-4oxazol-2diylurea- in 5-(6-phenyl-7H-) Add 265 mg of 2-oxazolyl carbamic acid phenyl ester and 10 ml of dimethyl succinite to 354 mg of pyrrolo[2,3-d]pyrimidin-4-ylthio)-2-thioaniline After the mixture was stirred for 2 hours, ethyl acetate and water were added, and the mixture was evaporated to dryness. h-NMR aperture: (DMSO.d6) 6·55 (1H, br s), 6.94 (1H, d J=4.2 Hz), 7.05 (lH, d, J=l.9Hz), 7.26 (lH, -d, J=4.2Hz), 7.28-7·50 (4H' m)' 7·82-7·90 (3H,m),8.49 (1H,s),10.42 (1H,br -268 - This paper scale applies to China National Standard (CNS) A4 Regulations) ----

線 1304061Line 1304061

s)，12·54 (1H，br s)。 中間體如.下述合成。 ΆΛΜ 162- 1 吩硫基）-6-苯比咯#「ndl嘧啶 ，在藉由製造例161-1合成之6_苯基_7札吡咯并[2,3-(1]嘧 哫-4-硫醇中，加入2-溴-5-硝基嘍吩1〇5 g，碳酸鉀〇 95 g 及二甲基甲醯胺15 ml，並於室溫攪掉終夜後加入水，濾取 ，出之結晶，風乾及減壓乾燥，得到標題化合物i 3〇 g。 Wnmr光譜：（DMS0-d6) 7·08 (1H，s)，7 4〇 (iH，t，j=8 〇s), 12·54 (1H, br s). The intermediate was synthesized as follows. 162 162- 1 phenothionyl-6-benzole #"ndl pyrimidine, 6-phenyl-7-zapyrrolo[2,3-(1]pyrimidin-4 synthesized by the manufacture of Example 161-1 - In the mercaptan, add 2-bromo-5-nitroporphine 1〇5 g, potassium carbonate 〇95 g and dimethylformamide 15 ml, and stir at room temperature overnight, add water, and filter. Crystallization, air drying and drying under reduced pressure gave the title compound i 3 〇 g. Wnmr spectrum: (DMS0-d6) 7·08 (1H, s), 7 4 〇 (iH, t, j = 8 〇

Hz)，7·48 (2H，t，J=8.0 Hz)，7.56 (1H，d，J=4.1 Hz)，7·98 (2H， d’ J-8.0 Hz)，8.16 (1H，d，J=4.1 Hz)，8.70 (1H，s)，12·68 (1H， br s) ° 製造例162-2 苯基-7H-吩咯生丨273-dl嘧啶-4-某硫i噗吩-2_某脖 在製造例462-1合成之4-( 5-硝基-2-硫苯硫基）·6-苯基· 7Η-说洛并[2,3-d]嘧啶中，加入鐵粉知3 mg，氣化銨 1.06g，二甲基甲醯胺1〇 ml，乙醇2〇 ml及水5 ml並於9〇艺 揽拌2小時，然後加入3〇 ml四氫呋喃，返回室溫後，經碎 藻土過濾，在濾液中加入乙酸乙酯及水並分液萃取。將有 機層用無水硫酸鈉乾燥，經绵栓過濾及濃縮乾固，得到435 mg之標題化合物。 MS 光譜（ESI) : 325(M+1)Hz), 7·48 (2H, t, J=8.0 Hz), 7.56 (1H, d, J=4.1 Hz), 7·98 (2H, d' J-8.0 Hz), 8.16 (1H, d, J =4.1 Hz), 8.70 (1H, s), 12·68 (1H, br s) ° Production Example 162-2 Phenyl-7H-phenohaline 丨273-dl pyrimidine-4-one sulfoximine-2 _A certain neck is added to the 4-(5-nitro-2-thiophenylthio)·6-phenyl·7Η-supplied [2,3-d]pyrimidine synthesized in Production Example 462-1, and iron powder is added. Know 3 mg, 1.06 g of ammonium sulfate, 1 〇ml of dimethylformamide, 2 〇ml of ethanol and 5 ml of water, and mix for 2 hours at 9 ,, then add 3 〇ml of tetrahydrofuran and return to room temperature. It was filtered through crushed seaweed, and ethyl acetate and water were added to the filtrate, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness MS spectroscopy (ESI): 325 (M+1)

h-NMR光譜：（DMS〇-d6) 5·98 (1H，d5 JM.2 Hz)，6.24 (2H s)5 6.27 (1H, d, J=2.〇 Hz), 7.00 (1H, d, J=4.2 Hz), 7.30-7 5〇 -269 -h-NMR spectrum: (DMS〇-d6) 5·98 (1H, d5 JM.2 Hz), 6.24 (2H s)5 6.27 (1H, d, J=2.〇Hz), 7.00 (1H, d, J=4.2 Hz), 7.30-7 5〇-269 -

1304061 … Λ, — _ _____Β7 五、發明説明（264 ) (3Η，m)，7.80 (2Η，d，J=7.6 Ηζ)，8·46 (1Η，s)，12.63 (1Η，br s)。 實施例163 1^_4-『3-(4-氟苯_羞上||丄苯氧基}-71^毗呔并「2,3-(11嘧治-6_ 羧酸乙酯 將4-(4-胺基苯氧基）·7Η-吡咯并[2,3_d]嘧啶-心羧酸乙酯 90 mg於110 C落於曱苯3 ml及乙腈1㈤丨中，然後加入異氰 酸4-氟苯酯16.6微升並於回流下攪拌丨小時。放置於室溫， 濾取析出之結晶及乾燥，得到標題化合物n〇mge WNMR光譜：（DMSO-d6) 1·31 (3H，t，Ι=7·9 Ηζ)，4·32 (2H，q J=7.9 Hz)，7·07-7·54 (9H，m)，8.42 (1H，s)，8·72 (1H，s)， 8.76 (1H，s)，13·03 (1H，br s)。 如下述合成中間體。 製造例163- 1 Κ,4·硝基赛氧基）-7H-吨咯并「2.3-dl痛螳-6-#酸乙酯 在WO 9702266( A1)記載之4-氯乙氧羰基^-7H-吡啥并[2,3-d]’呢577 mg中加入4-硝基酚390 mg，碳酸鉀703 mg及二 甲基曱醯胺8·7 ml並於120°C攪拌14小時後，再加入4-硝基 紛40 mg並攪拌1.5小時。置於室溫後，加入水，用乙酸乙 醋-四氫呋喃混合溶液分液萃取，然後將有機層用飽和食鹽 水洗淨，用無水硫酸鈉乾燥，經綿栓過濾，濃縮乾固，將 所得固體用乙醚洗淨，得到標題化合物52〇 mg。 iH-NMR光譜：（DMS〇-d6) 1·33 (3H，t，J=7.9 Hz)，4.35 (2H，q J=7.9 Hz), 7.28 (1H, s), 7.56-7.64 (2H, m), 8.30-8.38 (2H, __ - 270 - 本紙張尺度適用中國國家標準(CNS) A4規格(2l〇 x 297公愛） 1304061 A7 B7 265 五、發明説明（ m)，8.46 (1H，s)，13·21 (1H，br s)。 I造例163-2 1^1生:胺基苯氧棊）-711-吡咯並「2,3-€11_啶-6-藉酸乙酯 在4-(4-硝基苯氧基）-7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯 中，加入鐵粉110 mg，氯化銨220 mg ,乙醇1〇 ml及水2 ml，並於80- 85 °C攪拌2.5小時。回到室溫後加入四氫吡喃 2〇 ml，攪拌5分鐘後，經矽藻土過濾，在濾液中加入乙酸 乙酯100 ml及水50 ml，然後分液萃取。將有機層用飽和食 鹽水洗淨，用無水硫酸鈉乾燥，經綿栓過濾及濃縮乾固， 得到標題化合物90 mg。 H-NMR光譜：（DMSO-d6) 1·31 (3H，t，J=7.9 Ηζ)，4·31 (2H，q J-7.9 Hz), 5.10 (2H, s), 6.56-6.62 (2H, m), 6.86-9.92 (3H3 m)，8·40 (1H，s)，12·98 (1H，br s)。 f施例164 jir{4-「3-( 氛苯基）月尿基1笨氣某卜比哈并f2,3-dlp密咬_ ^ #酸 、 在實施例163合成之4- {4-[3-(4-氟苯基）脲基]苯氧基卜 7H-吡咯并[2,3-d]嘧啶-6-羧酸乙酯75 mg中，加入乙醇7 ml’水7 ml及氫氧化經1水合物31 mg，並於40-45 °C擾拌24 小時後，用2N HC1中和，濃縮乾固，得到40 mg之標題化合 物。 ^•NMR 光譜：（DMS〇-d6) 6·83 (1H，s)，7·06-7.16 (2H，m)， 7·19 (2H，m)，7·44-7·48 (2H，m)，7·51‘(2Η，d，J=8.0 Hz), 8·39 (1H，s)，8.72 (1H，s)，8.76 (1H，s)，12.88 (1H，br s)。 271 - 本畝張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 266 五、發明説明 實施例165 4- { 4: 4-氟苯某）脲暮基卜7Η·吡呔并「2 3· dl嘧畦· 6 -攻酸（3 -二乙胺某丙基）赫脸 在實施例164合成之4-{ 4-[3-(‘氟苯基）脲基]苯氧基卜 7H-吡咯并[2,3-d]嘧啶_6_幾酸12 mg中，加入二甲基甲醯 胺1 ml’二乙胺47/zl’二苯基鱗g盛胺18.5//1及1-甲基六氫 口比呼8.2 # 1 ’然後於室溫授摔整夜。加入水，用乙酸乙醋_ 四氫唉喃混合溶液分液萃取，然後付諸於NH矽凝膠管柱層 析（乙酸乙酯-甲醇），得到標題化合物27 mg。 1H-NMR 光譜：（DMSO-d6) 2.18 (3H，s)，2·28-2·48 (4H，m)， 3·58-3·70 (4H，m)，6.56 (1H，s)，7.06-7.56 (8H，m)，8.36 (1H， d，J=1.7 Hz)，8·78 (1H，s)，8·84 (1H，s)，12.67 (1H，br s)。 實施例166 4ϋ.·ϋ二(4-氟苯基）踩基1笨氩基比哈#f2T3-dln奈遠-6 -效故（3 -二、乙胺基丙基）酿脖 在實施例164合成之4- { 4- [ 3- (4-氟苯基、）脲基]苯氧基卜 7H-p比哈并[2,3-d] p密淀-6-幾酸12 mg中，加入二甲基甲龜 胺0.8 ml，三乙胺21#1，二苯基磷醯胺（DPPA)9.5 # 1及4-(3-胺基丙基）嗎福淋6.5 a 1，然後於室溫攪拌2日。加入飽 和氯化銨，用乙酸乙酯-四氫呋喃混合溶液分液萃取，將有 機層用飽和食鹽水洗淨，用無水硫酸#3乾燥，經绵检過遽 及濃縮乾固，得到標題化合物9 mg。 MS 光譜（ESI) : 534(M+1) : iH-NMR光譜：（DMSO-d6) 1.62-1.74 (2H，m)，2.20-2.42 (6H， -272 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 ——— A7 ____B7 五、發明説明（267 ) m)，2.88-2.98 (2H，m)，3.46·3·62 (4H，m)，7.06-7.56 (9H，m)， 8.34 (1H，s)，8.84-8.90 (2H，m)，12·68 (1H，br s)。 實施例167 氟苯基）-3 -「4-(_6-羥甲基- 7H-毗咯并「2.3-dl嘧啶- 4-墓氣）笨某1腽 在實施例163合成之4- {4-[ 3-(4-氟苯基）脲基]苯氧基卜 7H-0比嘻并[2,3- d]喊咬-6-羧酸55 mg中加入四氫吱喃9 ml， 於攪拌下在室溫加入氫化鋰鋁25 mg並攪拌2日。其後，加 入水，用乙酸乙酯-四氫呋喃混合溶媒分液萃取，將有機層 經矽藻土過濾，濃縮乾固，得到標題化合物35 mg。 MS 光譜（ESI) ·· 394(M+1)，416(M+23) iH-NMR光譜：（DMS〇-d6) 4·55 (2H，d，J=6.7 Hz)，5.32 (1H，t， J=6.7 Hz)，6.84 (1H，s)，7.06-7.55 (8H，m)，8.22 (1H，s)， 8·74 (1H，s)，8·76 (1H，s)，12.11 (1H，br s)。 實施例168 ^ 氟笨基V3-『4-(6-甲酿基-7H-外b嘻并「2.3- dl。密症-4- 基氧）苯某1脹 在1-(4-氟苯基）-3-[4-(6-羥曱基- 7H-吡咯并[2,3-d]嘧 咬-4-基氧）苯基]脲is mg*，加入氯仿3 mi及二氧化錳5〇 mg，並於室溫下攪掉整夜。在反應系統中加入四氫呋喃及 乙酸乙酯，經矽藻土過濾及濃縮乾固，得到標題化合物i 6 mg。 iH-NMR 光譜：（DMSO-d6) 6.82 (1H，s)，：7.03-7.60 (8H，m)， 8·46 (1H，s)，8·71 (1H，s)，8.75 (1H，s)，9·86 (1H，s)，13.08 _ - 273 - 本紙張尺歧if!中國g家料(CNS) A4規格(21Q x撕公爱了 &quot; 1304061 A7 B71304061 ... Λ, — _ _____Β7 V. Description of invention (264) (3Η, m), 7.80 (2Η, d, J=7.6 Ηζ), 8.46 (1Η, s), 12.63 (1Η, br s). Example 163 1^_4-"3-(4-Fluorophenyl- 羞上 ||丄 phenoxy}-71^ 呔 and "2,3-(11 acesulfame-6-carboxylic acid ethyl ester 4--( 4-aminophenoxy)·7Η-pyrrolo[2,3_d]pyrimidine-carboxycarboxylic acid ethyl ester 90 mg was dropped in 110 C at 10 C in cumene 3 ml and acetonitrile 1 (penta), followed by addition of 4-fluoroisocyanate 16.6 μL of phenyl ester and stirred under reflux for a few hours. After standing at room temperature, the precipitated crystals were collected by filtration and dried to give the title compound n 〇mge W NMR spectrum: (DMSO-d6) 1·31 (3H, t, Ι = 7·9 Ηζ), 4·32 (2H, q J=7.9 Hz), 7·07-7·54 (9H, m), 8.42 (1H, s), 8.72 (1H, s), 8.76 ( 1H, s), 13·03 (1H, br s). The synthesis intermediate is as follows. Production Example 163-1, 4, 4·Nitrosynyloxy)-7H-ton and "2.3-dl 螳-6 -#Acetylethyl ester 4-nitroethoxycarbonyl^-7H-pyridox[2,3-d]' 577 mg as described in WO 9702266 (A1), 4-nitrophenol 390 mg, potassium carbonate 703 Mg and dimethyl decylamine 8 · 7 ml and stirred at 120 ° C for 14 hours, then added 4-nitro-dissolved 40 mg and stirred for 1.5 hours. After standing at room temperature, add water, with ethyl acetate - Tetrahydrofuran mixed solution is extracted by liquid separation, and then the organic layer is The extract was washed with aq. br 33 (3H,t,J=7.9 Hz), 4.35 (2H,q J=7.9 Hz), 7.28 (1H, s), 7.56-7.64 (2H, m), 8.30-8.38 (2H, __ - 270 - this The paper scale applies to the Chinese National Standard (CNS) A4 specification (2l〇x 297 public) 1304061 A7 B7 265 V. Invention description (m), 8.46 (1H, s), 13·21 (1H, br s). Example 163-2 1^1: Aminophenoxypurine)-711-pyrrolo and 2,3-€11-pyridine-6-acidic acid ethyl ester in 4-(4-nitrophenoxy)-7H - Pyrrodro[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, adding iron powder 110 mg, ammonium chloride 220 mg, ethanol 1 〇 ml and water 2 ml, and stirring at 80-85 ° C 2.5 After returning to room temperature, 2 ml of tetrahydropyran was added, and after stirring for 5 minutes, it was filtered through celite, and 100 ml of ethyl acetate and 50 ml of water were added to the filtrate, followed by liquid separation. The organic layer was washed with brine, dried over anhydrous sodium sulfate H-NMR spectrum: (DMSO-d6) 1·31 (3H, t, J=7.9 Ηζ), 4·31 (2H, q J-7.9 Hz), 5.10 (2H, s), 6.56-6.62 (2H, m), 6.86-9.92 (3H3 m), 8·40 (1H, s), 12·98 (1H, br s). f Example 164 jir{4-"3-( phenyl) month urinary base 1 stupid gas abbiha and f2,3-dlp close bite _ ^ #酸, synthesized in Example 163 4- {4- [3-(4-Fluorophenyl)ureido]phenoxyb 7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester 75 mg, add ethanol 7 ml 'water 7 ml and hydrogen Oxidation of the hydrate 1 mg 31 mg, and the mixture was stirred at 40-45 ° C for 24 hours, then neutralized with 2N HCl, and concentrated to dryness to give 40 mg of the title compound. NMR spectrum: (DMS 〇-d6) 6 ·83 (1H, s), 7·06-7.16 (2H, m), 7·19 (2H, m), 7·44-7·48 (2H, m), 7·51' (2Η, d, J=8.0 Hz), 8·39 (1H, s), 8.72 (1H, s), 8.76 (1H, s), 12.88 (1H, br s). 271 - The Chinese National Standard (CNS) A4 size (210 x 297 mm) 1304061 A7 B7 266 V. DESCRIPTION OF THE INVENTION Example 165 4- { 4: 4-fluorophenyl) Urea sulfonyl 7 Η pyridinium and "2 3 · dl pyridinium 6 - 4-{4-[3-('Fluorophenyl)ureido]phenoxyb 7H-pyrrolo[2,3- synthesized by acid attack (3-diethylamine-propyl) d] pyrimidine _6_acid acid 12 mg, add dimethylformamide 1 ml 'diethylamine 47/zl' diphenyl G-amine 18.5//1 and 1-methylhexahydroport 8.2 # 1 ' and then drop at room temperature overnight. Add water, extract with ethyl acetate _ tetrahydrofuran mixed solution, then pay Chromatography on column chromatography (ethyl acetate-methanol) afforded the title compound 27 mg. 1H-NMR spectrum: (DMSO-d6) 2.18 (3H, s), 2·28-2·48 (4H ,m), 3·58-3·70 (4H,m), 6.56 (1H,s),7.06-7.56 (8H,m),8.36 (1H, d,J=1.7 Hz),8·78 (1H , s), 8. 84 (1H, s), 12.67 (1H, br s). Example 166 4ϋ.·ϋ二(4-fluorophenyl) treading 1 stupid argon-based haha#f2T3-dln Naiyuan -6 -Efficient (3-di-ethylaminopropyl) brewing neck 4-{4-[3-(4-fluorophenyl))ureido]phenoxyb 7H-p synthesized in Example 164 Biha and [2,3-d] p-precipitate-6-acid acid 12 mg, add dimethylformamide 0.8 ml, triethylamine 21#1, diphenylphosphoniumamine (DPPA) 9.5 # 1 and 4-(3-Aminopropyl) oxaflurane 6.5 a 1 and then stirred at room temperature for 2 days. After adding saturated ammonium chloride, the mixture was extracted with a mixed solution of ethyl acetate-tetrahydrofuran, and the organic layer was washed with saturated brine, dried over anhydrous sulphuric acid #3, dried and dried to give the title compound 9 mg. . MS spectroscopy (ESI): 534 (M+1): iH-NMR spectrum: (DMSO-d6) 1.62-1.74 (2H, m), 2.20-2.42 (6H, -272 This paper scale applies to the Chinese National Standard (CNS) A4 size (210 x 297 mm) 1304061 ——— A7 ____B7 V. Description of invention (267 ) m), 2.88-2.98 (2H, m), 3.46·3·62 (4H, m), 7.06-7.56 (9H , m), 8.34 (1H, s), 8.84-8.90 (2H, m), 12.68 (1H, br s). Example 167 Fluorophenyl)-3 - "4-(_6-hydroxymethyl-7H-pyrrolo-2.3-dl-pyrimidine- 4-teronary gas) 某 某 腽 腽 腽 腽 4- 4- 4- 4- 4- 4- 4- 4- 4- -[ 3-(4-Fluorophenyl)ureido]phenoxybu 7H-0 is more than hydrazino[2,3-d], chlorinated with -6-carboxylic acid, 55 mg of tetrahydrofuran, 9 ml, Add 25 mg of lithium aluminum hydride at room temperature and stir for 2 days. After that, water was added and the mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic layer was filtered over celite and concentrated to dryness 35 mg. MS Spectrum (ESI) ·· 394(M+1), 416 (M+23) iH-NMR spectrum: (DMS〇-d6) 4·55 (2H,d,J=6.7 Hz), 5.32 ( 1H,t, J=6.7 Hz), 6.84 (1H, s), 7.06-7.55 (8H, m), 8.22 (1H, s), 8·74 (1H, s), 8·76 (1H, s) , 12.11 (1H, br s). Example 168 ^ Fluoryl-based V3-"4-(6-carboxyl-7H-external b嘻 and "2.3-dl. cryptic-4-yloxy) benzene 1 Expansion in 1-(4-fluorophenyl)-3-[4-(6-hydroxyindolyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea is mg* Add 3 mi of chloroform and 5 mg of manganese dioxide, and stir overnight at room temperature. Add tetrahydrofuran to the reaction system. Ethyl acetate, filtered over EtOAc (EtOAc)EtOAc:EtOAc:jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 46 (1H, s), 8·71 (1H, s), 8.75 (1H, s), 9·86 (1H, s), 13.08 _ - 273 - This paper ruler is not! China g House (CNS) A4 specification (21Q x tearing public love &quot; 1304061 A7 B7

五、發明説明 (1H，br s)。 實施例16 9V. Description of the invention (1H, br s). Example 16 9

1^111^^^1-3-「4_(6-嗎福啉-4-某曱某-7只-朴：11!^[~:夂⑴ 嘧支：4二氣）菜某1M 在實施例168合成之1-(4-氟苯基）-3-[4-(6-甲醯基巧仏吡 哈并[2,3-d]喊淀-4-基氧）苯基]腺中，加入四氫攻喃〇 $ ml，嗎福啉1〇&quot; 1及三乙醯氧基硼氫化物26 mg，並於室溫 授拌整夜。將反應系統用四氫吱喃-乙酸乙醋混合溶媒分液 萃取，藉由無水硫酸鈉乾燥及濃縮乾固，得到標題化合物5 mg 0 MS 光譜（ESI) : 463 (M+1)。 實施例170 1·:_Ι1·:風苯基）-3 - { 4- Γ 6二(A-.甲基-1-六氧朴k 味甲某 V 1- 7H- 口t 嗒If 2,3- dl嘧啶-4-基氣1茉某}月#_ 在實施例468合成之1-(4-氟苯基）_3·[4_(6•曱醯基_7士外匕 咯并[2,3-d]嘧啶-4-基氧）苯基]脉中加入·四氫呋喃〇·4 ml， 1-甲基六氫吡畊11; 1及三乙醯氧基硼氫化物23 mg，並於 室溫撥拌整夜β將反應系統用四氫咬喃-乙酸乙酯混合溶媒 分液萃取’藉由無水硫酸鈉乾燥及濃縮乾固，得到標題化 合物5 m g。 MS光譜（ESI) ·· 476 (M+1)。 f施例17 1 氟苯基二蓋基.二咯#『2Ή1嘧啶-4-某^ 氣）笨基1脲 -274 - 本纸張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1304061 -s — 、.- _ A7 广 __B7 五、發明説明（269) 將4-(6-苯基-7H-,比洛并[2,3-d]嘧啶·4β基氧）苯胺4〇 mg 於ll〇°C溶於甲苯4·5 ml及乙腈4·5 ml，然後加入異氰酸心 氟苯酯（16·6/ζ 1)並攪拌1小時。放置於室溫，遽取析出之結 晶及乾燥’得到標題化合物3 7 m g。 MS 光譜（ESI) : 440(M+1)，462(M+23) 1H-NMR光譜：（DMSO-d6) 7.02 (1H，s)，7·06-7·52 (11H，m)， 7.94 (2H，d，J=8.0 Hz)，8·28 (1H，s)，8·77 (1H，s)，8·79 (1H， s)，12·68 (1H，br s) 〇 中間體如下述合成。 製造例171-1 4-( 4 -硝基笨氣基）-6 -笨基- 7H -吡咯并[2,3-d 1确冷 在 WO 97/02266，PCT/EP96/02728 記載之 4-氯-6_ 苯基-7H- 口比洛并[2,3- d] 口密咬113 mg中，加入4-硝基盼123 mg， 碳酸鉀136 mg及二曱基甲醯胺1·5 ml，並於130 °C-135 °C攪 拌15小時後〜再加入4-硝基酚60mg及碳酸鉀75 mg並攪拌6 小時。回到室溫後，加入水，用乙酸乙gf-四氫呋喃混合溶 媒分液萃取及濃縮乾固，將得到之固體用乙醚洗淨，得到 標題化合物112 mg。 iH-NMR 光譜：（DMS〇-d6) 7·13 (1H，s)，7.37 (1H，t，J=7.7 Hz), 7.47 (2H, t, J=7.7 Hz), 7.56-7.61 (2H5 m), 7.74-8.00 (2H，m)，8.30-8.38 (3H，m)，12.82 (1H，br s)。 f造例171-2 〔6-笨基-7H〇比咯并[2,3-dl嘧啶-4-篡氣）笨龜 在4-(4-硝基苯氧基）-6-苯基- 7H-吡咯并[2,3-d]嘧啶1 1〇 -275 - ____ — 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 ___B7 五、發明説明（270) mg中，加入鐵粉110 mg，氯化銨220 mg，乙醇10 mi及水2 m 1 ’並於8.0 - 8 5 C擴:拌2 · 5小時。回到室溫後，加入四氯咬 喃20 m卜攪拌5分鐘後，經矽藻土過濾，在濾液中加入乙 酸乙酯100 ml及水50 ml以分液萃取。將有機層用飽和食鹽 水洗淨，用無水硫酸鈉乾燥，經綿栓過濾及濃縮乾固，得 到標題化合物90 mg。 MS 光譜（ESI)m/z : 303(M+1) iH-NMR光譜：（DMSO-d6) 5·04 (2H，br s)，6.57-6.61 (2H，m), 6·84-6·90 (3H，m)，7·34 (1H，t，J=7.7 Hz)，7.45 (2H，t，J=7.7 Hz)，7.87 (2H，t，J=7.7 Hz)，8·26 (1H，s)，12.61 (1H，br s)。 實施例172 苯基）-3-『4-(6-苯 4二7H-吡咯 #「2^-d]嘧忒-4-早 氣）笨基1脲 以與貫施例17 1同樣之方法，使4_ (6-苯基_ 7H_吡咯并 [2,3-d]嘧啶-4-基氧）苯胺36 mg與異氰酸弘氟苯酯（14# ) 反應，得到24 mg之標題化合物。 \ MS光譜（ESI) : 440 (M+l)，462(M+23) iH-NMR光譜：（DMSO-d6) 7.02 (1H，s)，7.08154 (11H，m)， 7.94 (2H, d, J=8.0 Hz), 8.28 (1H, s), 8.88 (1H, s), 9.00 (1H, s)，12.68 (1H，br s)。 實施例173 h._環丙基-3-『4-(6-苯基二2111^^11^1嘧啶-4-基氫&gt;)芡 基1脲 -· 在4-(6-苯基-7H-吡咯并[2,3_d]嘧啶-4·基氧）苯胺4〇❿容 -276 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公愛)&quot; 1304061 〜 A7 ____B7 __ 五、發明説明（271 ) 中，加入環丙基胺基甲酸苯酯30 mg及二甲基亞颯0.5 ml ’ 並於80°C攪拌4小時。回到室溫後，加入水及用乙酸乙酯分 液萃取及濃縮乾固，將得到之固體用乙醚洗淨，得到標題 化合物6 mg ^ iH-NMR光譜：（DMSO-d6) 0·30-0·40 (2H, m)，0·55-0·65 (2H， m)，2.43-2.57 (1H，m，covered by DMSO peak)，6.20 (1H，br s)5 6.60 (2H5 d, J=8.90 Hz), 6.83 (1H, s), 6.87-6.91 (1H, m), 7.10-7.16 (lH，m)，7,30-7·50 (3H，m)，7.90 (2H，d，J=8.1 Hz)， 8.26 (1H，d，J=0.4 Hz)，8.92 (1H，br s)，12·60 (1H，br s)。 實施例174 ir丄4- ( 6-苯基r Ijj二峨哈并密症-4-基氣）宏基達 唑-2-基）脲 在4-(6-苯基- 7H-nb咯并[2,3-d]嘧啶-4-基氧）苯胺52〇 mg中，加入2-p塞啥基胺基甲故表酿492 mg並於80。〇擾摔4 小時。濾取/折出之結晶，用乙酸乙酯及四氫呋喃洗淨，得 到標題化合物275 mg。 、 iH-NMR光譜：（DMSO-d6) 7.03 (1H，d，J=2.0 Ηζ)，7·1〇 (1H, d, J-3.0 Hz), 7.18-7.50 (7H, m)5 7.54 (2H, d, J=8.7 Hz) 7 74 (2H, d, J-8.0 Hz), 8.29 (1H, s), 9.10 (1H, s), 12.69 (1H br s)。 實施例175 1-(4-氣笨基）_3.「2 -氣- 4- (6.笨基·7Η-口比♦幷『〇 〇 d 1崎A 4-基氣）苽某1脲 ， 以與實施例171同樣之方法’從2-氟_4_(6_苯基_7H_b比哈 -277 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 - A7 _ B7 五、發明説明（&quot;&quot;~' &quot;&quot;&quot;&quot;^ 并[2，3 - d]嘧啶-4-基氧）苯胺36 mg，得到26 mg之標題化合 物。 W-NMR光譜:（DMSO-d6) 7.05-7.18 (4H，m)，7·30-7·50 (6H， m)，7·94 (2Η，d，J=8.1 Ηζ)，8·21 (1Η，t，J=10.4 Ηζ)，8·32 (1Η， s)，8.55 (1H，d，J=1.9 Hz)，9·09 (1H，s)，12·73 (1H，br s)。 中間體如下述合成。 製造例175-1 4—- (3 -氣-4-硝基笨氧基）-6-茉某-7H-吡咯# Γ 2 T 3 - d 1 ,珐 在 WO 97/02266，PCT/EP96/02728 記載之 4-氯-6-苯基-7H-吡哈并[2,3-d]嘧啶360 mg中，加入3-氟-4-硝基酚328 mg，2,6-二甲基说咬〇·22 ml&amp;N_甲基吡咯啶〇9 m卜並於 130°C攪拌整夜後，回到室溫及加入水，濾取析出之固體， 用水及乙醚洗淨，將收集到之固體乾燥，得到標題化合物 112 mg 〇 H-NMR 光 if :(DMS〇-d6) 7·14 (1H，s)，7.34-7.44 (?H m) 7.48 (2H，t，J=7.8 Hz)，7.73 (1H，dd，J=i5 Hz，U 8 Hz)， 7·89 (2H，d，J=7.8 Hz)，8·28 (1H，t，卜8.5 Hz)，8 4〇 · d’ J=1.3 Hz)，12.87 (1H，bi* s)。 ’ ’ 製造例1 7 5 - 2 苯基-7H-吡咯并f2,3-dl嘧螳-肚 以與製造例171-2同樣之方法，從藉由上述中間體之人成 法合成之4-(3-氟-4-硝基苯氧基）_6_苯基-7h_吡咯并_ d]嘧啶I25 mg，得到us mg之標題化合备^ ’ W-NMR 光譜：（DMS〇-d6) 5.10 (2H，s) 6 7R7 H7.〇4 (4H，m)， -278 -1^111^^^1-3-"4_(6-morpholine-4-a certain -7--Pak: 11!^[~: 夂(1) pyridine: 4 two gas) dish 1M is implemented Example 168 Synthesis of 1-(4-fluorophenyl)-3-[4-(6-methylindolyl pyridinium [2,3-d] yam-4-yloxy)phenyl] gland Add tetrahydrotetramine 〇 $ ml, morpholine 1 〇 &quot; 1 and triethoxy borohydride 26 mg, and stir at room temperature overnight. The reaction system is tetrahydrofuran-acetic acid B The mixture was extracted with EtOAc EtOAc (EtOAc m.) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -3 - { 4- Γ 6 2 (A-.methyl-1-hexa-oxygen k-flavor A V 1- 7H- mouth t 嗒If 2,3- dl pyrimidine-4-yl gas 1 Mo Mo} #_1-(4-Fluorophenyl)_3·[4_(6•曱醯基_7士外匕[2,3-d]pyrimidin-4-yloxy)phenyl synthesized in Example 468 Add THF to 4 ml, 1-methylhexahydropyrazole 11; 1 and triethylhydrazine borohydride 23 mg, and mix at room temperature overnight to β to dilute the reaction system with tetrahydrogen Extracted by hexane-ethyl acetate mixed solvent, dried by anhydrous sodium sulfate and concentrated to dryness , the title compound was obtained as 5 mg. MS spectrum (ESI) ·· 476 (M+1). f Example 17 1 fluorophenyl dicapyl. dibromo #『2Ή1 pyrimidine-4-one^ gas) stupid 1 urea -274 - This paper size applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1304061 -s —,.- _ A7 广__B7 V. Description of invention (269) 4-(6-phenyl) -7H-, biluo[2,3-d]pyrimidin-4β-oxy)aniline 4〇mg is dissolved in toluene 4·5 ml and acetonitrile 4·5 ml at ll〇°C, then isocyanate is added The phenyl ester (16·6/ζ 1) was stirred for 1 hour, placed at room temperature, and the precipitated crystals were taken and dried to give the title compound: 37 mg. MS Spectrum (ESI): 440 (M+1), 462 ( M+23) 1H-NMR spectrum: (DMSO-d6) 7.02 (1H, s), 7·06-7·52 (11H, m), 7.94 (2H, d, J = 8.0 Hz), 8·28 ( 1H, s), 8.77 (1H, s), 8.79 (1H, s), 12·68 (1H, br s) The hydrazine intermediate was synthesized as follows. Production Example 171-1 4-( 4 - Nitrate Base-stirty base)-6-stupyl- 7H-pyrrolo[2,3-d 1 is indeed cold in WO 97/02266, PCT/EP96/02728, 4-chloro-6_phenyl-7H-port bilo And [2,3- d] mouth bite 113 mg, add 4-nitro hope 123 mg 136 mg potassium carbonate and two carboxylic groups Yue Amides 1 · 5 ml, and at 130 ° C-135 ° C ~ was stirred for 15 hours and then was added 60mg 4-nitrophenol and 75 mg of potassium carbonate and stirred for 6 hours. After returning to room temperature, water was added, and the mixture was extracted with EtOAc EtOAc EtOAc. iH-NMR spectrum: (DMS〇-d6) 7·13 (1H, s), 7.37 (1H, t, J = 7.7 Hz), 7.47 (2H, t, J = 7.7 Hz), 7.56-7.61 (2H5 m ), 7.74-8.00 (2H, m), 8.30-8.38 (3H, m), 12.82 (1H, br s). fExample 171-2 [6-Streprise-7H〇pyrolo[2,3-dlpyrimidin-4-indole] stupid turtle in 4-(4-nitrophenoxy)-6-phenyl- 7H-pyrrolo[2,3-d]pyrimidine 1 1〇-275 - ____ — This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304061 A7 ___B7 V. Description of invention (270) mg Add iron powder 110 mg, ammonium chloride 220 mg, ethanol 10 mi and water 2 m 1 ' and expand at 8.0 - 8 5 C: mix for 2.5 hours. After returning to room temperature, the mixture was stirred for 5 minutes by adding tetrachloromethane 20 m, and then filtered through celite, and 100 ml of ethyl acetate and 50 ml of water were added to the filtrate to extract. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. MS spectroscopy (ESI) m/z: 303 (M + 1): iH-NMR spectrum: (DMSO-d6) 5·04 (2H, br s), 6.57-6.61 (2H, m), 6·84-6· 90 (3H,m),7·34 (1H,t,J=7.7 Hz), 7.45 (2H,t,J=7.7 Hz), 7.87 (2H,t,J=7.7 Hz),8·26 (1H , s), 12.61 (1H, br s). Example 172 Phenyl)-3-"4-(6-benzene 4 bis7H-pyrrole #"2^-d]pyrimidin-4-early gas) Stupyl 1 urea in the same manner as in Example 17 1 The reaction of 4_(6-phenyl-7H_pyrrolo[2,3-d]pyrimidin-4-yloxy)aniline 36 mg with fluorophenyl p-cyanate (14#) gave 24 mg of the title compound MS spectrum (ESI): 440 (M+l), 462 (M+23) iH-NMR spectrum: (DMSO-d6) 7.02 (1H, s), 7.08154 (11H, m), 7.94 (2H, d , J = 8.0 Hz), 8.28 (1H, s), 8.88 (1H, s), 9.00 (1H, s), 12.68 (1H, br s). Example 173 h._Cyclopropyl-3-"4 -(6-phenyldi 2111^^11^1 pyrimidin-4-ylhydrogen&gt;) fluorenyl 1 urea-· in 4-(6-phenyl-7H-pyrrolo[2,3_d]pyrimidin-4· Base oxy) aniline 4 - -276 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) "quote 1304061 ~ A7 ____B7 __ five, invention description (271), add cyclo Phenyl carbazate 30 mg and dimethyl hydrazine 0.5 ml ' and stirred at 80 ° C for 4 hours. After returning to room temperature, adding water and extracting with ethyl acetate and concentrating to dryness, The solid was washed with diethyl ether to give the title compound 6 mg. iH-NMR spectrum: (DMSO-d6) 0·30-0·40 (2H, m), 0·55-0·65 (2H, m), 2.43-2.57 (1H, m, covered by DMSO peak), 6.20 (1H, br s) 5 6.60 (2H5 d, J=8.90 Hz), 6.83 (1H, s), 6.87-6.91 (1H, m), 7.10-7.16 (lH, m), 7, 30-7· 50 (3H, m), 7.90 (2H, d, J = 8.1 Hz), 8.26 (1H, d, J = 0.4 Hz), 8.92 (1H, br s), 12·60 (1H, br s). Example 174 ir丄4-(6-phenylr Ijj 二峨哈密密症-4-base gas) apodazol-2-yl)urea in 4-(6-phenyl-7H-nb-pyrene[2 , 3-d]pyrimidin-4-yloxy)aniline 52 〇mg, adding 2-p s-hydrazino group A, 492 mg was brewed at 80. The smashing fell for 4 hours. Washed with ethyl acetate and tetrahydrofuran to give the title compound 275 mg. , iH-NMR spectrum: (DMSO-d6) 7.03 (1H, d, J = 2.0 Ηζ), 7·1 〇 (1H, d, J-3.0 Hz), 7.18-7.50 (7H, m)5 7.54 (2H , d, J=8.7 Hz) 7 74 (2H, d, J-8.0 Hz), 8.29 (1H, s), 9.10 (1H, s), 12.69 (1H br s). Example 175 1-(4-gas base)_3. "2 - gas - 4- (6. Stupid · 7 Η - mouth ratio ♦ 幷 "〇〇 d 1 崎 A 4-base gas" 苽 1 urea, In the same manner as in Example 171 'from 2-fluoro_4_(6_phenyl_7H_b than Ha-277 - this paper scale applies Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304061 - A7 _ B7 V. Inventive Note (&quot;&quot;~' &quot;&quot;&quot;&quot;^ and [2,3 - d]pyrimidin-4-yloxy)aniline 36 mg to give 26 mg of the title compound. NMR spectrum: (DMSO-d6) 7.05-7.18 (4H, m), 7·30-7·50 (6H, m), 7.94 (2Η, d, J=8.1 Ηζ), 8·21 (1Η, t, J = 10.4 Ηζ), 8·32 (1Η, s), 8.55 (1H, d, J = 1.9 Hz), 9·09 (1H, s), 12.73 (1H, br s). The synthesis is as follows. Production Example 175-1 4—(3-Gas-nitrophenyloxy)-6-Momot-7H-pyrrole# Γ 2 T 3 - d 1 , 珐 in WO 97/02266, Add 3-fluoro-4-nitrophenol 328 mg, 2,6- to 4-chloro-6-phenyl-7H-pyhaha[2,3-d]pyrimidine 360 mg as described in PCT/EP96/02728 Dimethyl says bite · 22 ml &amp; N_methylpyrrolidinium 9 m and stir at 130 ° C overnight, return to room temperature and add Water, the precipitated solid was filtered, washed with water and diethyl ether, and the solid obtained was dried to give the title compound 112 mg 〇H-NMR light if: (DMS 〇-d6) 7·14 (1H, s), 7.34 7.44 (?H m) 7.48 (2H, t, J = 7.8 Hz), 7.73 (1H, dd, J = i5 Hz, U 8 Hz), 7·89 (2H, d, J = 7.8 Hz), 8· 28 (1H, t, 8.5 Hz), 8 4〇· d' J=1.3 Hz), 12.87 (1H, bi* s). ' ' Manufacturing Example 1 7 5 - 2 Phenyl-7H-pyrrole f2, 3-(3-fluoro-4-nitrophenoxy)-6-phenyl-formula synthesized by the human method of the above intermediate in the same manner as in Production Example 171-2. 7h_pyrrolo-d-pyrimidine I25 mg, the title compound of us mg is obtained. ^ W-NMR spectrum: (DMS〇-d6) 5.10 (2H, s) 6 7R7 H7.〇4 (4H, m), - 278 -

1304061 A7 B7 五、發明説明（273)1304061 A7 B7 V. Description of invention (273)

7.37 (1H，t，J=7.9 Ηζ)，7·47 (2H，t，J=7.9 Hz)，7,92 (2H d J=7.9 Hz)，8·38 (1H，s)，12.67 (1H，br s)。 ’ ’ 實施例176 卜（3 -氟苯基）.·:·_3_·:Ι1- 笔基· 7H•吡咯并门^ 4-基氣）笨基1脲 &quot; 以與實施例171同樣之方法，從2-氟_心（卜苯基_7h•吡咯 并[2,3-d]嘧啶-4-基氧）苯胺33 mg，得到27 mg之標題化合 物。 W-NMR 光譜：（01^〇-(16)6.78(111，〇^，】=3.3,9.5出)，7〇6- 7·52 (8H，m)，7.97 (2H，t，JU Hz)，8.11 (1H，t，&gt;9.5 Hz) 8·42 (1H，s)，8.62 (1H，s)，8.62 (1H，s)，9,28 (1H，s)，12 73 (lH，brs)。 ’ · 實施例177 lif 2-氟-4Ί_苯基-7Ιϋ咯并嘧啶 _4·某氧 3-(唼唑-2-¾ )胧 以與實施例171同樣之方法，從2_氟_4々6-苯基-7H-吡咯 并[2,3-d]卷淀-4-基氧）苯胺42 mg ,得到27 mg之標題化合 物。 lH-NMR光譜：（DMSO-d6) 7·〇6-7·16 (3H，m)，7.12-7.44 (3H， m)，7·47 (2H，t，J=8.1 Ηζ)，7·96 (2H，d，卜8.1 Hz)，8.12 (1H， t，J=9.1 Hz)，8·32 (1H，s)，8.96 (1H，br s)，1〇·78 (1H，br s), 12.73 (1H，br s) o 實施例1 7 8 : 1^6-(4-幾基苯基）-711-咄咯并[2.3-(1]嘧畦-4-某氫 ____ - 279 · I纸張尺度適用中S g家標準(CNS) A4規格(21Q x 297公爱）7.37 (1H,t,J=7.9 Ηζ),7·47 (2H,t,J=7.9 Hz), 7,92 (2H d J=7.9 Hz),8·38 (1H,s),12.67 (1H , br s). Example 176 卜(3-fluorophenyl).·:·_3_·: Ι1- pen base·7H•pyrrolo-[4-base gas) stupyl 1 urea &quot; In the same manner as in Example 171 From the 2-fluoro-heart (Phenyl-7h-pyrrolo[2,3-d]pyrimidin-4-yloxy)aniline 33 mg, 27 mg of the title compound. W-NMR spectrum: (01^〇-(16)6.78(111,〇^,]=3.3,9.5 out), 7〇6- 7·52 (8H, m), 7.97 (2H, t, JU Hz) , 8.11 (1H, t, &gt; 9.5 Hz) 8·42 (1H, s), 8.62 (1H, s), 8.62 (1H, s), 9, 28 (1H, s), 12 73 (lH, brs Example 177 lif 2-Fluoro-4-indole-phenyl-7-pyrrolopyrimidine_4·Oxygen 3-(carbazole-2-3⁄4)胧 In the same manner as in Example 171, from 2-fluoro _4々6-Phenyl-7H-pyrrolo[2,3-d]rollate-4-yloxy)aniline 42 mg gave 27 mg of the title compound. lH-NMR spectrum: (DMSO-d6) 7·〇6-7·16 (3H, m), 7.12-7.44 (3H, m), 7·47 (2H, t, J=8.1 Ηζ), 7.96 (2H,d,b 8.1 Hz), 8.12 (1H, t, J=9.1 Hz), 8·32 (1H, s), 8.96 (1H, br s), 1〇·78 (1H, br s), 12.73 (1H, br s) o Example 1 7 8 : 1^6-(4-methylphenyl)-711-fluorenyl[2.3-(1]pyrimidin-4-one hydrogen ____ - 279 · I paper size applies to the S g family standard (CNS) A4 specification (21Q x 297 public)

裝 訂 線 1304061 A7 B7 五、發明説明（274) j -複酸乙醯胺 將5-[6-(.4-芊氧基苯基）-7-(2-三甲矽烷乙氧甲基）-7H-吡 哈并[2,3-d]嘧啶-4-基氧]吲哚· 1-羧酸乙醯胺3〇 mg溶於三 氟乙酸1 ml及硫代苯甲醚〇·ι ml，並於50-55T：攪拌。其後 回到室溫，加入飽和礙酸氫鈉水溶液，調成鹼性後，用乙 酸乙酯-四氫呋喃（5 ·· 1)混合溶媒分液萃取。將有機層濃 縮，在殘餘物中加入四氫呋喃i ml及2當量氫氧化鈉水溶液 1 ml，並於室溫攪拌5分鐘。其後，用1當量鹽酸中和，用 乙酸乙酯-四氫呋喃（5 : 1)混合溶媒分液萃取。將有機層濃 縮及將殘餘物付諸於矽凝膠管柱層析（己烷-乙酸乙酯），得 到標題化合物5 mg。 MS 光譜（ESI) : 468 (M+55) ; (M+Na+MeOH) iH-NMR光譜：（DMSO-d6) 1·18 (3H，t，J=6.7 Ηζ)，3·20-3·50 (2H, m3 covered by H20 peak), 6.67 (1H, d, J=3.5 Hz), 6.78 (1H，s)，6‘8f (2H，d3 J=8.4 Hz)，7.12 (1H，dd，J=2.2, 8.4 Hz)， 7.44 (1H，d，J=2.2 Hz), 7·74 (2H，d，J=8.4、Hz)，7.89 (1H，d， J一3·3 Hz)，8.16-8.22 (2H，m)，8·25 (1H，d，J=8,4 Hz)，9.80 (1H，br s)，12·45 (1H，bi: s)。實施例179 U4-卞氧基苯皋）-4-ΠΗ-5-巧嗓惫·?比哈砰[7 將5-[6-(4-苄氧基苯基）-7-(2-三甲矽烷乙氧甲基卜7仏，比 洛并[2,3-d]嘧啶-4-基氧]吲哚-丨-羧酸乙醯胺22 mg溶於四 氫呋喃1.5 ml，加入四丁基銨氯化物之1M四氫呋喃溶液， -280 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）Gutter 1304061 A7 B7 V. Inventive Note (274) j-Resveric acid acetamidine 5-[6-(.4-methoxyphenyl)-7-(2-trimethyldecaneethoxymethyl)-7H - pyrha[2,3-d]pyrimidin-4-yloxy]indole 1-carboxylic acid acetaminophen 3 〇mg is dissolved in 1 ml of trifluoroacetic acid and thioanisole·ι ml, and At 50-55T: Stir. Thereafter, the mixture was returned to room temperature, and a saturated aqueous solution of sodium hydrogencarbonate was added thereto to adjust to basicity, followed by extraction with a mixture of ethyl acetate-tetrahydrofuran (5··1). The organic layer was concentrated, and 1 ml of tetrahydrofuran and 1N aqueous sodium hydroxide solution were added to the residue, and the mixture was stirred at room temperature for 5 minutes. Thereafter, it was neutralized with 1N hydrochloric acid, and extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (5:1). The organic layer was concentrated and the residue was applied to EtOAcjjjjjjjjj MS spectrum (ESI): 468 (M+55); (M+Na+MeOH) iH-NMR spectrum: (DMSO-d6) 1·18 (3H, t, J=6.7 Ηζ), 3·20-3· 50 (2H, m3 covered by H20 peak), 6.67 (1H, d, J=3.5 Hz), 6.78 (1H, s), 6'8f (2H, d3 J=8.4 Hz), 7.12 (1H, dd, J =2.2, 8.4 Hz), 7.44 (1H, d, J = 2.2 Hz), 7.74 (2H, d, J = 8.4, Hz), 7.89 (1H, d, J - 3·3 Hz), 8.16- 8.22 (2H, m), 8·25 (1H, d, J=8, 4 Hz), 9.80 (1H, br s), 12·45 (1H, bi: s). Example 179 U4-decyloxybenzoquinone)-4-ΠΗ-5- Qiao嗓惫·?比哈砰[7 5-[6-(4-Benzyloxyphenyl)-7-(2-trimethyl)矽 乙 ethoxymethyl b 7 仏, pirodi[2,3-d]pyrimidin-4-yloxy]indole-indole-carboxylic acid acetamide 22 mg dissolved in tetrahydrofuran 1.5 ml, tetrabutylammonium chloride added 1M tetrahydrofuran solution, -280 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂 線 1304061 A7 B7 五、發明説明（275)Binding line 1304061 A7 B7 V. Description of invention (275)

並回流2小時。回到室溫後，加入水，濾取析出之結晶，然 後付諸於矽凝膠管柱層析（己烷-乙酸乙酯），得到標題化合 物 2 mg 〇 iH-NMR 光譜：（DMS〇-d6) 5·17 (2H，s)，6.40-6.43 (1H，m) 6.80 (1H, s), 6.9j (1H, dd, 1=2.5, 8.8 Hz), 7.10 (2H, d, 1=8.8 Hz)，7.30-7,50 (8H，m)，7.83 (2H，d，J=8.8 Hz)，8·20 (1H，s)， 11·19 (1H，br s)，12.51 (1H，br s)。 中間體如下述合成。 製造例179-1 卜（4-芊氣基笨基5-钏哚氯）-7-(2-三甲矽烷乙氣t 基）-7H- g比鳴·并Γ 2,3- d~|，密症 在6-(4-苄氧基苯基）-4-氯-7-(2-三甲矽烷乙氧甲基）_ 7H-吡咯并[2,3-d]嘧啶190 mg中加入二甲基甲醯胺1.9 ml， 5-羥基吲哚108 mg及碳酸鉀112 mg，然後於135- 140°C授拌 4小時。之後回到室溫，加入水以及用乙酸乙酯-四氫吱喃 (5 : 1)混合溶媒分液萃取。將有機層濃縮及付諸於nh带凝 膠管柱層析（己烷-乙酸乙酯），得到標題化合物9〇 mg。 MS光譜（ESI) : 563 (M+1) iH-NMR 光譜：（DMSO-d6) -0.09 (9H，s)，〇·87 (2H，t，J==84Hz)，3.62(2H，t，J=8.4Hz)，5.19(2H，s)，5.59(2H，s)，6 42· 6.46 (1H，m)，6·65 (1H，s)，6.83 (2H，d，J=8.4 Hz)，6·97 (1H dd, J=2.6, 8.6 Hz), 7.16 (2H, d, J=8.6 Hz), 7.32-7.50 (8H m)7.70 (2H，d，J=8.6 Hz)，8·37 (1H，d，J=i.十 Hz)，11·21 (1H br s)。 ’ -281 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)And reflux for 2 hours. After returning to room temperature, water was added, and the crystals which precipitated were collected by filtration, and then applied to a silica gel column chromatography (hexane-ethyl acetate) to give the title compound 2 mg 〇iH-NMR spectrum: (DMS〇- D6) 5·17 (2H, s), 6.40-6.43 (1H, m) 6.80 (1H, s), 6.9j (1H, dd, 1=2.5, 8.8 Hz), 7.10 (2H, d, 1=8.8 Hz), 7.30-7,50 (8H,m), 7.83 (2H,d,J=8.8 Hz),8·20 (1H,s), 11·19 (1H,br s),12.51 (1H,br s). The intermediate was synthesized as follows. Production Example 177-1 卜(4-芊气基笨基5-钏哚chloro)-7-(2-trimethyl decyl ethane t-)-7H- g ratio Γ Γ Γ 2,3-d~|, Addition of dimethyl to 6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethyldecaneethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine 190 mg Baseamidine 1.9 ml, 5-hydroxyindole 108 mg and potassium carbonate 112 mg were then mixed for 4 hours at 135-140 °C. After that, it was returned to room temperature, and water was added thereto and extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (5:1). The organic layer was concentrated and purified to mjjjjjjjjjjj MS spectroscopy (ESI): 563 (M +1):::::::::::::::::::::::::::::::::::: J=8.4Hz), 5.19(2H, s), 5.59(2H, s), 6 42· 6.46 (1H, m), 6·65 (1H, s), 6.83 (2H, d, J=8.4 Hz) ,6·97 (1H dd, J=2.6, 8.6 Hz), 7.16 (2H, d, J=8.6 Hz), 7.32-7.50 (8H m)7.70 (2H,d,J=8.6 Hz),8·37 (1H, d, J = i. ten Hz), 11·21 (1H br s). ’ -281 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂Binding

線 1304061 〜 A7 B7 五、發明説明（276) 製造例179-2 5-「6-( 4-辛氣某茉基）-7-(2-三甲矽烷乙氧甲基V7H-吡咯毛 f2,3-dl嘧啶-4基氣1吲哚-1-#酸乙醯胺_ 將6-(4-苄氧基苯基）-4-( 1H-5-啕哚氧）-7-(2-三甲矽烷乙 氧甲基）-7H-吡咯并[2,3-d]嘧啶（81 mg)溶於二甲基曱醯胺 (1 ml)中，加入氫氧化鈉（60%分散液）7 mg，及於室溫攪掉 5分鐘後，加入乙胺基甲酸苯酯3 1 mg，再攪捽2小時。之 後，加入水及用乙酸乙酯分液萃取。將有機層濃縮，付諸 於矽凝膠管柱層析（己烷-乙酸乙酯），得到62 mg之標題化 合物。 MS 光譜（ESI) : 634 (M+1)，688 (M+55) ; (M+Na+Me〇H) 1H-NMR 光譜：（DMS〇-d6) -0·09 (9H，s)，0·87 (3H，t, J=8.5 Hz), 1.20 (2H, t, J=6.7 Hz), 3.10-3.70 (5H, m, covered by H20 peak), 5.20 (2H, s), 5.60 (2H, s), 6.67 (1H, s), 6.70 (1H? d, J=3.8 Hz)； 7.12-7.20 (3H, m), 7.30-7.52 (6H, m), 7.72 (2H, d, J=9.0 Hz), 7.91 (1H, d, J=3.8 Hz), 8.23 〇H, t, J=5.9 Hz), 8·29 (1H，d，J=9.0 Hz)，8.38 (1H，s)。 實施例180 N-『4-(2-環丙基-3-曱某咪唑并「4,5-bl吡啶-4-基）氲茉某1- 乱笨基）服 將Ν-[4·(2-環丙基- 3H-咪唑并[4,5-b]吡啶-4-基）氧苯 基]-N'-(4-氟苯基）脲25 mg，破甲燒13 mg，碳酸奸26 mg 及二甲基甲醯胺5 ml於70°C攪拌20分鐘·。加入水及用乙酸 乙酯萃取’繼而在萃取液中加入矽凝膠及減壓餾去溶媒。 ____- 282 -____ 本紙張尺度適财國S家標準(CNS) A4規格(21G X 297公董） &quot;&quot; Ϊ304061 A7Line 1304061 ~ A7 B7 V. Description of Invention (276) Production Example 179-2 5-"6-(4-Xinqimum)-7-(2-Trimethyldecaneethoxymethyl V7H-pyrrole f2,3 -dl pyrimidine-4 base gas 1吲哚-1-# acid acetamidine _ 6-(4-benzyloxyphenyl)-4-(1H-5-oxime)-7-(2-trimethyl矽 乙 ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (81 mg) was dissolved in dimethyl decylamine (1 ml), and sodium hydroxide (60% dispersion) 7 mg was added. After stirring for 5 minutes at room temperature, 3 1 mg of phenyl phenyl carbamate was added, and the mixture was further stirred for 2 hours. Thereafter, water was added and extracted with ethyl acetate. The organic layer was concentrated and concentrated. Chromatography (hexane-ethyl acetate) gave 62 mg of the title compound. MS (ESI): 634 (M+1), 688 (M+55); (M+Na+Me〇H) 1H-NMR spectrum: (DMS〇-d6) -0·09 (9H, s), 0·87 (3H, t, J=8.5 Hz), 1.20 (2H, t, J=6.7 Hz), 3.10-3.70 (5H, m, covered by H20 peak), 5.20 (2H, s), 5.60 (2H, s), 6.67 (1H, s), 6.70 (1H? d, J=3.8 Hz); 7.12-7.20 (3H, m), 7.30-7.52 (6H, m), 7.72 (2H, d, J=9.0 Hz), 7.91 (1H, d, J=3.8 Hz), 8.23 〇H, t, J=5. 9 Hz), 8·29 (1H, d, J = 9.0 Hz), 8.38 (1H, s). Example 180 N- "4-(2-cyclopropyl-3-indole imidazole "4,5 -bl pyridin-4-yl) 氲 某 1- 1- disordered base) Ν-[4·(2-cyclopropyl-3H-imidazo[4,5-b]pyridin-4-yl)oxybenzene 25], N-(4-fluorophenyl)urea 25 mg, 13 mg of smoldering, 26 mg of carbaryl and 5 ml of dimethylformamide at 70 ° C for 20 min. Add water and acetic acid Ethyl ester extraction' Then add hydrazine gel to the extract and distill off the solvent under vacuum. ____- 282 -____ This paper scale is suitable for the country's S standard (CNS) A4 specification (21G X 297 dong) &quot;&quot; Ϊ304061 A7

將該矽凝膠饋入充填有矽凝膠之乾燥管柱中，然後藉管柱 層析（乙酸.乙酯，繼而乙酸乙酯：甲醇=〗〇 :丨）精製，得到 為白色粉末之目的物3 mg。The ruthenium gel was fed into a dry column packed with a ruthenium gel, and then purified by column chromatography (ethyl acetate: ethyl acetate: methanol = 〇: 丨) to obtain a white powder. 3 mg.

lH-NMR (CDCl3)(5(ppni): 1.13-1.19 (2H, m), 1.28^1.3 5 (2H m)，2.03-2.11 (1H，m)，3·95 (3H，s)，6.43 (1H，d，J=5,6 Hz) 6.95-7.04 (4H，m)，7·26-7·35 (4H，m)，8,19 (1H，d，J=5 6lH-NMR (CDCl3) (5 (ppni): 1.13-1.19 (2H, m), 1.28^1.3 5 (2H m), 2.03-2.11 (1H, m), 3.95 (3H, s), 6.43 ( 1H,d,J=5,6 Hz) 6.95-7.04 (4H,m),7·26-7·35 (4H,m),8,19 (1H,d,J=5 6

Hz) 〇 ，， · 實施例1 81 丁胺吡啶-4-某）氧苯基甚 將4-(4-胺基苯氧基）-2-丁胺吡啶54 mg，異氰酸對-氟苯 酿34·5 mg及四氫呋喃5 ml在室溫下攪拌2.5小時。在反應溶 液中加入NH型矽凝膠，減壓餾去溶媒，以及使反應生成物 吸著於矽凝膠上。將該矽凝膠饋入充填有NH型矽凝膠之乾 燥管柱中，然後進行管柱精製（己烷：乙酸乙酯=1 : 1，繼 而乙酸乙醋〇。減壓餾去溶媒，殘餘物藉由乙酸乙酯-己烷 固體化，得到為淡黃色粉末之目的物15 mg。 lH-NMR (DMSO-d6) δ (ppm): 0.87 (3H, t, J=7.2 Hz), 1.30 (2H, tq3 J=7.2 Hz, 7.2 Hz), 1.44 (2H, tt, J=7.2 Hz, 7.2 Hz), 3·16 (2H，q，J=7.2 Hz)，5.80 (1H，d，J=2.0 Hz)，6·09 (1H，ddd， J=5.0 Hz, 2.0 Hz, 2.0 Hz), 6.45 (1H, dd, J=5.0 Hz, 5.0 Hz), 7.03-7.18 (4H，m)，7.43-7.55 (4H，m)，7·83 (1H，dd，JN5.0 Hz， 2·0 Hz), 8.70 (1H，s)，8·74 (1H，s)。 藉由下述方法得到中間體。 _· f i告例 1 81- 1 -283 - I紙張尺中國國家標準(CNS) A4規格（210 x 297公釐） 1304061 〜 — A7 B7 五、發明説明（278) 4“4-胺基笨氫基）-2- 丁胺吡啶 將4-(4-硝基苯氧基）-2- 丁胺吡啶80 mg溶於四氫呋喃8 ml，於室溫及攪拌下加入氫化鋰鋁67 mg，並於70°C攪拌10 分鐘。加入水及用乙酸乙酯萃取，繼而將矽凝膠加至萃取 液中及減壓餾去溶媒。將該矽凝膠饋入充填有NH型矽凝膠 之乾燥管柱中，然後藉由管柱層析精製（乙酸乙酯），得到 為褐色油狀物之目的物5 4 m g。 ^-NMR (CDCl3)(5(ppm): 0.93 (3H, t, J=7.2 Hz), 1.40 (2H, tq, J=7.2 Hz, 7.2 Hz), 1.56 (2H, tt, J=7.2 Hz, 7.2 Hz), 3.14 (2H, q5 J=7.2 Hz), 5.82 (1H, d3 J=2.0 Hz), 6.14 (1H, dd3 J=6.0 Hz, 2.0 Hz), 6.66-6.74 (2H, m), 6.86-6.94 (2H, m)3 7·87 (1H，d，J=6.0 Hz) 〇 實施例1 8 2Hz) 〇,, · Example 1 81 butylamine pyridine-4- oxyphenyl and 4-(4-aminophenoxy)-2-butylamine pyridine 54 mg, isocyanate p-fluorobenzene Stirring 34. 5 mg and 4 ml of tetrahydrofuran were stirred at room temperature for 2.5 hours. An NH type hydrazine gel was added to the reaction solution, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the hydrazine gel. The ruthenium gel is fed into a drying column packed with an NH type ruthenium gel, and then subjected to column purification (hexane: ethyl acetate = 1: 1, followed by acetonitrile acetate. The solvent is distilled off under reduced pressure, and the residue The product was solidified by ethyl acetate-hexane to give 15 mg of the object as pale yellow powder. lH-NMR (DMSO-d6) δ (ppm): 0.87 (3H, t, J = 7.2 Hz), 1.30 ( 2H, tq3 J=7.2 Hz, 7.2 Hz), 1.44 (2H, tt, J=7.2 Hz, 7.2 Hz), 3·16 (2H, q, J=7.2 Hz), 5.80 (1H, d, J=2.0 Hz),6·09 (1H,ddd, J=5.0 Hz, 2.0 Hz, 2.0 Hz), 6.45 (1H, dd, J=5.0 Hz, 5.0 Hz), 7.03-7.18 (4H,m),7.43-7.55 (4H, m), 7·83 (1H, dd, JN 5.0 Hz, 2·0 Hz), 8.70 (1H, s), 8.74 (1H, s). Intermediate was obtained by the following method. _· fi 例1 81- 1 -283 - I paper ruler China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 ~ — A7 B7 V. Description of invention (278) 4 "4-Amine-based hydrogen 4-(4-nitrophenoxy)-2-butylamine pyridine 80 mg was dissolved in tetrahydrofuran (8 ml), and lithium aluminum hydride 67 mg was added at room temperature with stirring. Stir at °C for 10 minutes. The water is extracted with ethyl acetate, and then the ruthenium gel is added to the extract and the solvent is distilled off under reduced pressure. The ruthenium gel is fed into a dry column packed with a NH-type ruthenium gel, and then passed through a column. Chromatography (ethyl acetate) to give the title compound (md.) Tq, J=7.2 Hz, 7.2 Hz), 1.56 (2H, tt, J=7.2 Hz, 7.2 Hz), 3.14 (2H, q5 J=7.2 Hz), 5.82 (1H, d3 J=2.0 Hz), 6.14 ( 1H, dd3 J=6.0 Hz, 2.0 Hz), 6.66-6.74 (2H, m), 6.86-6.94 (2H, m)3 7·87 (1H, d, J=6.0 Hz) 〇Example 1 8 2

Er.(4-氟苯基Μ- ΓΠ-酮基-5,6,7,8-四着 Γ 1，81 :¾:咗-4- 基）氧Ί茉某飞月尿 將4- [(7-酮基- 5,6,7,8-四氫[1，8]蕃啶-、4-基）氧]苯胺43 m§ ’異氰酸對-氟苯酯28 mg，四氫吱喃5 ml及二曱基曱醯 胺2 ml於室溫下授掉3 〇分鐘。在室溫下滴入水直至結晶析 出為止’濾取結晶，得到為白色結晶之目的物48 mg。 H-NMR (DMSO^d6) (5 (ppm): 2.50 (2H, t, J=8.0 Hz), 2.91 (2H, t3 J=8.0 Hz), 6.24 (1H, d, 1=6,0 Hz), 7.03-7.35 (4H, m), 7.40-7.55 (4H，m)，7·94 (1H，d，J=6.0 Hz)，8.70 (1H，s)，8.74 ΠΗ，s)，10.48 (1H，s)。 : 如下述得到中間體。 __________ - 284 - 本紙条尺度適用巾g國家標準(cNs) A4規格(21QX 297公爱） 1304061 * A7 ________B7五、發明説明（279) Ψ T# 1 82- 1 4- 碘-2-_吡啶脸 將為公知化合物之N-( 4-氯-2-吡啶基）胺基甲酸第三丁酯 10 g，Ν，Ν，Ν’，Ν·-四曱基乙二胺16 6 ml及四氫呋喃200 ml之 溶液冷卻至-75^，於攪拌下經30分鐘滴入正-丁基鋰（2.6 Μ己燒溶液）42加。於75艺攪拌丨小時後，將碘28 g溶於四 氫呋喃28 ml之溶液經3〇分鐘滴入。滴入終了後再於75它攪 拌30分鐘’其後回到室溫，加入硫酸氫鈉水溶液及用乙酸 乙醋萃取°在萃取液中加入NH型矽凝膠，減壓饍去溶媒及 使反應生成物吸著於矽凝膠。將該矽凝膠饋入充填有1^1型 石夕凝膠之乾燥管柱中，然後進行管柱層析精製（己烷：乙酸 乙醋=3 · 1)。減壓餾去溶媒，在殘餘物中加入48%ηβγ水溶 液並於100 C攪掉5分鐘。在反應溶液中加入冰水及5Ν氫氧 化鈉水落液並濾取析出之固體。得到7.4 g淡黃色固體。 ^-NMR (E^MSO-d6) δ (ppm): 6.50 (2H? bs), 6.72 (1H, d, J=5.6 Hz), 7·82 (1H，d，J=5.6 Hz) « 、 製造例182-2 3-琪-4二〔4-確基笨i某2·毗冷眩 將4-氯-3-碘-2-吡啶胺ΐ·〇 g ,對-硝基酚l lg ,二異丙基 乙胺1.0 ml及N-甲基-2-吡咯啶酮2 ml於170°C攪拌17小時。 使反應ϋ液回到室溫，加入水及用乙酸乙酯萃取。在萃取 液中加入ΝΗ型矽凝膠，減壓餾去溶媒，以使反應生成物吸 著於矽凝膠。該矽凝膠饋入充填有^^]^型矽凝膠之乾燥管柱 中’然後進行管柱精製（己烷：乙酸乙酯=3 :丨）。減恩餘去 ___ - 285 - I紙張尺度適用t國國家標準(CNS) Α4規格(210 X 297公愛) ----Er.(4-fluorophenylfluorene-fluorenone-keto-5,6,7,8-tetraquinone 1,81 :3⁄4:咗-4-yl) oxo Ί 某 a certain moon urinary will 4- [( 7-keto- 5,6,7,8-tetrahydro[1,8]-pyridine, 4-yl)oxy]aniline 43 m§ 'p-Fluorophenyl isocyanate 28 mg, tetrahydrofuran 5 ml and 2 ml of dimethyl decylamine were given at room temperature for 3 〇 minutes. The water was added dropwise at room temperature until the crystals were precipitated, and the crystals were collected by filtration to give the object as white crystals (yield: 48 mg). H-NMR (DMSO^d6) (5 (ppm): 2.50 (2H, t, J=8.0 Hz), 2.91 (2H, t3 J=8.0 Hz), 6.24 (1H, d, 1=6,0 Hz) , 7.03-7.35 (4H, m), 7.40-7.55 (4H, m), 7.94 (1H, d, J = 6.0 Hz), 8.70 (1H, s), 8.74 ΠΗ, s), 10.48 (1H, s). : Intermediates were obtained as described below. __________ - 284 - This paper size applies to the national standard (cNs) of the towel. A4 specification (21QX 297 public) 1304061 * A7 ________B7 V. Invention description (279) Ψ T# 1 82- 1 4- Iodine-2-pyridyl face It will be a known compound of N-(4-chloro-2-pyridyl)carbamic acid tert-butyl ester 10 g, Ν, Ν, Ν', Ν·-tetradecylethylenediamine 16 6 ml and tetrahydrofuran 200 ml The solution was cooled to -75 °, and 42 g of n-butyllithium (2.6 Μ hexane solution) was added dropwise over 30 minutes with stirring. After stirring for 75 hours, a solution of 28 g of iodine in tetrahydrofuran (28 ml) was added dropwise over 3 minutes. After the end of the dropwise addition, it was stirred at 75 for 30 minutes. Then it was returned to room temperature, and an aqueous solution of sodium hydrogensulfate was added and extracted with ethyl acetate. The NH-type hydrazine gel was added to the extract, and the solvent was removed under reduced pressure. The product is absorbed in the gel. The ruthenium gel was fed into a dry column packed with a 1^1 type of Xixi gel, and then subjected to column chromatography purification (hexane: acetic acid ethyl acetate = 3 · 1). The solvent was distilled off under reduced pressure, and a 48% ηβγ aqueous solution was added to the residue and the mixture was stirred at 100 C for 5 minutes. Ice water and 5 Torr of sodium hydroxide water were added to the reaction solution, and the precipitated solid was collected by filtration. This gave 7.4 g of a pale yellow solid. ^-NMR (E^MSO-d6) δ (ppm): 6.50 (2H? bs), 6.72 (1H, d, J=5.6 Hz), 7·82 (1H,d,J=5.6 Hz) « , manufacture Example 182-2 3-Qi-4 bis [4- succinct stupid i 2 contiguous cold dip 4-chloro-3-iodo-2-pyridinium ΐ·〇g, p-nitrophenol l lg, two 1.0 ml of isopropylethylamine and 2 ml of N-methyl-2-pyrrolidone were stirred at 170 ° C for 17 hours. The reaction mash was returned to room temperature, water was added and extracted with ethyl acetate. A ruthenium-type ruthenium gel was added to the extract, and the solvent was distilled off under reduced pressure to cause the reaction product to adsorb to the ruthenium gel. The ruthenium gel was fed into a drying column packed with a gel of the type ’ gel and then subjected to column purification (hexane: ethyl acetate = 3: hydrazine).减余余去 ___ - 285 - I paper scale applies to national standards (CNS) Α 4 specifications (210 X 297 public) ----

裝 訂Binding

線 1304061 二 _ 〜—-. A7 _ B7__ 五、發明説明（~^〇) — 一 溶媒，在殘餘物中加入乙酸乙酯及己烷使之固體化。得到 淡黃色結晶540 mg。 ^-NMR (DMSO-d6) (5 (ppm): 6.22 (1H, d, J-5.2 Hz), 6.37 (2H，br s)，7.19 (2H，d，J=9.2 Hz)，7.87 (1H，d，J=5.2 Hz)， 8·26 (2H, d，J=9.2 Hz) 〇 製造例182-3 (£).:2二[2-胺基-4-(4-硝基笨氯基）-3-吡啶某1-2-丙嬌酸乙Line 1304061 II _~--. A7 _ B7__ V. Description of the invention (~^〇) — A solvent which was solidified by the addition of ethyl acetate and hexane to the residue. A pale yellow crystal of 540 mg was obtained. ^-NMR (DMSO-d6) (5 (ppm): 6.22 (1H, d, J-5.2 Hz), 6.37 (2H, br s), 7.19 (2H, d, J = 9.2 Hz), 7.87 (1H, d, J = 5.2 Hz), 8·26 (2H, d, J = 9.2 Hz) 〇Production Example 182-3 (£).: 2 bis[2-amino-4-(4-nitro stupyl) )-3-pyridine a 1-2-propionate B

|L 將3-碘-4-( 4-硝基苯氧基）-2-吡啶胺500 mg，丙婦酸乙酯 0.3 ml，乙酸鈀（Π)3〇 mg，三丁基胺0.66 ml及二曱基曱醛5 ml於130°C攪拌20分鐘。使反應溶液回到室溫，加入水及用 乙酸乙酯萃取。在萃取液中加入NH型矽凝膠及減壓餾去溶 媒’並使反應生成物吸著於矽凝膠上。將該矽凝膠饋入充 填有NH型矽凝膠之乾燥管柱中，然後進行管柱精製（己 烷：乙酸乙1旨=3 : 1)。減壓餾去溶媒，得到為黃色油狀物 之目的物330 mg。 ' lH-NMR (CDC13) (5 (ppm): 1.31 (3H, t5 J=7.2 Hz), 4.25 (2H, q，J=7.2 Hz)，5.01 (2H，s)，6·18 (1H，d，J=6.0 Hz)，6.57 (1H， d，J=16 Hz)，7.12-7.19 (2H，m)，7·73 (1H，d，J=16 Hz)，7.99 (1H，d，J=6.0 Hz)，8.24-8.32 (2H，m) 〇 製造例182-4 4- Γ(7-酮基-5,6,7,8-四氫fl，81餐:啶·4·某）氧i苯胺 將（Ε)-3-[2 -胺基- 4-(4-硝基苯氧基）：3- ρ比咬基]-2-丙烯 酸乙酯330 mg，鈀/碳（10%，含水）100 mg，甲醇5 ml及四 -286 - I紙張尺度適用中國S家標準(CNS) A4規格( X 297公爱5 ' ' Ϊ304061|L 3-iodo-4-(4-nitrophenoxy)-2-pyridinamine 500 mg, ethyl acetoacetate 0.3 ml, palladium acetate (Π) 3 〇 mg, tributylamine 0.66 ml and 5 ml of dimercaptofurfural was stirred at 130 ° C for 20 minutes. The reaction solution was returned to room temperature, water was added and extracted with ethyl acetate. An NH type hydrazine gel was added to the extract, and the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the hydrazine gel. The ruthenium gel was fed into a dry column packed with an NH type ruthenium gel, and then subjected to column purification (hexane: acetic acid B = 3: 1). The solvent was evaporated under reduced pressure to give the title compound (yield: 330 mg). ' lH-NMR (CDC13) (5 (ppm): 1.31 (3H, t5 J=7.2 Hz), 4.25 (2H, q, J=7.2 Hz), 5.01 (2H, s), 6.18 (1H, d , J=6.0 Hz), 6.57 (1H, d, J=16 Hz), 7.12-7.19 (2H, m), 7.73 (1H, d, J=16 Hz), 7.99 (1H, d, J= 6.0 Hz), 8.24-8.32 (2H, m) 〇Production Example 182-4 4-Γ(7-keto-5,6,7,8-tetrahydrofl,81 meal: pyridine·4·m) Oxygen i Aniline (Ε)-3-[2-amino-4-(4-nitrophenoxy):3- ρ than dimethyl 2-ethyl acrylate 330 mg, palladium/carbon (10%, water-containing ) 100 mg, methanol 5 ml and four-286 - I paper scale applicable to China S standard (CNS) A4 specification (X 297 public love 5 ' ' Ϊ304061

A7 B7 五、發明説明（ 281 ) 氫呋喃5 ml在1氣塵之氫氣流下攪拌一夜。濾去鈀/碳，將 濾液減壓蒸餾後’將殘餘物用矽凝膠管柱層析（乙酸乙醋， 繼而乙酸乙酯：甲醇= 5:1)精製，得到為白色固體之目的物 43 mg 〇 ^^NMR (DMSO-d6) (5 (ppm): 2.49 (2H? t5 J=8.0 Hz), 2.89 (2H，t，J=8.0 Hz)，5.09 (2H，s)，6.15 (1H，dd，J=6.0.Hz，2.0A7 B7 V. INSTRUCTIONS (281) 5 ml of hydrogen furan was stirred overnight under a stream of hydrogen gas of 1 gas. The palladium/carbon was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel column (ethyl acetate, ethyl acetate:methanol = 5:1) to give the object as a white solid. Mg 〇^^NMR (DMSO-d6) (5 (ppm): 2.49 (2H? t5 J=8.0 Hz), 2.89 (2H, t, J=8.0 Hz), 5.09 (2H, s), 6.15 (1H, Dd, J=6.0.Hz, 2.0

Hz), 6,58 (2H, dd, J=8.4 Hz, 2,0 Hz)3 6.79 (2H, dd, J=8.4 Hz, 2·0 Hz)，7·89 (1H，dd，J=6.0 Hz，2.0 Hz)，10.38 (1H，s)。 f施例1 83 么11·氟苯基）-Ν’ - { 4_:丄（7-酮幕-7,8-兰氫π ·81革冷-n 苯基}脲 將 N-(4-氟苯基）-Ν·-{4-[(7-酮基-7,8-二氫[u]茶淀·4· 基）氧]冬胺30 mg ’兴讯酸對-氟苯醋0.016 ml及二甲基甲酶 胺6 ml於70°C攪拌，直至原料消失。使反應溶液回到室溫 後，滴入水z及濾取析出之固體。得到淡褐色固體22 mg。Hz), 6,58 (2H, dd, J=8.4 Hz, 2,0 Hz)3 6.79 (2H, dd, J=8.4 Hz, 2·0 Hz), 7·89 (1H, dd, J=6.0 Hz, 2.0 Hz), 10.38 (1H, s). fExample 1 83 11 fluorophenyl)-Ν' - { 4_: 丄 (7-ketone curtain-7,8-lanine hydrogen π ·81 leather cold-n phenyl} urea N-(4-fluoro Phenyl)-Ν·-{4-[(7-keto-7,8-dihydro[u]chad 4·yl)oxy]methanol 30 mg 'Xingxin acid p-fluorophenyl vinegar 0.016 ml 6 ml of dimethylformamide was stirred at 70 ° C until the starting material disappeared. After the reaction solution was returned to room temperature, water z was added dropwise and the precipitated solid was filtered to give a pale brown solid (22 mg).

1 H-NMR (DMSO-d6) δ (ppm): 6.3 5 (1H, d5 5.6 Hz), 6.54 (1H1 H-NMR (DMSO-d6) δ (ppm): 6.3 5 (1H, d5 5.6 Hz), 6.54 (1H

d，J=10 Hz)，7.05-7.20 (4H，m)，7.40-7.60 (4H，m)，8.14 (ih d，J=10 Hz)，8·29 (1H，d，J=5.6 Hz)，8·70 (1H，s)，8·78 (1H s)，12·13 (1H，s)。 ’ 中間體如下述得到。 製造例183- 1 4-(4-硝基苯氲某）-7-酮基-7.8-二氤Γ 1.8]^^ 將（E)-3-[2 -胺基- 4-(4 -硝基苯氧基）Ht;淀基]·2-丙缔 酸乙酯350 mg，2、乙酿基蕃艱150 mg及甲哮80 ml在搜摔下 -287 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)d, J=10 Hz), 7.05-7.20 (4H, m), 7.40-7.60 (4H, m), 8.14 (ih d, J=10 Hz), 8·29 (1H, d, J=5.6 Hz) , 8·70 (1H, s), 8.78 (1H s), 12·13 (1H, s). The intermediate was obtained as follows. Production Example 183-1 4-(4-Nitrobenzoquinone)-7-keto-7.8-dioxene 1.8]^^ (E)-3-[2-Amino-4-(4-nitrate) Ethylphenoxy)Ht; decyl]·2-propionic acid ethyl ester 350 mg, 2, B-branched ruthenium 150 mg and sorrel 80 ml under search and fall -287 - This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm)

裝 訂Binding

線 1304061 〜 一… A7 B7 五、發明説明（282) 用光照射4小時，以及濾取析出之固體。得到淡黃色固體 156 mg 0 W-NMR (DMSO-d6)5(ppm): 6·57 (1H，d，J=9 6 Hz) 6.70 (1H，d，J=5.6 Hz)，7·46 (2H，d，J=8.0 Hz)，8.05 d J=9 όLine 1304061 ~ a... A7 B7 V. Description of the Invention (282) Irradiation with light for 4 hours, and filtration of the precipitated solid. Obtained as a pale yellow solid 156 mg 0 W-NMR (DMSO-d6) 5 (ppm): 6·57 (1H,d,J=9 6 Hz) 6.70 (1H,d,J=5.6 Hz),7·46 ( 2H,d,J=8.0 Hz), 8.05 d J=9 ό

Hz)，8·33 (2H，d，J=8.0 Hz)，8.42 (1H，d，J=5.6 Ήζ) 12·3ι (lH，s)。 ’ 製造例183-2 4-f (7-酮基-7,8-二 i. Π,81¾ 啶-4-甚 將4-(4-硝基苯氧基）-7-酮基-7,8-二氫π，8]茶啶156 mg，鐵粉300 mg，氯化銨600 mg，二甲基曱醯胺2 ml，乙 醇1 ml及水1 ml在l〇〇°C攪拌20分鐘。經矽藻土過遽及用水 及乙酸乙酯萃取。將有機層用氯化銨水溶液洗淨4次後，用 硫酸鎂乾燥。濾去乾燥劑及減壓餾去溶媒，得到為淡黃色 固體之目的物30 mg。 !H-NMR (EfMS〇-d6)5(ppm): 5.19 (2H，br s)，6·29 (1H，d， 1=5.6 Hz), 6.51 (1H, d, J=9.6 Hz), 6.30 (2H, d5 J=8.0 Hz)5 6.87 (2H, d, 1=8.0 Hz), 8.12 (1H, d, J=9.6 Hz), 8.25 (1H, d, J=5.6 Hz)，12.10 (1H，s)。 實施例1 84 環丙赛某）胺某1-4-(4-{以4-氣笨胺基）蕤基1胺 基}尽乳某）-3 -外b淀基1-2-丙烯酸乙醋 將（E)-3-[2-胺基-4-(4-{[(4-氟苯胺基）羰基]胺基}苯氧 基）-3-毗啶基]-2-丙烯酸乙酯200 mg、環丙烷羰基氯58 mg’二乙胺0.1 ml，四氮咬喃4 ml及二甲基甲酿胺1 ml在室 ______ - 288 - 本紙張尺度適财㈣轉準(CNS) Μ規格(21QX297公爱） 1304061 :一一 A7 _______ B7 _______ 五、發明説明（283) 溫下攪拌20分鐘。滴入少量水及濾取析出之固體。得到微 黃色固體130 mg。 lH-NMR (DMSO-d6) δ (ppm): 0.74 (4H, m), 1.21 (3H, t, J=7.2 Hz)3 1.88-1.95 (1H, m), 4.14 (2H, q, J=7.2 Hz), 6.53 (1H, d, J=5.6 Hz), 6.90 (1H, d, J=16 Hz), 7.07-7.19 (4H, m), 7.40-7.48 (3H, m)5 7.55 (2H, d, J=8.0 Hz), 8.21 (1H, d, J=5.6 Hz), 8.72 (1H, s)5 8.81 (1H, s), 10.61 (1H, s) 〇 如下述得到中間體。 製造例184- 1 - 3 -「2'胺基-4_ (4-胺基苯氧基）-3 - tr比咬基1 2-丙埽齡λHz), 8·33 (2H, d, J = 8.0 Hz), 8.42 (1H, d, J = 5.6 Ήζ) 12·3ι (lH, s). 'Production Example 183-2 4-f (7-keto-7,8-dii. Π, 813⁄4 pyridine-4- and 4-(4-nitrophenoxy)-7-keto-7, 8-Dihydro π,8]Tealidine 156 mg, iron powder 300 mg, ammonium chloride 600 mg, dimethyl decylamine 2 ml, ethanol 1 ml and water 1 ml were stirred at 10 ° C for 20 minutes. The organic layer was washed with aqueous solution of ammonium chloride for 4 times, then dried over magnesium sulfate. The dried solvent was filtered off and the solvent was evaporated under reduced pressure to give a pale yellow solid. Target 30 mg. !H-NMR (EfMS〇-d6) 5 (ppm): 5.19 (2H, br s), 6.29 (1H, d, 1 = 5.6 Hz), 6.51 (1H, d, J= 9.6 Hz), 6.30 (2H, d5 J=8.0 Hz) 5 6.87 (2H, d, 1=8.0 Hz), 8.12 (1H, d, J=9.6 Hz), 8.25 (1H, d, J=5.6 Hz) , 12.10 (1H, s). Example 1 84 Cyclopropene a) Amine 1-4-(4-{4- 4- phenylamino) fluorenyl 1 amine group} Precipitation 1-2-ethyl acrylate vinegar (E)-3-[2-amino-4-(4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-3-pyridine Ethyl 2-ethyl acrylate 200 mg, cyclopropane carbonyl chloride 58 mg 'diethylamine 0.1 ml, tetrazole 4 ml and dimethyl ketoamine 1 ml in the room ______ - 28 8 - The paper scale is suitable for money (4) Alignment (CNS) Μ Specifications (21QX297 public) 1304061: One A7 _______ B7 _______ V. Invention description (283) Stir for 20 minutes under temperature. A small amount of water was added dropwise and the precipitated solid was collected by filtration. A yellowish solid 130 mg was obtained. lH-NMR (DMSO-d6) δ (ppm): 0.74 (4H, m), 1.21 (3H, t, J = 7.2 Hz) 3 1.88-1.95 (1H, m), 4.14 (2H, q, J=7.2 Hz), 6.53 (1H, d, J=5.6 Hz), 6.90 (1H, d, J=16 Hz), 7.07-7.19 (4H, m), 7.40-7.48 (3H, m)5 7.55 (2H, d , J = 8.0 Hz), 8.21 (1H, d, J = 5.6 Hz), 8.72 (1H, s)5 8.81 (1H, s), 10.61 (1H, s) The intermediate is obtained as follows. Production Example 184- 1 - 3 - "2'Amino-4_(4-aminophenoxy)-3 - tr ratio bite base 1 2-propionium age λ

IL 將（Ε)-3 - [2 -胺基- 4-(4-硝基苯氧基）-3 - 0比淀基]-2·丙晞 酸乙酯350 mg，鐵粉700 mg，氣化銨1.4 g，二甲基曱酿胺7 ml，乙醇2 ml及水2 ml在100 °C攪捽20分鐘。經矽藻土過 濾，加入水，及乙酸乙酯以萃取。將有機層用氯化銨水溶液 洗淨5次後，用硫酸鎂乾燥。濾去乾燥劑义減壓餾去溶媒， 得到為淡黃色固體之目的物230 mg。 lH-NMR (CDC13) (5 (ppm): 1.33 (3H, t, J=7.2 Hz), 3.68 (2H, br s)，4·26 (2H，q，J=7.2 Hz)，4.87 (2H，bs)，6·02 (1H，d， J=6.0 Hz)，6.68 (1H，d，J=16 Hz)，6.70 (2H，d，J=8.8 Hz)， 6.87 (2H, d, J=8.8 Hz), 7.82 (1H, d, J=6.0 Hz), 7.85 (1H, d, J=16 Hz) 0IL (Ε)-3 - [2-Amino-4-(4-nitrophenoxy)-3 - 0 - aryl] -2 - ethyl propyl citrate 350 mg, iron powder 700 mg, gas 1.4 g of ammonium, 7 ml of dimethylamine, 2 ml of ethanol and 2 ml of water were stirred at 100 ° C for 20 minutes. It was filtered through celite, and water and ethyl acetate were added to extract. The organic layer was washed 5 times with an aqueous solution of ammonium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (yield: 230 mg). lH-NMR (CDC13) (5 (ppm): 1.33 (3H, t, J = 7.2 Hz), 3.68 (2H, br s), 4·26 (2H, q, J = 7.2 Hz), 4.87 (2H, Bs),6·02 (1H,d, J=6.0 Hz), 6.68 (1H,d,J=16 Hz), 6.70 (2H,d,J=8.8 Hz), 6.87 (2H, d, J=8.8 Hz), 7.82 (1H, d, J=6.0 Hz), 7.85 (1H, d, J=16 Hz) 0

製造例184-2 J (£)-3-「2'胺基卜4-(4」『（4—-氣笨_胺基）蕤某1胺某}茇寄|葚1 -289 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 〜— 一 … A7 — _ __ B7 五、發明説明（^~ 3-吡啶基1-2-丙烯酸乙酯 將（幻-3-[2-胺基-4-(4-胺基苯氧基）-3_吡啶基]_2-丙烯 酸乙酯230 mg ,異氰酸對-氟苯酯〇 u mi及四氫呋喃6如在 室溫攪掉30分鐘。在反應溶液中加入NH型矽凝膠及減壓餾 去;4媒，以使反應生成物吸著於碎凝膠上。將該碎凝膠饋 入充填有NH型矽凝膠之乾燥管柱中，以進行管柱精製（乙 酸乙酯）。減壓餾去溶媒，得到白色固體2〇〇 mg。 ^-NMR (DMSO-d6) (5 (ppm)： 1.22 (3H, t3 J=7.2 Hz), 4.14 (2H，q，J=7.2 Hz)，5·83 (1H，d，J=5.6 Hz)，6.41 (2H，br s)， 6.62 (1H? d, J=16 Hz), 7.04-7.14 (4H, m), 7.40-7.53 (4H, m), 7.72 (1H, d, J=16 Hz), 7.79 (1H, d, J=5.6 Hz), 8.69 (lH, s), 8·75 (1H，s)。 ’ ， t施例185 氟苯幕）-Ν’ -「4- (1H-吡咯并f 2·3- bl毗哇-4-莘笨基 脲 ^ 將M1H-吡咯并[2,3-b]吡啶-4-基氧）苯·按90叫於室溫下 落於乙酸乙酯，然後滴入異氰酸對_氟苯酯〇〇5 ml。濾取析 出之白色結晶，得到目的物65 mg。 H-NMR (DMSO-d6) (5 (ppm): 6.21 (1H, d, J=3.6 Hz), 6 38 OH, d5 J=5.6 Hz), 7.08-7.18 (4H, m), 7.34 (1H, d, J-3.6 Hz), 7.43-7.56 (4H, m), 8.06 (1H, d5 J=5.6 Hz), 8.72 (1H, S)3 8.76 (1H，s)，11.72 (1H，s)。 如下述得到中間體。 ·· 製造例185- 1 ___- 290 - 本我張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） 1304061 A7 __ B7 五、發明説明（285) i二(4-硝某茇氩基）-3-『2-Π, 1,1-三甲矽统基）-1-乙炔基1-2-比啶胺 將4-(4-硝基苯氧基）-3-碘-2-吡啶胺1.5 g，（三甲矽烷基） 乙炔1·5 ml，肆（三苯膦）鈀（0)4 80 mg，碘化銅（1)80 mg , 二甲基甲醯胺3 ml及三乙胺3 ml於100°C攪拌35分鐘。回到 室溫後，加入水及用乙酸乙酯萃取。在萃取液中加入NH型 矽凝膠及減壓餾去溶媒，以使反應生成物吸著於矽凝膠 上。將該矽凝膠饋入充填有NH型矽凝膠之乾燥管柱中，以 進行管柱精製（己烷：乙酸乙酯=4 ·· 1)。減壓餾去有機溶 媒，在殘餘物中加入乙酸乙酯及己烷以使之固化，得到為 微褐色粉末之目的物560 mg。 lH-NMR (DMSO-d6) δ (ppm): 0.30 (9H, s), 6.60 (1H, d, J=5.6 Hz), 6.67 (2H, br s), 7.47 (2H, d, J=8.0 Hz), 8.24 (1H, d，J=5.6 Hz)，8.52 (2H，d，J=8.0 Hz)。 製造例185-2 肖基笨氣基1H-吡咯# f 2.3-bl毗^ 將4-(4-硝基苯氧基）-3-[2-( 1，1，1-三甲矽烷基）-1-乙烯 基;1-2-吡啶胺560 mg，碘化銅（1)68'0 mg及二甲基曱醯胺5 ml於環流下攪拌25分鐘。濾去不溶物後，在反應液中加入 NH型矽凝膠及減壓餾去溶媒，以使反應生成物吸著於矽凝 膠上。將該矽凝膠饋入充填有NH型矽凝膠之乾燥管柱中， 以進行管柱精製（己烷··乙酸乙酯=2 : 1 ,繼而1 : 1)。減壓 餾去有機溶媒，得到淡黃色固體84 111§。： lH-NMR (DMSO-d6) 5 (ppm): 6.14 (1H, d, J=3.6 Hz), 6.78 ____-291 - ___ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 s 一 A7 _____ B7 了^減 0月(~^ - (1H, d, J=5.2 Hz), 7.28 (2H, d, J=9.2 Hz), 7.43 (1H, d, J=3.6Production Example 184-2 J (£)-3-"2'Amine Group 4-(4"『(4-- 气笨_胺基)蕤一胺胺}茇送|葚1 -289 - This paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 ~ - a... A7 - _ __ B7 V. Description of the invention (^~ 3-pyridyl1-2-ethyl acrylate will (magic-3) -[2-Amino-4-(4-aminophenoxy)-3-pyridyl]_2-ethyl acrylate 230 mg, p-fluorophenyl isocyanate 〇u mi and tetrahydrofuran 6 as at room temperature The mixture was stirred for 30 minutes, and a NH-type ruthenium gel was added to the reaction solution and distilled off under reduced pressure to remove the reaction product onto the crushed gel. The crushed gel was fed with a NH-type condensate. The column was dried in a gel column to purify the column (ethyl acetate). The solvent was evaporated under reduced pressure to give a white solid (yield: 2 NMR) NMR (DMSO-d6) (5 (ppm): 1.22 (3H, T3 J=7.2 Hz), 4.14 (2H, q, J=7.2 Hz), 5·83 (1H, d, J=5.6 Hz), 6.41 (2H, br s), 6.62 (1H? d, J=16 Hz), 7.04-7.14 (4H, m), 7.40-7.53 (4H, m), 7.72 (1H, d, J=16 Hz), 7.79 (1H, d, J=5.6 Hz), 8.69 (lH, s ), 8·75 (1H, s). ' , t Example 185 fluorobenzene curtain)- Ν' - "4-(1H-pyrrolo-f 2·3- bl-vi- 莘 莘 基 基 ^ 将 ^ M1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzene The mixture was dropped to ethyl acetate at room temperature, and then 5 ml of p-fluorophenyl isocyanate was added dropwise. The precipitated white crystals were collected by filtration to give the title compound 65 mg. H-NMR (DMSO-d6) (5 ( Ppm): 6.21 (1H, d, J=3.6 Hz), 6 38 OH, d5 J=5.6 Hz), 7.08-7.18 (4H, m), 7.34 (1H, d, J-3.6 Hz), 7.43-7.56 (4H, m), 8.06 (1H, d5 J=5.6 Hz), 8.72 (1H, S)3 8.76 (1H, s), 11.72 (1H, s). Intermediates were obtained as follows: · Manufacturing Example 185- 1 ___- 290 - I use the Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1304061 A7 __ B7 V. Invention description (285) i II (4-nitrogen argon)-3 - "2-Π, 1,1-trimethylthyridinyl)-1-ethynyl 1-2-bi-pyridylamine 4-(4-nitrophenoxy)-3-iodo-2-pyridinamine 1.5 g , (trimethyldecyl) acetylene 1. 5 ml, hydrazine (triphenylphosphine) palladium (0) 4 80 mg, copper iodide (1) 80 mg, dimethylformamide 3 ml and triethylamine 3 ml Stir at 100 ° C for 35 minutes. After returning to room temperature, water was added and extracted with ethyl acetate. An NH type hydrazine gel was added to the extract, and the solvent was distilled off under reduced pressure to cause the reaction product to be adsorbed on the ruthenium gel. The hydrazine gel was fed into a drying column packed with an NH type hydrazine gel to carry out column purification (hexane: ethyl acetate = 4 ··1). The organic solvent was evaporated under reduced pressure, and ethyl acetate and hexane were added to the residue to solidified to afford 560 mg of the object as a brown powder. lH-NMR (DMSO-d6) δ (ppm): 0.30 (9H, s), 6.60 (1H, d, J = 5.6 Hz), 6.67 (2H, br s), 7.47 (2H, d, J=8.0 Hz ), 8.24 (1H, d, J = 5.6 Hz), 8.52 (2H, d, J = 8.0 Hz). Production Example 185-2 Schottky Stupid Substituted 1H-Pyrrol # f 2.3-bl Pivotinous 4-(4-Nitrophenoxy)-3-[2-(1,1,1-trimethyldecyl)- 1-vinyl; 1-2-pyridylamine 560 mg, copper iodide (1) 68'0 mg and dimethyl decylamine 5 ml were stirred under a loop for 25 minutes. After the insoluble matter was filtered off, an NH type hydrazine gel was added to the reaction liquid, and the solvent was distilled off under reduced pressure to cause the reaction product to be adsorbed on the ruthenium gel. The ruthenium gel was fed into a dry column packed with an NH type ruthenium gel to perform column purification (hexane·ethyl acetate = 2:1, and then 1:1). The organic solvent was evaporated under reduced pressure to give a pale yellow solid. : lH-NMR (DMSO-d6) 5 (ppm): 6.14 (1H, d, J=3.6 Hz), 6.78 ____-291 - ___ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ) 1304061 s A7 _____ B7 ^^ minus 0 month (~^ - (1H, d, J=5.2 Hz), 7.28 (2H, d, J=9.2 Hz), 7.43 (1H, d, J=3.6

Hz), 8.21 (1H, d, J=5.2 Hz), 8.27 (2H, d, J=9.2 Hz), 11.92 (1H，br s)。 邀造例185-3 心（比^并f 2,3- bl吡啶-4-某氛）茉脖 將4-(4-硝基苯氧基）-1^1-吡咯并[2,3-1}]吡啶84 11^，鐵粉 160 mg，氯化按320 ml，二甲基甲醯胺4 ml，乙醇2 ml及水 2 ml在100 C授拌15分鐘。經碎藻土過遽，加入乙酸乙酯以 萃取將有機層用氣化按水落液洗淨5次後，用硫酸錢乾 燥。濾去乾燥劑及減壓餾去溶媒，得到為褐色油狀物之目 的物23 0 mg。 ^-NMR (CDC13) 5 (ppm): 6.41 (1H, d, J=3.6 Hz), 6.42 (1H, d，J=5.6 Hz)，6·74 (2H，d，J=8.8 Hz)，7.00 (2H，d，J=8.8 Hz), 7.20 (1H，d，J=3.6 Hz)，8·11 (1H，d，&gt;5.6 Hz)，10.00 (ih，br s) 0 實施例186 ίϋ二環丙幾棊-_ni-「3-(l-乙炔某K4-氯苯胺甚、盎 基]胺基丨苯氧基）-2-吡啶基1-1-環丙烷淼醢眩 在N-(4-{[2-胺基-3-(1-乙炔基吡啶基]氧}苯基）·Ν、 (4-氟苯基）脲1〇〇 mg，三乙胺012 ml及四氫呋喃5如之溶 液中，於室溫攪掉下加入環丙烷羰基氯化物57 mg ,並攪拌 1.5小時。在反應溶液中加入NH型矽凝膠及減壓餾去溶媒， 以使反應生成物吸著於矽凝膠上。將該·矽凝膠饋入充填有 NH型矽凝膠之乾燥管柱中，以進行管柱精製（乙酸乙酯）。 -292 -Hz), 8.21 (1H, d, J=5.2 Hz), 8.27 (2H, d, J=9.2 Hz), 11.92 (1H, br s). Inviting Example 185-3 heart (than ^ and f 2,3- bl pyridin-4-one atmosphere) will lead 4-(4-nitrophenoxy)-1^1-pyrrolo[2,3- 1}]pyridine 84 11^, iron powder 160 mg, chlorination 320 ml, dimethylformamide 4 ml, ethanol 2 ml and water 2 ml were mixed at 100 C for 15 minutes. After passing through the crushed algae soil, ethyl acetate was added to extract, and the organic layer was washed with a watering solution for 5 times by gasification, and then dried with sulfuric acid. The desiccant was filtered off and the solvent was evaporated under reduced pressure to give the title compound (30 mg) ^-NMR (CDC13) 5 (ppm): 6.41 (1H, d, J = 3.6 Hz), 6.42 (1H, d, J = 5.6 Hz), 6.74 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz), 7.20 (1H, d, J = 3.6 Hz), 8·11 (1H, d, &gt; 5.6 Hz), 10.00 (ih, br s) 0 Example 186 ίϋ二Cyclopropanol-_ni-"3-(l-acetylene K4-chloroaniline, yl)aminophenoxy)-2-pyridyl1-1-cyclopropane dizzy in N-(4 -{[2-Amino-3-(1-ethynylpyridyl)oxy}phenyl)·Ν, (4-fluorophenyl)urea 1〇〇mg, triethylamine 012 ml and tetrahydrofuran 5 as solution Add 57 mg of cyclopropane carbonyl chloride under stirring at room temperature, and stir for 1.5 hours. Add NH-type hydrazine gel to the reaction solution and distill off the solvent under reduced pressure to sorb the reaction product on the ruthenium gel. The 矽 gel is fed into a drying column packed with an NH type 矽 gel to perform column purification (ethyl acetate).

1304061 A7 ___B7 五、發明説明（287) 減壓餾去有機溶媒，在殘餘物中加入甲醇及水使之固體 化，而得到為白色粉末之目的物j 5 mg。 ^-NMR (DMSO-d6) 5 (ppm): 0.97-L03 (8H, m), 1.93-2.02 (2H，m)，4·75 (1H，s)，6·74 (1H，d，Hz)，7.08-7.20 (4H， m)，7·42-7·49 (2H，m)，7·56 (2H，d，J=8.8 Hz)，8·35 (1H，d， J=5.6 Hz)，8·72 (1H，s)，8·81 (1H，s)。 如下述得到中間體。製造例186-1 乙炔基）-4“ 4·确基笨氣某）-2-说泰 將4-(4-硝基苯氧基）-3-[2-(l，i，i-三甲矽烷基）-卜乙烯 基]-2-p比咬胺560 mg，四丁基銨氟化物（溶於四氫呋喃之 1.0M溶液）1 ml及四氫呋喃2 ml於室溫攪拌1〇分鐘 。加入氯 化銨水溶液及乙酸乙酯以進行萃取，並將萃取液通過塗敷 碎凝膠之玻璃濾器。將矽凝膠用乙酸乙酯充分洗淨，減壓 餾去乙酸乙黯，得到為褐色粉末之目的物4〇〇 mg。^-NMR (DMSO-d6) δ (ppm): 4.52 (1H/%s)5 6.23 (1H, d5 J=5.6 Hz), 6.46 (2H, br s), 7.24 (2H, d, J=7.2 Hz), 7.94 (1H, d，J=5.6 Hz)，8·27 (2H，d，J=7.2 Hz)。製造例186-2 4-_( 4-.胺基苯氧基）-3-Π -乙炔某2-毗凃fe 將3-(1-乙炔基）-4-(4-硝基苯氧基）-2-吡啶胺400 mg，鐵 粉800 mg，氯化銨1.6 g，二曱基曱醯胺3 ml，乙醇1 mi及 水1 ml在100°C攪拌30分鐘。經矽藻土遍濾，加入水及乙酸 乙酯以萃取。將有機層用氣化按水溶液洗淨5次後，用硫酸 -293 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 … A7 Β7 五、發明説明（288) 鎂乾燥。濾去乾燥劑及減壓餾去溶媒，得到為褐色固體之 目的物260.mg。 H-NMR (CDC13) (5 (ppm): 3.63 (1H, s), 3.64 (2H, br s), 5.12 (2H, br s), 5.95 (1H, d, J=5.6 Hz), 6.69 (2H, dd, J=6.4 Hz, 2.0 Hz), 6.91 (2H, dd, J=6.4 Hz, 2.0 Hz), 7.81 (1H, d, J=5.6 Hz)。 製造例186-3 ^^4-{『2-胺某-3-〔1-广炔基）-4-吡啶基1氲}苽基）-：^-(4-氟笨某）Μ 將4-(4-胺基苯氧基）-3-(1-乙炔基）-2-吡啶胺260 mg，異 氰酸對-氟苯酯0.13 ml及四氫呋喃5 ml在室溫下攪摔20小 時。在反應溶液中加入水及蒸餾除去四氫呋喃，繼而加入 少量乙酸乙酯及濾取析出之固體。得到淡褐色固體200 mg。 lH-NMR (£5ΊνΙ50-(16) (5 (ppm): 4.53 (1H, s), 5.80 (1H, d5 J=5.6 Hz), 6.22 (2H, br s), 7.00-7.15 (4H, m), 7.40-7.53 (4H, m)，7·76 (1H, d，J=5.6 Hz)，8·69 (1H，s)，8.73 (1H，s)。 實施例1871304061 A7 ___B7 V. Inventive Note (287) An organic solvent was distilled off under reduced pressure, and methanol and water were added to the residue to solidify to give a white powder of object 5 g. ^-NMR (DMSO-d6) 5 (ppm): 0.97-L03 (8H, m), 1.93-2.02 (2H, m), 4·75 (1H, s), 6.74 (1H, d, Hz) ,7.08-7.20 (4H, m), 7·42-7·49 (2H,m),7·56 (2H,d,J=8.8 Hz),8·35 (1H,d, J=5.6 Hz) , 8.72 (1H, s), 8.81 (1H, s). The intermediate was obtained as follows. Production Example 186-1 Acetylene)-4"4·Accord to a stupidity)-2-Taitai 4-(4-nitrophenoxy)-3-[2-(l,i,i-trimethyl)矽alkyl)-buvinyl]-2-p octoberidine 560 mg, tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran) 1 ml and tetrahydrofuran 2 ml stirred at room temperature for 1 hr. The ammonium aqueous solution and ethyl acetate were extracted, and the extract was passed through a glass filter coated with a gelatin gel. The ruthenium gel was thoroughly washed with ethyl acetate, and ethyl acetate was distilled off under reduced pressure to obtain a brown powder. 4 NMR (DMSO-d6) δ (ppm): 4.52 (1H/% s) 5 6.23 (1H, d5 J=5.6 Hz), 6.46 (2H, br s), 7.24 (2H, d, J = 7.2 Hz), 7.94 (1H, d, J = 5.6 Hz), 8.27 (2H, d, J = 7.2 Hz). Production Example 186-2 4-_(4-. Aminophenoxy ))-3-Π-acetylene a 2-adsorbent. 3-(1-ethynyl)-4-(4-nitrophenoxy)-2-pyridinamine 400 mg, iron powder 800 mg, chlorinated 1.6 g of ammonium, 3 ml of dimethyl decylamine, 1 ml of ethanol and 1 ml of water were stirred at 100 ° C for 30 minutes. After filtration through diatomaceous earth, water and ethyl acetate were added for extraction. The organic layer was gasified. Wash 5 times with aqueous solution After, use sulfuric acid -293 - this paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ... A7 Β7 5, invention description (288) Magnesium drying. Filter desiccant and vacuum distillation solvent 260. mg of the object was obtained as a brown solid. H-NMR (CDC13) (5 (ppm): 3.63 (1H, s), 3.64 (2H, br s), 5.12 (2H, br s), 5.95 (1H , d, J=5.6 Hz), 6.69 (2H, dd, J=6.4 Hz, 2.0 Hz), 6.91 (2H, dd, J=6.4 Hz, 2.0 Hz), 7.81 (1H, d, J=5.6 Hz) Production Example 186-3 ^^4-{"2-Amine-3-[1-Alkynyl)-4-pyridyl 1氲}indenyl)-:^-(4-Fluoro) 4-(4-Aminophenoxy)-3-(1-ethynyl)-2-pyridinamine 260 mg, p-fluorophenyl isocyanate 0.13 ml and tetrahydrofuran 5 ml stirred at room temperature for 20 hours Water was added to the reaction solution, and tetrahydrofuran was distilled off, and then a small amount of ethyl acetate was added, and the precipitated solid was collected by filtration to give a pale brown solid. lH-NMR (£5ΊνΙ50-(16) (5 (ppm): 4.53 (1H, s), 5.80 (1H, d5 J=5.6 Hz), 6.22 (2H, br s), 7.00-7.15 (4H, m) , 7.40-7.53 (4H, m), 7.76 (1H, d, J = 5.6 Hz), 8.69 (1H, s), 8.73 (1H, s). Example 187

Nl-彡哀丙基-5-「（2-(|~4-(4-經基六氢7比遠某）丁酿某1胺基}二 L吡啶基）氣1-1H-1-4哚淼S忘fe 在5-[(2-{[4-(4-羥基六氫吡啶）丁醯基]胺基卜4-吡啶基） 氧]啕哚260 mg，氫化鈉（60%，分散於油中）53 mg及二甲 基甲酿胺5 ml之溶液中，於室溫及攪拌下，加入N-環丙基 胺基甲酸苯酯120 mg。攪拌10分鐘後，加入水及用乙酸乙 • 294 - _ 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（289) 醋萃取。在乙酸乙酯層中加入NH型矽凝膠及減壓館去溶 媒，以使反應生成物吸著於矽凝膠上。將該碎凝膠饋入充 填有NH型矽凝膠之乾燥管柱中，以及藉管柱層析精製（氯 仿：甲醇=30 : 1)。減壓餾去溶媒，將殘餘物溶於乙酸乙酯 中’以及用1N氫氧化鈉水溶液洗淨2次。用硫酸鈉乾燥後， 減壓餾去溶媒，得到為白色粉末之目的物2〇 mg。 iH-NMR (DMS〇-d6)5(ppm): 0·57-0·64 (2H，m)，0·68·0·75 (2H，m)，1.24-1.34 (2H，m)，1·55-1·67 (4H，m)，1.83-1.94 (2H，m)，2.17(2H，t，J=7.2Hz)，2.28(2H，t，J=7,2Hz)，2.55-2·66 (2H，m)，2.73-2.80 (1H，m)，3.30-3.40 (1H，m)，4.47 (1H，d，J=3.6 Hz)，6.62 (1H，dd，J=5.6 Hz，2·4 Hz)，6.64 (1H， d, 1=3.6 Hz), 7.04 (1H, dd5 J=8.8 Hz, 2.4 Hz), 7.36 (1H, d, J=2.4 Hz)，7.61 (1H，d，J=2.4 Hz)，7·87 (1H，d，J=3.6 Hz)， 8.12 (1H，d，J=5.6 Hz)，8.25-8.30 (2H，m)，10.40 (1H，s)。 實施例188、Nl-彡 丙基 propyl-5-"(2-(|~4-(4-carbyl hexahydro 7 is more than far) butyl 1 amino group} bis L pyridyl) gas 1-1H-1-4哚淼S forget fe in 5-[(2-{[4-(4-hydroxyhexahydropyridine)butanyl]aminopyr 4-pyridyl)oxy] 啕哚260 mg, sodium hydride (60%, dispersed in oil To a solution of 53 mg and dimethylamine in 5 ml, add 120 mg of phenyl N-cyclopropylcarbamate at room temperature with stirring. After stirring for 10 minutes, add water and use acetic acid. 294 - _ This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Invention description (289) Vinegar extraction. Add NH type gel and decompression hall to ethyl acetate layer. The solvent is removed to cause the reaction product to be adsorbed on the ruthenium gel. The pulverized gel is fed into a dry column packed with a NH-type ruthenium gel and purified by column chromatography (chloroform: methanol = 30: 1) The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, and washed twice with 1N aqueous sodium hydroxide. After drying over sodium sulfate, the solvent was evaporated under reduced pressure to give a white powder. 2〇mg. iH-NMR (DMS〇-d6) 5 (ppm): 0·57-0 64 (2H,m),0·68·0·75 (2H,m),1.24-1.34 (2H,m),1·55-1·67 (4H,m),1.83-1.94 (2H,m) , 2.17 (2H, t, J = 7.2 Hz), 2.28 (2H, t, J = 7, 2 Hz), 2.55-2·66 (2H, m), 2.73-2.80 (1H, m), 3.30-3.40 ( 1H, m), 4.47 (1H, d, J = 3.6 Hz), 6.62 (1H, dd, J = 5.6 Hz, 2·4 Hz), 6.64 (1H, d, 1 = 3.6 Hz), 7.04 (1H, Dd5 J=8.8 Hz, 2.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.61 (1H, d, J=2.4 Hz), 7·87 (1H, d, J=3.6 Hz), 8.12 ( 1H, d, J = 5.6 Hz), 8.25-8.30 (2H, m), 10.40 (1H, s). Example 188,

Nl-(2-氟乙基-與某六鱼^走咬基）丁酿基1胺 基]»-4 -口比違基）乳1-111-1-口弓|口果籍驢胺 使用N-(2-氟乙基）胺基甲酸苯酯，以與實施例188同樣之 方式得到目的物。 lH-NMR (DMSO-d6) 5 (ppm): 1.24-L35 (2H, m), 1.57-1.67 (4H, m), 1.88 (2H, t, J=10.4 Hz), 2.17 (2H, t, J=7.2 Hz), 2.28 (2H, t, J=7.2 Hz), 2.56-2.55 (2H, m), 3.30-3.40 (1H, m), 3.55 (1H, q, J=4.8 Hz), 3.61 (1H, q, J=4：8 Hz), 4.48 (1H, d, J=4.0 Hz), 4.52 (1H, J=4.8 Hz), 4.64 (1H3 t, J=4.8 Hz), -295 - _ 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）Nl-(2-fluoroethyl- and a certain six fish ^ bite base) butyl 1 amino group»»-4 - mouth ratio base) milk 1-111-1-mouth bow | mouth fruit amide use The objective compound was obtained in the same manner as in Example 188 from phenyl N-(2-fluoroethyl)amine. lH-NMR (DMSO-d6) 5 (ppm): 1.24-L35 (2H, m), 1.57-1.67 (4H, m), 1.88 (2H, t, J = 10.4 Hz), 2.17 (2H, t, J =7.2 Hz), 2.28 (2H, t, J=7.2 Hz), 2.56-2.55 (2H, m), 3.30-3.40 (1H, m), 3.55 (1H, q, J=4.8 Hz), 3.61 (1H , q, J=4:8 Hz), 4.48 (1H, d, J=4.0 Hz), 4.52 (1H, J=4.8 Hz), 4.64 (1H3 t, J=4.8 Hz), -295 - _ paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

訂Order

線 1304061 A7 B7 五、發明説明（29〇) 6.62 (1H3 dd, J=5.6 Hz, 2A Hz), 6.70 (1H, d, J=3.6 Hz), 7.05 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.38 (1H, d, J=2.4 Hz), 7.62 (1H, d, J=2.4 Hz), 7.95 (1H, d5 J=3.6 Hz), 8.12 (1H, d, J=5.6 Hz), 8·28 (1H，d，J=8.8 Hz), 8.44-8.49 (1H，m), 10.41 (1H，s)。 實施例189Line 1304061 A7 B7 V. Description of the invention (29〇) 6.62 (1H3 dd, J=5.6 Hz, 2A Hz), 6.70 (1H, d, J=3.6 Hz), 7.05 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.38 (1H, d, J=2.4 Hz), 7.62 (1H, d, J=2.4 Hz), 7.95 (1H, d5 J=3.6 Hz), 8.12 (1H, d, J=5.6 Hz), 8·28 (1H,d,J=8.8 Hz), 8.44-8.49 (1H,m), 10.41 (1H,s). Example 189

Hr苯基-5-K2-( [4-(4-羥基六氤吡啶某）丁醯基1胺基卜4-淀基）氣l-ίΗ- 1-叫1哚羧醯胺 使用異氰酸苯酯，以與實施例1 87同樣之方式得到目的 物。 lH-NMR (DMSO-d6) 5 (ppm): 1.24-1.35 (2H, m)5 1.57-1.67 (4H，m)，1.84-1.96 (2H，m)，2.18 (2H，t，J=6.8 Hz)，2·29 (2H， t, J=6.8 Hz), 2.56-2.66 (2H, m), 3.30-3.40 (1H, m), 4.48 (1H, d, J=4.4 Hz), 6.65 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.77 (1H, d5 J=3.6 Hz)，7.09 (1H，dd，J=8.8 Hz，2.4 Hz)，7.10-7.16 (1H， m)，7·35-7·41 (2H，m)，7.43 (1H，d，J=2.4 Hz)，7.62-7·67 (3H， m)，8.10-8.15 (2H，m)，8.27 (1H，d，J=8.8 ήζ)，10·10 (1H，s)， 10.42 (1H，s)。 實施例190 反1-環丙基-5-「（2“『2-(4-羥某六氤吡啶基）乙醯基1脖^^ 比淀基）氣1 - 1 Η- 1- &lt;嗓致酿胺 使用5-[(2-{[2-(4-羥基六氫吡啶基）乙醯基]胺基卜‘叶匕 啶基）氧]啕哚，以與實施例188同樣之方式得到目的物。 lH-NMR (DMSO-d6) 5 (ppm): 0.58-0.63 ^ (2H, m), 0.69-0.75 (2H, m)，1.35-1.45 (2H，m)，1.66-1.74 (2H，m)，2.17-2.25 -296 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公爱) 1304061 A7 B7 五、發明説明（ 291 )Hr phenyl-5-K2-([4-(4-hydroxyhexapyridine)) butyl sulfonyl 1 amide -4-diyl) gas l-ίΗ- 1-called 1 carboxy carbamide using phenyl isocyanate The object was obtained in the same manner as in Example 1 87. lH-NMR (DMSO-d6) 5 (ppm): 1.24-1.35 (2H, m)5 1.57-1.67 (4H, m), 1.84-1.96 (2H, m), 2.18 (2H, t, J = 6.8 Hz ), 2·29 (2H, t, J=6.8 Hz), 2.56-2.66 (2H, m), 3.30-3.40 (1H, m), 4.48 (1H, d, J=4.4 Hz), 6.65 (1H, Dd, J=5.6 Hz, 2.4 Hz), 6.77 (1H, d5 J=3.6 Hz), 7.09 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.10-7.16 (1H, m), 7·35- 7·41 (2H,m), 7.43 (1H,d,J=2.4 Hz), 7.62-7·67 (3H, m), 8.10-8.15 (2H,m), 8.27 (1H,d,J=8.8 Ήζ), 10·10 (1H, s), 10.42 (1H, s). Example 190 trans 1-cyclopropyl-5-"(2"『2-(4-hydroxy-hexa-pyridyl)ethenyl) 1^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 5-[(2-{[2-(4-hydroxyhexahydropyridinyl)ethenyl]amino)-[' acridinyl)oxy]oxime was used in the same manner as in Example 188. Get the target. lH-NMR (DMSO-d6) 5 (ppm): 0.58-0.63 ^ (2H, m), 0.69-0.75 (2H, m), 1.35-1.45 (2H, m), 1.66-1.74 (2H, m), 2.17-2.25 -296 - This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 public) 1304061 A7 B7 V. Description of invention ( 291 )

(2H，m)5 2·64-2·72 (2H，m)，2·72-2·80 (1H，m)，3.04 (2H，s)， 3·38-3·49 (1H，m)，4·57 (1H，d，J=4.4 Hz)，6·65 (1H，d，j=3 6 Hz)，6·68 (1H，dd，J=5.6 Hz，2.4 Hz)，7·05 (1H，dd，J=8 8 Hz 2·4 Hz)，7·38 (1H，d，J=2.8 Hz)，7.59 (1H，d，J=2.8 Hz)，7·87 (1H，d，J=3.6 Hz), 8·15 (1H，d，J=5.6 Hz)，8·27-8·82 (2H，m)， 9.85 (1H，s)。 如下述得到中間體e 黎造例190-1 5 -「（ 2- {f 2- (4-與基六氡外k症基）乙縫基1胺某卜4- p比免玉丄氣丄 口弓丨g朵 . 在N1-環丙基-5-[(2-胺基-4-吡啶基）氧]-1H-1-啕哚羧醯 胺2.0 g，三乙胺2.3 ml及四氫呋喃20 之溶液中，於室溫 及授拌下加入漠乙酿氯2.14 ge授拌30分鐘後加入水，用乙 酸乙酯萃取。令萃取液通過塗敷矽凝膠之玻璃濾器。將矽 凝膠用乙酸^乙酯充分洗淨，將乙酸乙酯層合併及減壓餾 去，得到綠褐色油狀物900 mg。將得到乏油狀物900 mg與 4-#至基六氫^7比淀640 mg’竣酸钟1·2 g及二甲基曱酿胺20 ml 於70 °C攪拌35分鐘。加入水及用乙酸乙酯萃取。將萃取液 用水洗淨3次，用食鹽水洗淨1次，然後通過塗敷矽凝膠之 玻璃濾器。將矽凝膠用乙酸乙酯充分溶離，減壓餾去溶 媒，得到為淡黃色粉末之目的物530 mg。 lH-NMR (DMSO-d6) 5 (ppm): 1.35-1.47 (2H, m), 1.68-1.75 (2H, m), 2.21 (2H, t, J=10.00 Hz), 2.64-2.74 (2H, m), 3.03 (2H, s), 3.40-3.50 (1H, m), 4.57 (1H, d, J=4.0 Hz), 6.42 (1H, -297 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公爱)(2H,m)5 2·64-2·72 (2H,m),2·72-2·80 (1H,m),3.04 (2H,s), 3·38-3·49 (1H,m ), 4·57 (1H, d, J = 4.4 Hz), 6·65 (1H, d, j = 3 6 Hz), 6.68 (1H, dd, J = 5.6 Hz, 2.4 Hz), 7· 05 (1H, dd, J=8 8 Hz 2·4 Hz), 7·38 (1H, d, J=2.8 Hz), 7.59 (1H, d, J=2.8 Hz), 7·87 (1H, d , J = 3.6 Hz), 8·15 (1H, d, J = 5.6 Hz), 8·27-8·82 (2H, m), 9.85 (1H, s). The intermediate e is obtained as follows. Example 190-1 5 - "( 2- {f 2- (4-) with hexamethylene sulphate) A sulphide 1 amine 卜 4 - p than 丄 丄 丄 丄Oral 丨g朵. In N1-cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide 2.0 g, triethylamine 2.3 ml and tetrahydrofuran 20 In the solution, add 2.64 g of chloroethylene chloride to the mixture at room temperature and under stirring for 30 minutes, then add water and extract with ethyl acetate. The extract is passed through a glass filter coated with ruthenium gel. The ethyl acetate was thoroughly washed, and the ethyl acetate layer was combined and evaporated to give a white brown oil (yield: 900 mg). Mg' citrate clock 1·2 g and dimethyl hydrazine 20 ml were stirred at 70 ° C for 35 minutes. Water was added and extracted with ethyl acetate. The extract was washed 3 times with water and washed with saline 1 Then, it was passed through a glass filter of a ruthenium gel, and the ruthenium gel was sufficiently dissolved in ethyl acetate, and the solvent was evaporated under reduced pressure to give 530 mg of the object as pale yellow powder. lH-NMR (DMSO-d6) 5 (ppm): 1.35-1.47 (2H, m), 1.68-1.75 (2H, m), 2.21 (2H, t, J=10.00 Hz), 2.64-2.74 (2H, m), 3.03 (2H, s), 3.40-3.50 (1H, m), 4.57 (1H, d, J=4.0 Hz), 6.42 (1H, -297 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 public)

裝 訂Binding

線 !3〇4〇61 -s A7 ---_— _B7 _^_ 五、發明説明（292) s), 6.63 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.86 (1H, dd3 J=8.8 Hz, 2.4 Hz), 7.30 (in, s)5 7.42 (1H, d, J=2.4 Hz), 7.45 (1H, d, J=8.8 Hz), 7.59 (1H, d, J=2.4 Hz)3 8.12 (1H, d3 J=5.6 Hz), 9.81(lH，S)，U.25nH，s)。 f施例19 1 ^1二(2-氟&amp;基丄：1__「（2“「2^4-淼签六氤吡啶基）乙醯基1胺 基丄:·4^比淀基lH-lH-i-W唤淼醢胺 使用5-[(2-{[2-(4-羥基六氫吡啶基）乙醯基]胺基卜4-吡 咳:基）氧]巧嗓及N-(2-氟乙基）胺基甲酸酯，以與實施例187 同樣之方式得到目的物。 lH-NMR (DMS〇.d6) (5 (ppm)*, 1.35-1.45 (2H, m), 1.66-1.74 (2H，m)，2·21 (2H，t，J=l〇.〇 Hz)，2·65-2·72 (2H，m)，3·04 (2H，s)，3.38-3.50 (1H，m)，3·55 (1H，q，J=4.8 Hz)，3·62 (1H， q, J=4.8 Hz), 4.52 (1H, t, J=4.8 Hz), 4.56 (1H, d, J=4.4 Hz), 4.64 (1H, Hz), 6.67 (1H5 dd, J=5.6 Hz, 2.4 Hz), 6.70 (1H，d，J=3.6 Hz)，7·$6 (1H，dd，J=8.8 Ηζ，·2.4 Hz)，7·40 (1H， d, J=2.4 Hz), 7.60 (1H3 d, J=2.4 Hz), 7.95 (1H5 d, J=3.6 Hz), 8.1) (1H，d，J=5.6 Hz)，8.30 (1H，d，J=8.8 Hz)，8·47 (1H，t， J=4.8 Hz)，9·85 (1H，s)。 實施例192 H壤丙基.jilr「（ 2- { (4-羥基六i吡啶某）雨醢签1 甚^ irK基）氣卜1 Η- 1 - W g朵藉gj胺 使用5- [(2- {[3-(4-羥基六氫吡啶基）丙醯基]胺基卜4_吡 咬基）氧]4噪，以與實施例187同樣之方式得到目的物。 -298 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（293) lH-NMR (DMS〇.d6) 5 (ppm): 0.58-0.64 (2H, m), 0.70-0.76 (2H，m)，1..29-1.91 (2H，m), 1.62-1.72 (2H，m)，1.95-2.06 (2H, m), 2.38-2.58 (4H, m), 2.63-2.73 (2H, m), 2.70-2.80 (1H，m)，3.35-3.46 (1H，m)，4.51 (1H，s)，6.61-6.66 (2H，m)， 7.04 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.59 (1H，d，J=2.4 Hz)，7·87 (1H，d，J=3.6 Hz)，8.13 (1H，d，J=5.6 Hz)，8·25-8·30 (2H，m)，10.77 (1H，s)。 如下述得到中間體。 製造例192-1 5-「（ 2- ( f 3- (4-羥某六氤吡啶某）丙8蒸美1脖臬卜4-也屋A1U 在N1-環丙基-5-[(2-胺基-4-吡啶基）氧]哚羧醯 胺2.0 g，三乙胺2.3 ml及四氫呋喃80 ml之溶液中，於冰冷 攪拌下加入3-溴環丙醯基氯1.4 ml。攪摔10分鐘後於室溫攪 拌10分鐘，加入水並用乙酸乙酯萃取。使萃取液通過塗敷 矽凝膠之玻璃濾器。將矽凝膠用乙酸乙磕充分洗拳，將乙 乙S旨層合併及減壓条鶴’得到微黃色油狀物1.7 g。將得 到之油狀物900 mg與4·經基六氫吡畊470 mg，碳酸鉀880 mg及二甲基甲醯胺10 ml—起於70°C攪拌30分鐘。加入水及 用乙酸乙醋萃取。在乙酸乙酯層中加入NH型碎凝膠及減壓 館去;谷媒’以使反應生成物吸奢於碎凝膠上將該碎凝膠 饋入充填有NH型碎凝膠之乾燥管柱中，以及藉管柱層析精 製（氯仿··甲醇= 100 ·· 3)。減壓餾去溶媒，得到為白色粉末 之目的物170 mg。 -299 - 本畝張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)Line! 3〇4〇61 -s A7 ---_- _B7 _^_ V. Description of invention (292) s), 6.63 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.86 (1H, dd3 J =8.8 Hz, 2.4 Hz), 7.30 (in, s)5 7.42 (1H, d, J=2.4 Hz), 7.45 (1H, d, J=8.8 Hz), 7.59 (1H, d, J=2.4 Hz) 3 8.12 (1H, d3 J=5.6 Hz), 9.81 (lH, S), U.25nH, s). f Example 19 1 ^1 2 (2-Fluoro &amp; base: 1__ "(2" "2^4-淼 signed hexamethylenepyridinyl) ethinyl 1 amine hydrazine: · 4 ^ than the base lH- lH-iW calls for the use of 5-[(2-{[2-(4-hydroxyhexahydropyridinyl)ethenyl]amino) 4-pyrifid: yl)oxy] 嗓 and N-(2 -Fluoroethyl)carbamate, the object was obtained in the same manner as in Example 187. lH-NMR (DMS 〇.d6) (5 (ppm)*, 1.35-1.45 (2H, m), 1.66- 1.74 (2H,m),2·21 (2H,t,J=l〇.〇Hz), 2·65-2·72 (2H,m),3·04 (2H,s), 3.38-3.50 ( 1H,m),3·55 (1H,q,J=4.8 Hz),3·62 (1H, q, J=4.8 Hz), 4.52 (1H, t, J=4.8 Hz), 4.56 (1H, d , J=4.4 Hz), 4.64 (1H, Hz), 6.67 (1H5 dd, J=5.6 Hz, 2.4 Hz), 6.70 (1H,d,J=3.6 Hz),7·$6 (1H,dd,J= 8.8 Ηζ, · 2.4 Hz), 7·40 (1H, d, J=2.4 Hz), 7.60 (1H3 d, J=2.4 Hz), 7.95 (1H5 d, J=3.6 Hz), 8.1) (1H,d , J = 5.6 Hz), 8.30 (1H, d, J = 8.8 Hz), 8.47 (1H, t, J = 4.8 Hz), 9·85 (1H, s). Example 192 H. Jilr "( 2- { (4-hydroxy hexapyridine) rain 醢 sign 1 very ^ irK base) gas 1 1 Η - 1 - W g l by gj amine The object was obtained in the same manner as in Example 187, using 5-[(2-{[3-(4-hydroxyhexahydropyridyl)propanyl]amino-4-ylpyridinyloxy). -298 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (293) lH-NMR (DMS〇.d6) 5 (ppm): 0.58-0.64 ( 2H, m), 0.70-0.76 (2H, m), 1..29-1.91 (2H, m), 1.62-1.72 (2H, m), 1.95-2.06 (2H, m), 2.38-2.58 (4H, m), 2.63-2.73 (2H, m), 2.70-2.80 (1H, m), 3.35-3.46 (1H, m), 4.51 (1H, s), 6.61-6.66 (2H, m), 7.04 (1H, Dd, J=8.8 Hz, 2.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.59 (1H, d, J=2.4 Hz), 7·87 (1H, d, J=3.6 Hz), 8.13 (1H, d, J = 5.6 Hz), 8·25-8·30 (2H, m), 10.77 (1H, s). The intermediate was obtained as follows. Production Example 192-1 5-"(2-(f 3-(4-hydroxy-hexa-pyridinyl))-Chen 8 steamed beauty 1 neck 臬Bu 4-Yingya A1U in N1-cyclopropyl-5-[(2 -Amino-4-pyridyl)oxy]oximecarboxamide 2.0 g, triethylamine 2.3 ml and tetrahydrofuran 80 ml solution, add 3-bromocyclopropanyl chloride 1.4 ml under ice-cooling stirring. After a minute, stir at room temperature for 10 minutes, add water and extract with ethyl acetate. The extract was passed through a glass filter coated with a gel. The enamel gel was thoroughly washed with acetic acid, and the layers were combined. The decompressed crane has a yellowish oil of 1.7 g. The oil is obtained from 900 mg and 4· hexahydropyrazine 470 mg, potassium carbonate 880 mg and dimethylformamide 10 ml. Stir at 70 ° C for 30 minutes, add water and extract with ethyl acetate. Add NH-type broken gel and decompression chamber to the ethyl acetate layer; the solvent will make the reaction product absorb the broken gel. The crushed gel was fed into a drying column packed with NH-type broken gel, and purified by column chromatography (chloroform··methanol = 100 ··3). The solvent was distilled off under reduced pressure to obtain a white powder. 170 mg. -299 - this mu Scale applicable Chinese National Standard (CNS) A4 size (210 X 297 mm)

裝 訂Binding

線 1304061 A7 B7 五、發明説明（294) lH-NMR (DMSO-d6) 5 (ppm): 1.29-1.42 (2H3 m)? 1.62-1.72 (2H, m), 2.00 (2H, t, J=7.2 Hz), 2.37-2.55 (4H, m), 2.62-2.72 (2H, m)，3.35-3.46 (1H，m)，4.52 (1H，d，J=4.0 Hz), 6.42 (1H， s), 6.59 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.85 (1H, dd5 J=8.8 Hz, 2·4 Hz)，7·29 (1H，s)，7.41 (1H，d，J=2.4 Hz)，7·44 (1H，d， J=8.8 Hz)，7·59 (1H，d，J=2.4 Hz)，8,l〇 (ih，d，1=5.6’Hz)， 10.74 (1H，s)，11.22 (1H，s) 〇 實施例193 N W 2·氣乙基5- ({ 2- f (4-六氫p比啶葚羰某）眩某1 - 4- P比症 某m-lH-l-W哚羧醯胺 將Nl-(2-#L乙基）-5-[(2-{[(l -第三丁氧羧基六氫p比咬 基）羧基]胺基} - 4-p比啶基）氧]-1H-1-啕嗓致醯胺160 mg溶 解於三氟乙酸10 ml以及於室溫攪掉1〇分鐘。加入乙酸乙醋 及竣酸氫鈉水溶液，調成驗性及分液。將乙酸乙§旨層用食 鹽水洗淨1次及用硫酸鎂乾燥。減壓餾去溶媒，得到無色粉 末 86 mg 〇 ^-NMR (DMSO-d6) 5 (ppm): 1.60-1.73 (2H3 m), 1.83-1.91 (2H，m)，2.65-2.73 (1H，m)，2.77-2.87 (2H，m)，3.22·3 39 (2H, m)3 3.55 ( 1H, q, J=5.2 Hz), 3.62 (1H, q, j=5&gt;2 Hz), 4.52 (1H, t, J=5.2 Hz), 4.64 (1H, t, J=5.2 Hz), 6.67 (1H, dd, J=5 6 Hz, 2.4 Hz), 6.70 (1H, d, J=3.6 Hz), 7.05 (1H, dd, J=8.8 Hz 2·4 Hz), 7.38 (1H，d，J=2.4 Hz), 7·59 (1H，d，J=2.4 Hz)，7.96 (1H, d, J=3.6 Hz), 8.16 (1H, d, J=5.6 Hzj, 8.29 (1H, d, J = 8 8 Hz)，8·49 (1H，t，J=5.2 Hz)，10.59 (1H，s)。 -300 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 — A7 _______ B7____ 五、發明说明（295) 如下述得到中間體。 掣浩例1 9 3 - 1 Ν1-_ϋΐ·氟基）-5-『（2- {「Π -第s 丁氧羰基·4-六氤吡哇甚、 蕤某1胺基卜4- ρ比淀基）氣1- n 1 - Μ丨哈教酿胺 將&gt;Π-(2-氟乙基）-5-[(2-胺基-4-吡啶基）氧]-111-1-吲哚 羧醯胺500 mg，1-第三丁氧羰基六氫吡啶_4•羧酸44〇 mg , 苯并二吐-1-基氧參（二甲胺基）鱗六氟罐酸鹽（B〇p試劑）84〇 mg，三乙胺〇·44 ml及二曱基甲醯胺1〇 mi於室溫攪掉17小 時。加入水及用乙酸乙酯萃取，在萃取液中加aNH型矽凝 膠及減塵館去洛媒’以使反應生成物吸著於碎凝膠上。將 該碎凝膠债入充填有NH型碎凝膠之乾燥管柱中，以及進行 管柱精製酸乙.1: υ。減鞋去溶媒，得到為 白色粉末之目的物160 mg。 ^-NMR (DMSO-d6)c5(ppm): 1.28-1.40 (2Η? m)&gt; ^36(9^ 5) 1.64-1.72 (2Ή, m), 2.54-2.80 (3H, m), 3.55 (1H, q, J=5.2 Hz) 3·61 (1H，q，J=5.2 Hz)，3·86-3·96 (2H，m)，、4 52 (1H，t，J=5 2Line 1304061 A7 B7 V. Description of the invention (294) lH-NMR (DMSO-d6) 5 (ppm): 1.29-1.42 (2H3 m)? 1.62-1.72 (2H, m), 2.00 (2H, t, J=7.2 Hz), 2.37-2.55 (4H, m), 2.62-2.72 (2H, m), 3.35-3.46 (1H, m), 4.52 (1H, d, J=4.0 Hz), 6.42 (1H, s), 6.59 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.85 (1H, dd5 J=8.8 Hz, 2·4 Hz), 7·29 (1H, s), 7.41 (1H, d, J=2.4 Hz) ,7·44 (1H,d, J=8.8 Hz),7·59 (1H,d,J=2.4 Hz),8,l〇(ih,d,1=5.6'Hz), 10.74 (1H,s ), 11.22 (1H, s) 〇 Example 193 NW 2 · gas ethyl 5- ({ 2- f (4-hexahydrop than pyridine carbonyl) glare 1 - 4- P ratio m-lH -lW哚carboxyxantamine will be Nl-(2-#Lethyl)-5-[(2-{[(l -t-butoxycarboxy hexahydrop) carboxy]amino} - 4-p比 基 ) 氧 氧 氧 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 160 And the mixture was washed once with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a colorless powder, 86 mg, NMR (DMSO-d6) 5 (ppm): 1.60- 1.7 3 (2H3 m), 1.83-1.91 (2H, m), 2.65-2.73 (1H, m), 2.77-2.87 (2H, m), 3.22·3 39 (2H, m)3 3.55 ( 1H, q, J =5.2 Hz), 3.62 (1H, q, j=5>2 Hz), 4.52 (1H, t, J=5.2 Hz), 4.64 (1H, t, J=5.2 Hz), 6.67 (1H, dd, J =5 6 Hz, 2.4 Hz), 6.70 (1H, d, J=3.6 Hz), 7.05 (1H, dd, J=8.8 Hz 2·4 Hz), 7.38 (1H,d,J=2.4 Hz), 7 · 59 (1H, d, J = 2.4 Hz), 7.96 (1H, d, J = 3.6 Hz), 8.16 (1H, d, J = 5.6 Hzj, 8.29 (1H, d, J = 8 8 Hz), 8 · 49 (1H, t, J = 5.2 Hz), 10.59 (1H, s). -300 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 — A7 _______ B7____ V. INSTRUCTIONS (295) Intermediates are obtained as follows.掣浩例1 9 3 - 1 Ν1-_ϋΐ·Fluoro)-5-『(2- {"Π- s butyloxycarbonyl·4-hexapyrene, 蕤一一胺基卜4- ρ ratio淀)) gas 1-n 1 - Μ丨ha taught amine > Π-(2-fluoroethyl)-5-[(2-amino-4-pyridyl)oxy]-111-1-吲Carbarylamine 500 mg, 1-tert-butoxycarbonylhexahydropyridine_4•carboxylic acid 44〇mg, benzodioxin-1-yloxyglycol (dimethylamino)scale hexafluorotanate (B 〇p reagent) 84〇mg, triethylamine 〇·44 ml and dimethylformamide 1〇mi were stirred at room temperature for 17 hours, water was added and extracted with ethyl acetate, and aNH type 矽 was added to the extract. The gel and the dust-removing hall go to the media to make the reaction product sorb on the broken gel. The gel is deposited into a dry column packed with NH-type broken gel, and the column is refined. .1: υ. Reduce the shoe to the solvent to obtain 160 mg of the object as a white powder. ^-NMR (DMSO-d6) c5 (ppm): 1.28-1.40 (2Η? m)&gt; ^36(9^ 5) 1.64-1.72 (2Ή, m), 2.54-2.80 (3H, m), 3.55 (1H, q, J=5.2 Hz) 3·61 (1H, q, J=5.2 Hz), 3·86-3·96 (2H,m),,4 52 (1H,t,J=5 2

Hz)，4·64 (1H，t，J=5.2 Hz)，6·66 (1H，dd，Hz，2.4 Hz) 6.70 (m，d，J=3.6 Hz)，7.05 (1H，dd，h8 8 Hz，2 4 Hz)，7 38 (1H，d，J=2.4 Hz)，7·59 (1H，d，】=2·4 H2)，7.95 (n d，J=3.6 Hz)，8.14 (1H，d，卜5·6 Hz)，8.28 (1H，d，J=8 8 Hz)，8.48 ⑽ t，J=5.2 Hz)，10.49 (1H，s)。 實施例194 氟乙基）二5二f (2- 吡啶某）.某飞脖 基1- 4-毗啶某）氣1 - 1 Η- 1 - 4嗓羧醯胗 • 301 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐） 1304061 、- '-·· A7 B7 五、發明説明（296) 將N1-環丙基-5-( { 2- [(4-六氫吡啶羰基）胺基]•吡啶基） 氧㈣哚羧醯胺70 mg，甲醛（37%水溶液）〇1 ml，乙 酸20 mg及四氫呋喃5 ml於室溫攪拌5分鐘，接下來加入三 乙醯氧硼氫化鈉70 mg並攪摔10分鐘。加入碳酸氫鈉水溶液 及用乙酸乙酯萃取。將萃取液通過塗敷NH型石夕凝勝之玻璃 濾器。將矽凝膠用乙酸乙酯充分洗淨，合併乙酸乙酯層及 減壓蒸館，得到無色粉末40 mg。 ^-NMR (DMSO-d6) (5 (ppm): 1.45-1.56 (2H, m), 1.59-1·68 (2H，m)，1·73-1·83 (2H，m)，2·09 (3H，s)，2.30-2.40 (lH，m)， 2.69-2.77 (2H，m)，3·56 (1H，q，J=5.2 Hz)，3·62 (1H，Φ J==5·2 Hz)，4.52 (1H，t，J=5.2 Hz)，4·64 (1H，t，J=5.2 Hz)，6·65 (1H， dd，J=5.6 Hz，2.4 Hz)，6.70 (1H，d，J=3.6 Hz)，7·05 (旧，dd， J=8.8 Hz，2.4 Hz)，7·38 (1H，d，J=2.4 Hz)，7.60 (1H，山 Hz)，7.95 (1H，d，J=3.6 Hz)，8.13 (1H，d，J=5.6 Hz)，8·29 (1H， d，J=8.8 Hz·)*; 8·48 (1H，t，J=5.2 Hz)，10.41 (1H, s) e 實施例195’ 、 環丙基-5-({2-『（4-六氤吡啶棊羰某）胺基^4-^^^^ 氣）-1Η-1-㈣哚#醯胺 使用N1-環丙基-5-[(2-{[(1-第三丁氧羰基-4-六氫吡症基） 羰基]胺基卜4-吡啶基）氧]-1H-1-啕哚致醯胺，以與實旅例 19 3同樣之方法，得到目的物。 ^H-NMR (DMS〇-d6) 3 (ppm): 0.59-0.66 (2H，m)，0·67-0.75 (2H，m)，1·30-1·43 (2H, m)，1.54-1.62-(2H，m)，2.3卜2·45 (2H，m)，2.45-2.54 (1H，m)，2.73-2.80 (1H，m)，2·8、2·94 __—— — _ 302 _^- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） !304061Hz), 4·64 (1H, t, J = 5.2 Hz), 6.66 (1H, dd, Hz, 2.4 Hz) 6.70 (m, d, J = 3.6 Hz), 7.05 (1H, dd, h8 8 Hz, 2 4 Hz), 7 38 (1H, d, J = 2.4 Hz), 7·59 (1H, d, 】 = 2·4 H2), 7.95 (nd, J = 3.6 Hz), 8.14 (1H, d, 卜 5·6 Hz), 8.28 (1H, d, J = 8 8 Hz), 8.48 (10) t, J = 5.2 Hz), 10.49 (1H, s). Example 194 fluoroethyl) bis 5 dif (2-pyridyl). A certain flying neck base 1- 4-pyridinyl) gas 1 - 1 Η- 1 - 4 嗓 carboxy 醯胗 • 301 - This paper scale applies Chinese National Standard (CNS) Α4 Specifications (210 X 297 mm) 1304061, - '-·· A7 B7 V. Description of Invention (296) N1-Cyclopropyl-5-( { 2- [(4-hexahydro) Pyridylcarbonyl)amino]•pyridyl) Oxygen (tetra) hydrazide 70 mg, formaldehyde (37% in water) 〇 1 ml, acetic acid 20 mg and tetrahydrofuran 5 ml were stirred at room temperature for 5 minutes, then triethoxy oxime was added Sodium borohydride 70 mg and stirred for 10 minutes. Aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. The extract was passed through a glass filter coated with a NH-type stone. The ruthenium gel was washed thoroughly with ethyl acetate, and the ethyl acetate layer was combined and evaporated to give a colorless powder 40 mg. ^-NMR (DMSO-d6) (5 (ppm): 1.45-1.56 (2H, m), 1.59-1·68 (2H, m), 1.73-1·83 (2H, m), 2.09 (3H, s), 2.30-2.40 (lH, m), 2.69-2.77 (2H, m), 3.56 (1H, q, J = 5.2 Hz), 3·62 (1H, Φ J==5· 2 Hz), 4.52 (1H, t, J = 5.2 Hz), 4·64 (1H, t, J = 5.2 Hz), 6.65 (1H, dd, J = 5.6 Hz, 2.4 Hz), 6.70 (1H ,d,J=3.6 Hz),7·05 (old, dd, J=8.8 Hz, 2.4 Hz), 7·38 (1H, d, J=2.4 Hz), 7.60 (1H, mountain Hz), 7.95 ( 1H,d,J=3.6 Hz), 8.13 (1H,d,J=5.6 Hz),8·29 (1H, d,J=8.8 Hz·)*; 8·48 (1H,t,J=5.2 Hz ), 10.41 (1H, s) e Example 195', cyclopropyl-5-({2-"(4-hexa-pyridinium carbonyl) amine group ^4-^^^^ gas)-1Η-1 - (4) 醯 #醯amine using N1-cyclopropyl-5-[(2-{[(1-tert-butoxycarbonyl-4-hexahydropyridyl)carbonyl]amino-4-pyridyl)oxy] -1H-1-indoleamine, the title compound was obtained in the same manner as in the procedure of Example 193. ^H-NMR (DMS 〇-d6) 3 (ppm): 0.59-0.66 (2H, m), 0·67-0.75 (2H, m), 1·30-1·43 (2H, m), 1.54-1.62-(2H, m), 2.3 Bu 2·45 (2H, m), 2.45-2.54 (1H ,m), 2. 73-2.80 (1H,m),2·8,2·94 __—— — _ 302 _^- This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) !304061

(2H, m), 6.60-6.67 (2H, m), 7.〇4 (1H, dd, J=8&gt;g HZj 2.4 Hz), 7.36 (1H，d’ &gt;2.4 Hz)，7.60 (1H，d，I=2 4 Hz)，7 92 (1H，d， J-2.4 Hz), 8.13 (1H, d, J=5.6 Hz), 8.29 (1H, d, J=8.8 Hz), 8.34 (1H，s)，10.36 (1H，s)。 如下述得到中間體。 製造例195-1 -¾•基-5-「（2二iig-··第三 六氤毗啶基）瘦AJ 底羞土吡啶基）1 農廬复 使用Nl-裱丙基-5-[(2·胺基-4_吡啶基）氧]-1Η^ •啕哚羧 醯胺，以與製造例193-1同樣之方法得到目的物。 'H-NMR (DMSO-d6) 5 (ppm): 0.59-0.64 (2H, m), 0.70-0.75 (2H, m), 1.28-1.42 (1H, m), 1.64-1.71 (2H, m), 2.55-2.82 (4H，m)，3.87-3.97 (2H，m)，6·64,6·68 (2H，m)，7.03 (1H，dd， J=8.8 Hz, 2.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.59 (1H, d, J=2.4Hz)，7·87 (ΓΉ，d，J=3.6 Hz)，8·14 (1H，d，J=5,6 Hz)，8.27 (1H， s)，8.29 (1H，d，J=8.8 Hz)，10·48 (1H，s)。、 實施例196 HI:環丙基5- f (2- {「（ 1 -甲基_ 4-六氮吡啶某）蕤某1胺墓卜 4^，比咬基）氣1 -1 Η-1 - 嗓藉醯胺 使用Nl-ί哀丙基- 5·({2-[(4-：τ：氫p比咬基談基）胺基]-4 -叶匕 啶基}氧）-111-啕哚羧醯胺，以與實施例194同樣之方法， 得到目的物。 lH-NMR (DMSO-d6) 5 (ppm): 0.59-0.65 '(2H, m), 0.70-0.76 (2H，m)，1.43-1.56 (2H，m)，1.59-1.68 (2H，m)，1.70-1.81 -303 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）(2H, m), 6.60-6.67 (2H, m), 7.〇4 (1H, dd, J=8&gt;g HZj 2.4 Hz), 7.36 (1H, d' &gt; 2.4 Hz), 7.60 (1H, d, I=2 4 Hz), 7 92 (1H, d, J-2.4 Hz), 8.13 (1H, d, J=5.6 Hz), 8.29 (1H, d, J=8.8 Hz), 8.34 (1H, s), 10.36 (1H, s). The intermediate was obtained as follows. Production Example 195-1 -3⁄4•基-5-"(2二iig-··三六氤pyridine)sweet AJ 羞 羞 pyridine base) 1 Nl-裱propyl-5-[ (2. Amino-4-pyridyl)oxy]-1Η^ • Carboxylamidine was obtained in the same manner as in Production Example 193-1. 'H-NMR (DMSO-d6) 5 (ppm) : 0.59-0.64 (2H, m), 0.70-0.75 (2H, m), 1.28-1.42 (1H, m), 1.64-1.71 (2H, m), 2.55-2.82 (4H, m), 3.87-3.97 ( 2H,m),6·64,6·68 (2H,m),7.03 (1H,dd, J=8.8 Hz, 2.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.59 (1H, d , J=2.4Hz),7·87 (ΓΉ,d,J=3.6 Hz),8·14 (1H,d,J=5,6 Hz), 8.27 (1H, s), 8.29 (1H,d, J=8.8 Hz), 10·48 (1H, s)., Example 196 HI: cyclopropyl 5-f (2-{"(1-methyl-4-cyclohexapyridine) 蕤1 amine tomb Bu 4^, than bite base gas 1 -1 Η-1 - 嗓 醯 醯 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用The title compound was obtained in the same manner as in Example 194. lH-NMR (DMSO-d6) 5 (ppm):::::::::::::::::::::::::::::::::::::::::::::::::::::: '(2H, m), 0.70-0.76 (2H, m), 1.43-1.5 6 (2H,m), 1.59-1.68 (2H,m),1.70-1.81 -303 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

装 訂Binding

線 1304061 A7 B7 五、發明説明（298) (2H, m), 2.09 (3H, s), 2.30-2.40 (1H, m), 2.69-2.80 (3H, m), 6.62-6.70 (2H, m)&gt; 7.04 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.36 (1H, τ'-59 〇H，d，；=2'4 Hz)，7·87 0H&gt; J=3·6 Hz)^ (，，J=)·6 Hz)，8.27-8·83 (2H，m), 10.41 (1H，s)。Line 1304061 A7 B7 V. INSTRUCTIONS (298) (2H, m), 2.09 (3H, s), 2.30-2.40 (1H, m), 2.69-2.80 (3H, m), 6.62-6.70 (2H, m) &gt; 7.04 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.36 (1H, τ'-59 〇H,d,;=2'4 Hz),7·87 0H&gt; J=3·6 Hz) ^ (,, J=)·6 Hz), 8.27-8·83 (2H, m), 10.41 (1H, s).

Nl-Nl-

口比矣基）氧1-1H-〗朵藉 醯胺 使苯基j({2_[(4·六氫吡啶基羰基)胺基]_4·吡啶 基}氧）丨哚幾醯胺，以與實施例I%同樣之方法，得 到目的物。 H-NMR (DMS〇.d6)5(ppm): 1.44-1.56 (2H, m), 1.59-1.67 (2H，m)，1·73-1·82 (2H，m)，2·〇9 (3H，s)，2·30-2·44 (1H，s)， 2.69-2.76 (2H, s)3 6.66-6.70 (1H, m), 6.77 (1H, d, J=3.6 Hz), 7.07-7.15 (2H, m), 7.35-7.45 (3H, m), 7.60-7.68 (3H, m), 8.10-8.18 (2H, m), 8.27 (1H, d, J=8.8 Hz), 10.10 (1H, s) 10.42 (1H, s) 〇 如下述得到中間體。 製造例197-1 別-..毛盖二：)-〖(.21^基-4-说咬幻氣1_111_14卜朵羧醯胺 將5-[(2 -胺基-4-吡啶基）氧]-啕哚3〇 g溶解於二甲 基甲醯胺落液，於室溫加入氫化鈉（6〇%，在油中）28 mg&amp; 攪拌5分鐘後，加入異氰酸苯酯16 g並攪掉2〇分鐘。加入水 及用乙酸乙酯萃取，將有機層用水洗淨履，加入矽凝膠及 減塵館去落媒。將該矽凝膠饋入充填矽凝膠之乾燥管柱 -304 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱丁 1304061 〜 A7 B7 五、發明説明（299) 中，然後用管柱層析精製（乙酸乙酯）。得到3.4g無色粉 末。 lH-NMR (DMSO-d6) 5 (ppm): 5.77 (1H, d, J=2.4 Hz), 5.85 (2H，s)，6.14 (1H，dd，J=5.6 Hz，2·4 Hz)，6·75 (1H，d，J=4.0 Hz)，7.06 (1H，dd，J=8.8 Hz，2.4 Hz)，7.13 (1H，dd，J=8.0 Hz， 8.0 Hz)，7.36-7.43 (3H，m)，7.64 (2H，d，J=8.0 Hz)，7·77 (1H， d，J=5.6 Hz)，8.10 (1H，d，J=4.0 Hz)，8.25 (1H，d，J=8.8 Hz), 10.08 (1H，s)。 製造例197-2 4- { K 4- Π 1 -(笨胺羰基）-1 Η- 5-钊哚基1氣卜2-吡啶基）胺基1 羰基卜1-六氫吡啶羧酸第三丁酯 使用N1-苯基-5-[(2-胺基-4-吡啶基）氧]-1H-1-吲哚羧醯 胺，以與實施例193-1同樣之方法，得到目的物。 lH-NMR (DMSO-d6) (5 (ppm): 1.38-1.41 (11H, m), 1.64-1.72 (2H，m)，2.52-2.75 (3H，m)，3·87-3·97 (2H，m)，6.68 (1H，dd， J=5.6 Hz，2.4 Hz)，6·77 (1H，d，J=3.6 H、z)，7.09 (1H，dd， J = 8.8 Hz，2·4 Hz)，7·13 (1H，dd，J=7.2 Hz，7.2 Hz)，7.38 (2H， dd，J=7.2 Hz，7.2 Hz)，7·43 (1H，d，J=2.4 Hz)，7·61 (1H，d， J=2.4 Hz), 7.65 (2H, d, J=7.2 Hz), 8.13 (1H5 d, 1=3.6 Hz), 8.15 (1H, d, 1=5.6 Hz), 8.27 (1H, d, J=8.8 Hz), 10.10 (1H, s), 10.50 (1H，s)。 製造例197-3矣 ) ) ) ) ) ) ) ) ) ) 氧 氧 氧 氧 氧 氧 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使 使The same procedure as in Example I% gave the desired product. H-NMR (DMS 〇.d6) 5 (ppm): 1.44-1.56 (2H, m), 1.59-1.67 (2H, m), 1.73-1·82 (2H, m), 2·〇9 ( 3H, s), 2·30-2·44 (1H, s), 2.69-2.76 (2H, s)3 6.66-6.70 (1H, m), 6.77 (1H, d, J=3.6 Hz), 7.07- 7.15 (2H, m), 7.35-7.45 (3H, m), 7.60-7.68 (3H, m), 8.10-8.18 (2H, m), 8.27 (1H, d, J=8.8 Hz), 10.10 (1H, s) 10.42 (1H, s) The intermediate is obtained as follows. Production Example 197-1 --..Mao cover 2:)-〖(.21^基-4-说咬幻气1_111_14卜朵carboxy amide will be 5-[(2-amino-4-pyridyl)oxy ]-啕哚3〇g dissolved in dimethylformamide falling solution, adding sodium hydride (6〇% in oil) 28 mg &amp; at room temperature for 5 minutes, then adding 16 g of phenyl isocyanate Stir for 2 minutes. Add water and extract with ethyl acetate. Wash the organic layer with water, add to the gel and reduce the dust. Add the gel to the dry tube filled with gel. -304 - This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 Gong Ai 1304061 ~ A7 B7 5. Inventive Note (299), and then purified by column chromatography (ethyl acetate). g colorless powder. lH-NMR (DMSO-d6) 5 (ppm): 5.77 (1H, d, J = 2.4 Hz), 5.85 (2H, s), 6.14 (1H, dd, J = 5.6 Hz, 2·4 Hz),6·75 (1H,d,J=4.0 Hz), 7.06 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.13 (1H, dd, J=8.0 Hz, 8.0 Hz), 7.36-7.43 (3H,m), 7.64 (2H,d,J=8.0 Hz),7·77 (1H, d,J=5.6 Hz), 8.10 (1H,d,J=4.0 Hz), 8.25 (1H,d, J=8.8 Hz), 10.08 (1H, s). Production Example 197-2 4- { K 4- Π 1 -(stupylcarbonyl)-1 Η- 5-fluorenyl 1 gas 2 2-pyridyl)amino 1 carbonyl 1 - 6 The n-butyl hydropyridine carboxylic acid ester was the same as in Example 193-1, using N1-phenyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide. Method, the object was obtained. lH-NMR (DMSO-d6) (5 (ppm): 1.38-1.41 (11H, m), 1.64-1.72 (2H, m), 2.52-2.75 (3H, m), 3.87 -3·97 (2H,m), 6.68 (1H,dd, J=5.6 Hz, 2.4 Hz),6·77 (1H,d,J=3.6 H,z),7.09 (1H,dd, J = 8.8 Hz, 2·4 Hz), 7·13 (1H, dd, J=7.2 Hz, 7.2 Hz), 7.38 (2H, dd, J=7.2 Hz, 7.2 Hz), 7·43 (1H, d, J= 2.4 Hz), 7.61 (1H, d, J = 2.4 Hz), 7.65 (2H, d, J = 7.2 Hz), 8.13 (1H5 d, 1 = 3.6 Hz), 8.15 (1H, d, 1=5.6 Hz), 8.27 (1H, d, J=8.8 Hz), 10.10 (1H, s), 10.50 (1H, s). Manufacturing Example 197-3

Nl -笨基- 5-( (2-「（4-六氫吡啶基羰基〗胺基1-4-吡啶基} 氣）-1H- 1- 4丨嗓藉酿胺 -305 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） !3〇4〇61Nl-stupyl- 5-((2-"(4-hexahydropyridylcarbonyl)amino)-4-ylpyridyl} gas)-1H- 1- 4丨嗓 by amine-305 - This paper size applies China National Standard (CNS) A4 specification (210 X 297 mm) !3〇4〇61

使用4-u(M[1-(苯胺羰基).1H〜㈣基]氧}〜比咬 基）胺基]羰基}-1-77氫吡啶羧酸第三丁酉旨 同樣之方法得到目的物。 以與實施例193 H-NMR (DMSO-d6)(5(ppm): 1.32-1.43 (2H, m)5 j.55-1.63 (2H，m)，2·37-2·53 (3H，m)，2.88:95 (2H，m)，6·67 (1H，dd， J=5.6 Hz, 2.4 Hz), 6.77 (1H3 d5 J^.6 Hz), 7.09 (1H, dd5 J-8.8 Hz，2.4 Hz)，7.13 (1H，dd，J=7.2 Hz，7·2 Hz)，7.38 (2H， 賦 J=7.2 Hz，7.2 Hz)，7.43 (1H，2·4 HZ)，7.62-7.67 (3H，m)， 8.13 (1H, d, J=3.6 Hz), 8.15 (1H, d5 J=5.6 Hz), 8.27 (1H, d, &gt;8.8 Hz)，10.10 (1H，bs)，10.40 (1H，s)。 實施例198 ^LL·苯基-5- {「2- ((「Π -環丙甲基）-4-六翁毗忒某1蒜某}胺― 基）-4-吡啶基1氩丨-1H-1-W哚# sife 使用N1 -苯基-5- ({ 2- [(4-六氫吡啶基羰基）胺基]-4-毗啶 基}氧）-1-吲哚幾醯胺及環丙曱醛，以與實施例194同樣 之方法，得到目的物。 、 lH-NMR (DMSO-d6) 5 (ppm): 0.00-0.06 (2H, m)3 0.39-0.45 (2H，m)，0·72·0·82 (1H，m)，1·46-1·59 (2H，m)，1.60-1.70 (2H, m), 1.80-1.90 (2H, m), 2.10 (2H, d, J=6.0 Hz), 2.33- 2·43 (1H，m)，2.90-3.00 (2H，m)，6.67 (1H，dd，J二5.6 Hz，2.4 Hz)，6.76 (1H，d，J=3.6 Hz)，7.06-7.16 (2H，m)，7·35-7·45 (3H，m)，7.60-7.68 (3H，m)，8.12 (1H，d，J=3.6 Hz)，8.14 (1H， d, J=5.6 Hz)，8.27 (1H，d，J=8.8 Hz), 1Ό.09 (1H，s)，10.40 (1H，s)。 -306 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐)4-u(M[1-(phenylaminocarbonyl).1H~(tetra)yloxy]oxy}~amino)carbonyl}-1-77hydropyridinecarboxylic acid tert-butyl was obtained by the same method. And Example 193 H-NMR (DMSO-d6) (5 (ppm): 1.32-1.43 (2H, m) 5 j.55-1.63 (2H, m), 2·37-2·53 (3H, m ), 2.88:95 (2H,m),6·67 (1H,dd, J=5.6 Hz, 2.4 Hz), 6.77 (1H3 d5 J^.6 Hz), 7.09 (1H, dd5 J-8.8 Hz, 2.4 Hz), 7.13 (1H, dd, J=7.2 Hz, 7·2 Hz), 7.38 (2H, J=7.2 Hz, 7.2 Hz), 7.43 (1H, 2·4 HZ), 7.62-7.67 (3H, m), 8.13 (1H, d, J=3.6 Hz), 8.15 (1H, d5 J=5.6 Hz), 8.27 (1H, d, &gt; 8.8 Hz), 10.10 (1H, bs), 10.40 (1H, s Example 198 ^LL·Phenyl-5- {"2-(("Π-cyclopropylmethyl)-4-hexonium 忒1 1 garlic} amine-based)-4-pyridyl 1 argon丨-1H-1-W哚# sife using N1-phenyl-5-({ 2-[(4-hexahydropyridylcarbonyl)amino]-4-pyridinyl}oxy)-1-anthracene The title compound was obtained in the same manner as in Example 194. mp NMR (DMSO-d6) 5 (ppm): 0.00-0.06 (2H, m) 3 0.39-0.45 (2H, m),0·72·0·82 (1H,m),1·46-1·59 (2H,m),1.60-1.70 (2H, m), 1.80-1.90 (2H, m), 2.10 (2H , d, J=6.0 Hz), 2.33- 2·43 (1H, m), 2.90-3.00 (2H, m), 6.67 (1H, dd, J 2 5.6 Hz, 2.4 Hz), 6.76 (1H, d, J = 3.6 Hz), 7.06-7.16 (2H, m), 7·35-7·45 (3H, m), 7.60-7.68 (3H, m), 8.12 (1H, d, J = 3.6 Hz), 8.14 (1H, d, J = 5.6 Hz), 8.27 (1H, d, J = 8.8 Hz), 1Ό.09 (1H, s), 10.40 (1H, s -306 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

装Loading

線 1304061 A7 B7 301 ) 五、發明説明（ 重施例199 4:i ( 基）胺某1 - 3-氣笨氣甚} - 2- 口比咬某、^ ϋ - 4-六氫p比咬卷醯脖 將4-{[(4-{4-[(苯胺羰基）胺基]-3-氯苯氧基卜2-吡啶基） 胺基]談基}-1-六氫吡啶羧酸第三丁酯12〇 mg溶於三氟乙酸 5 ml並於室溫攪拌5分鐘。加入碳酸氫鈉水溶液及5N氫氧化 制水溶·液並用乙酸乙酯萃取β將萃取液用食鹽水洗淨以及 用硫酸納乾燥。將乾燥劑濾去及減壓餾去溶媒。將殘餘物 中加入四氫呋喃5 ml，乙酸26 mg ,三乙醯氧基硼氫化鈉92 mg及甲醛（37%水溶液）0·5 ml並於室溫攪掉1〇分鐘。在反應 溶液中加入碳酸氫鈉水溶液及5N氫氧化鈉水溶液並用乙酸 乙酯萃取。將萃取液用食鹽水洗淨，繼而通過塗敷^只型矽 凝膠之玻璃濾器。將矽凝膠用乙酸乙酯充分洗淨，合併乙 酸乙酯層及減壓蒸餾，殘餘物藉由乙酸乙酯及己^固體 化，以得到1色粉末80 mg。 Ά ^-NMR (DMSO-d6) 5 (ppm): 1.48^1.62 (2H9 m), i 62-1 7? (2H, m), 1.76-1.86 (2H, m)5 2.12 (3H, s)5 2.34-2.44 (iH, m)5 2·72-2·81 (2H，m)，6·68 (1H，dd，J=5,6 Hz，2·4 Hz)，6.98 (1H， dd，J=7.2 Hz，7.2 Hz)，7·15 (1H，dd，J=8.8 Hz，2.4 Hz)，7.29 (2H, dd, J=7.2 Hz, 7.2 Hz)5 7.3 8 ( 1H, d, 1=2.4 Hz), 7.46 (2H, d，J=7.2 Hz), 7·66 (1H，d，J=2.4 Hz)，8·17 (1H，d，J=5.6 Hz) 8.22 (IH, d3 J=8.8 Hz), 8.38 (IH, s), 9.42 (IH, s)! 10.49 (1H| s) 0 - 製造例199- 1 -307 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 B7 五、發明説明（302 ) 4-((『4-(4-胺基-3-#苳氧基）-2-吡啶某1胺基丨羰某）-1_立 氤吡啶羧酸第三丁酯 將2 -胺基- 4-(4-胺基-3-氯苯氧基）p比咬600 mg，1-第三丁 氧羰基六氫吡啶-4-羧酸700 mg，苯并三唑-1-基氧參（二曱 胺基）鳞六氟磷酸鹽（Bop試劑）1.4 g，三乙胺0.71 ml及二甲 基甲醯胺10 ml於60°C攪拌3.5小時，繼而於室溫攪掉19小 時。在反應溶液中加入水及用乙酸乙酯萃取，將有機層用 水洗淨後，加入矽凝膠及減壓饀去溶媒。將該矽凝膠饋入 充填有矽凝膠之乾燥管柱中，以及藉由管柱層析（己烷：乙 酸乙酯=1 : 1，繼而用乙酸乙酯）精製。得到66〇 mg之赤褐 色粉末。 ]H-NMR (DMS0-d6) (5 (ppm): 1.30-1.45 (1 1H, m)3 1.65-1.74 (2H，m)，2.56-2.76 (3H，m)，3.88-4.03 (2H，m)，5·37 (2H，s)， 6.59 (1H, dd, J=5.6 Hz, 2.4 Hz)3 6.82-6.88 (2H, m), 6.07 (1H5 d，J-2.4 Hz·):，7·57 (1H, d，J=2.4 Hz)，8,12 (1H，d，J=5.6 Hz)， 10.48 (1H，s)。 ·、 製造例199-2 4-(174-丨3-氯-4-K芄氳羰基）胺基1笨氳某丨_2·吡啶某）胺基] 羰基卜卜六氫吡啶羧酸第三丁酯 在4-({[4-(4-胺基-3-氯苯氧基）-2-批淀基]胺基}羧基）_ 1-六氫说咬幾酸第三丁酯660 mg，p比淀〇· 14 ml及四氫咬喃 10 ml之溶液中，於室溫授拌下加入氯曱酸苯酯〇·21 ml並擾 捽13小時。在反應溶液中加入水及用乙··酸乙酯萃取，將有 機層用水洗淨後，加入碎凝膠及減壓館去溶媒。將該碎凝 -308 - 本纸俵尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂Line 1304061 A7 B7 301) V. Description of the invention (Re-example 199 4: i (base) amine 1 - 3-gas stupid even - 2 - mouth than bite, ^ ϋ - 4- hexa-p ratio The coiled neck will be 4-{[(4-{4-[(phenylaminocarbonyl)amino]-3-chlorophenoxy-2-ylpyridyl)amino] cyano}-1-hexahydropyridinecarboxylic acid 12 mg of tributyl ester was dissolved in 5 ml of trifluoroacetic acid and stirred at room temperature for 5 minutes. Add aqueous sodium hydrogencarbonate solution and 5N aqueous solution of hydrogen peroxide to extract and extract β with ethyl acetate. Wash the extract with saline solution and use Drying with sodium sulfate, filtering off the desiccant and distilling off the solvent under reduced pressure. Add 4 ml of tetrahydrofuran, 26 mg of acetic acid, 92 mg of sodium triacetoxyborohydride and formaldehyde (37% aqueous solution) 0·5 ml. And the mixture was stirred at room temperature for 1 。 minutes. Aqueous sodium hydrogencarbonate solution and 5N aqueous sodium hydroxide solution were added to the reaction solution and extracted with ethyl acetate. The extract was washed with brine, and then coated with a gel. The glass filter was thoroughly washed with ethyl acetate, and the ethyl acetate layer was combined and evaporated under reduced pressure. Ά ^-NMR (DMSO-d6) 5 (ppm): 1.48^1.62 (2H9 m), i 62-1 7? (2H, m), 1.76-1.86 (2H, m)5 2.12 (3H, s)5 2.34-2.44 (iH, m)5 2·72-2·81 (2H,m),6·68 (1H,dd,J=5,6 Hz, 2·4 Hz), 6.98 (1H, dd, J =7.2 Hz, 7.2 Hz), 7·15 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.29 (2H, dd, J=7.2 Hz, 7.2 Hz) 5 7.3 8 ( 1H, d, 1=2.4 Hz), 7.46 (2H, d, J=7.2 Hz), 7·66 (1H, d, J=2.4 Hz), 8·17 (1H, d, J=5.6 Hz) 8.22 (IH, d3 J=8.8 Hz), 8.38 (IH, s), 9.42 (IH, s)! 10.49 (1H| s) 0 - Manufacturing Example 199- 1 -307 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297) PCT) 1304061 A7 B7 V. INSTRUCTION DESCRIPTION (302) 4-(("4-(4-Amino-3-#苳-oxy)-2-pyridine 1 amino group hydrazine carbonyl)-1_ 氤 pyridine Tert-butyl carboxylic acid 2-amino-4-(4-amino-3-chlorophenoxy)p ratio 600 mg, 1-tert-butoxycarbonylhexahydropyridine-4-carboxylic acid 700 mg , benzotriazol-1-yloxyglycol (dioxin) hexafluorophosphate (Bop reagent) 1.4 g, triethylamine 0.71 ml and dimethylformamide 10 ml stirred at 60 ° C for 3.5 hours Then, it was stirred at room temperature for 19 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and then the mixture was stirred and evaporated to remove solvent. The hydrazine gel was fed into a dry column packed with a hydrazine gel and purified by column chromatography (hexane: ethyl acetate = 1 : 1 and then ethyl acetate). A 66 mM mg brown powder was obtained. H-NMR (DMS0-d6) (5 (ppm): 1.30-1.45 (1 1H, m) 3 1.65-1.74 (2H, m), 2.56-2.76 (3H, m), 3.88-4.03 (2H, m ),5·37 (2H,s), 6.59 (1H, dd, J=5.6 Hz, 2.4 Hz)3 6.82-6.88 (2H, m), 6.07 (1H5 d, J-2.4 Hz·):,7· 57 (1H, d, J = 2.4 Hz), 8, 12 (1H, d, J = 5.6 Hz), 10.48 (1H, s) ·, Manufacturing Example 199-2 4-(174-丨3-Chloro- 4-K芄氲carbonyl)amino 1 氲 氲 · · · · · ) ) ) 胺 羰 羰 羰 羰 羰 羰 羰 羰 羰 羰 羰 羰 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- -chlorophenoxy)-2-batch-based]amino}carboxy)_1-hexahydro-sodium butylate 660 mg, p-precipitate · 14 ml and tetrahydrocyanate 10 ml solution In the mixture, phenyl chlorate 21 21 ml was added at room temperature and disturbed for 13 hours. Water was added to the reaction solution, and extracted with ethyl acetate, and the organic layer was washed with water, and then the crushed gel and the decompression chamber were added to the solvent. The condensed -308 - paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm).

線 1304061 二 _ 、- A7 __ B7 五、發明説明（303 ) 知*饋入充填有石夕凝膠之乾燥管柱中，以及藉由管柱層析（己 燒·乙酸乙酉旨=1 : 1 ’繼而用乙酸乙g旨）精製。得到mcr 之無色油狀物β h-NMR (DMSO-d6) 5 (ppm): 1·30-1·45 (11Η，m)，1.67-1.77 (2H，m)，2·58-2·80 (3H，m)，3·88-4·00 (2H，m)，6.71 (1H，dd， J=5.6 Hz，2.4 Hz)，7.17-7.28 (4H，m)，7.37-7.46 (3H，m)， 7.67 (1H，d，J=2.4 Hz)，7·79 (1H，d，J=8.8 Hz)，8.20 (1H，d， 卜5.6 Hz)，9·78 (1H，bs)，10.58 (1H，s)。 製造例199-3 1^1£14-丨4-『（笨胺羰基)胺基卜3-氪茉氣某丨-?二?比咬基、脸甚1 盪基卜1-六氫吡啶藉酸第三丁酯 將4-{[(4-{3-氯-4-[(苯氧羰基）胺基]苯氧基卜2_吡淀基） 胺基]羰基卜1-六氫吡啶羧酸第三丁酯250 mg，苯胺84 mg 及二甲基曱醯胺3 ml在130 °C攪拌70分鐘。回到室溫後，加 入水並用乙破乙酯萃取。在萃取溶液中加入矽凝膠及減壓 餾去溶媒，以使反應生成物吸著於矽凝膠上。將該碎凝膠 饋入充填有矽凝膠之乾燥管柱中，以及進行管柱精製（己 烷：乙酸乙酯=1 : 1，繼而用乙酸乙酯）。減壓餘去溶媒， 得到為無色油狀物120 mg。 lH-NMR (DMSO-d6) 5(ppm): 1.28-1.45 (1 1H, m), 1.67-1.75 (2H，m)，2.57-2.80 (3H，m)，3.87-4.03 (2H，m)，6.69 (1H，dd， J=5.6 Hz, 2.4 Hz), 6.93 (1H, dd? J=7.2 Hz, 7.2 Hz), 7.15 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.28 (2H, dd5 J=7：2 Hz, 7.2 Hz), 7.39 (1H，d，J=2.4 Hz)，7.45 (2H，d，J=7.2 Hz)，7.64 (1H，d，J=2.4 -309 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 裝 訂Line 1304061 _, - A7 __ B7 V. Description of the invention (303) Knowing that * is fed into a dry tube column filled with Shixi gel, and by column chromatography (hexane + acetic acid) = 1: 1 'There was then refined with acetic acid. Obtaining a colorless oil of mcr, β h-NMR (DMSO-d6) 5 (ppm): 1·30-1·45 (11Η, m), 1.67-1.77 (2H, m), 2·58-2·80 (3H,m),3·88-4·00 (2H,m),6.71 (1H,dd, J=5.6 Hz, 2.4 Hz), 7.17-7.28 (4H,m),7.37-7.46 (3H,m ), 7.67 (1H, d, J = 2.4 Hz), 7.79 (1H, d, J = 8.8 Hz), 8.20 (1H, d, 5.6 Hz), 9·78 (1H, bs), 10.58 ( 1H, s). Production Example 199-3 1^1£14-丨4-"(stupidylcarbonyl)Amineyl-3- 氪 气 丨 丨 ? ? ? ? ? ? ? ? ? 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Acidic tert-butyl ester 4-{[(4-{3-chloro-4-[(phenoxycarbonyl)amino]phenoxy b 2-pyridyl)amino]carbonyl] 1-hexahydropyridinecarboxylate The acid tert-butyl ester 250 mg, aniline 84 mg and dimethyl decylamine 3 ml were stirred at 130 ° C for 70 minutes. After returning to room temperature, water was added and extracted with ethyl acetate. A ruthenium gel was added to the extraction solution and the solvent was distilled off under reduced pressure to cause the reaction product to be adsorbed on the ruthenium gel. The crushed gel was fed into a dry column packed with a ruthenium gel, and column purification was carried out (hexane: ethyl acetate = 1: 1, followed by ethyl acetate). The solvent was removed under reduced pressure to give a colorless oil 120 mg. lH-NMR (DMSO-d6) 5 (ppm): 1.28-1.45 (1 1H, m), 1.67-1.75 (2H, m), 2.57-2.80 (3H, m), 3.87-4.03 (2H, m), 6.69 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.93 (1H, dd? J=7.2 Hz, 7.2 Hz), 7.15 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.28 (2H, dd5 J=7:2 Hz, 7.2 Hz), 7.39 (1H,d,J=2.4 Hz), 7.45 (2H,d,J=7.2 Hz), 7.64 (1H,d,J=2.4 -309 - the paper size Applicable to China National Standard (CNS) A4 Specification (210 x 297 mm) Binding

線 1304061 A7 B7 五、發明説明（3〇4Line 1304061 A7 B7 V. Description of invention (3〇4

Hz), 8.18 (1H, d, J=5.6 Hz), 8.21 (1H, d, J=8.8 Hz), 8.36 (1H, s)，9.33 (1H，s)，10.55 (1H，s)。 實施例200 N4-『4-(3 -紊(環丙胺基）魏基1胺基}苯乳基）-2-?比症 基Ί - 1 -甲基· 4 -六氣ρ比症義酿胺 使用4-({ [4-(3-氯-4-{[(環丙胺基）羰基]胺基}苯氧基）-2-吡啶基]胺基}羰基）-1-六氫吡啶羧酸第三丁酯，以與實 施例19 9同樣之方法得到目的物。 ^-NMR (DMSO-d6)5(ppm): 0.38-0.48 (2H, br s)5 0.60-0.70 (2H，m)，1·5(Μ·85 (6H，m)，2.11 (3H，s)，2.33-2.45 (1H，m)， 2.45-2.58 (1H，m)，2.70-2.80 (2H，m)，6.66 (1H，dd，J=5.6 Hz， 2A Hz), 7.09 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.16 (1H, d, J=2.4 Hz), 7.32 (1H, d, J=2.4 Hz), 7.62 (1H, s), 7.93 (1H, s), 8.16 (1H，d, J=5.6 Hz)，8.20 (1H，d，J=8.8 Hz)，10.46 (1H，s)。 如下述得。到中間體。 製造例200-1 、 心氪-4-ΠΎ瑷丙胺某）蕤基1胺基）苯氧基）-2-?比—達― 基1胺基}羰墓）-1-六氣毗々淼酸第三丁 11_ 使用製造例199- 2合成之原料以及環丙胺，以與製造例 199-3同樣之方法，得到目的物。 lH-NMR (DMSO-d6) 5 (ppm): 0.38-0.44 (2H, m), 0.60-0.68 (2H, m), 1.30-1.44 (1 1H, m), 1.67-1.74 (2H, m), 2.50-2.80 (4H，m)，3.88-4.00 (2H，m)，6·67 (1H，dcT，J=5.6 Hz，2·4 Hz)， 7.09 (1H, dd, J=8.8 Hz5 2.4 Hz), 7.16 (1H, d, J=2.4 Hz), 7.32 -310 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 裝 訂Hz), 8.18 (1H, d, J=5.6 Hz), 8.21 (1H, d, J=8.8 Hz), 8.36 (1H, s), 9.33 (1H, s), 10.55 (1H, s). Example 200 N4-"4-(3- 紊(cyclopropylamino)weiyl 1 amino}} benzyl)-2-? ratio Ί - 1 - methyl · 4 - hexa ρ ratio The amine is 4-({[4-(3-chloro-4-{[(cyclopropylamino)carbonyl)amino}phenoxy)-2-pyridinyl]amino}carbonyl)-1-hexahydropyridinecarboxylate The title product was obtained in the same manner as in Example 19 9 as the acid. ^-NMR (DMSO-d6) 5 (ppm): 0.38-0.48 (2H, br s) 5 0.60-0.70 (2H, m), 1·5 (Μ·85 (6H, m), 2.11 (3H, s ), 2.33 - 2.45 (1H, m), 2.45 - 2.58 (1H, m), 2.70 - 2.80 (2H, m), 6.66 (1H, dd, J = 5.6 Hz, 2A Hz), 7.09 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.16 (1H, d, J=2.4 Hz), 7.32 (1H, d, J=2.4 Hz), 7.62 (1H, s), 7.93 (1H, s), 8.16 (1H , d, J = 5.6 Hz), 8.20 (1H, d, J = 8.8 Hz), 10.46 (1H, s). Obtained as follows. Intermediates. Production Example 200-1, Heart 氪-4-ΠΎ瑷 propylamine蕤 1 1 1 1 胺 1 1 1 1 1 1 1 基 -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- _ _ _ The title compound was obtained in the same manner as in Production Example 199-3. lH-NMR (DMSO-d6) 5 (ppm): 0.38-0.44 (2H, m), 0.60-0.68 (2H, m), 1.30-1.44 (1 1H, m), 1.67-1.74 (2H, m), 2.50-2.80 (4H, m), 3.88-4.00 (2H, m), 6.67 (1H, dcT, J = 5.6 Hz, 2·4 Hz), 7.09 (1H, dd, J=8.8 Hz5 2.4 Hz) , 7.16 (1H, d, J=2.4 Hz), 7.32 -310 - This paper size applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) Binding

線 1304061 A7 B7 五、發明説明（305 ) (1H，d，J=2.4 Hz)，7.61 (1H，s)，7·93 (1H，s)，8·16 (1H，d， J=5.6 Ηζ)，8·20 (1Η，d，J=8.8 Ηζ)，1〇·54 (1Η，s)。 實施例2〇l N4-i4-(H-4-{『（4-氟苯胺基）羰某1胺某}茇氧莘 啶基1 - 4-六氫吡啶#醯胺 將4-{[4-(3-氯-4-{[(4-氟苯胺基）羰基]胺基}苯氧基广2· 叶匕淀基]胺基}羧基-1-六氫p比咬幾酸第三丁酯320 mg溶於三 氟乙酸10 ml並於室溫授摔5分鐘。加入乙酸乙酯及碳酸氫 鈉水溶液，以調成鹼性及分液。將乙酸乙酯層用食鹽水洗 淨1次及用硫酸鎂乾燥。減壓餾去溶媒，得到無色粉末240 mg 0 lH-NMR (DMSO-d6) (5 (ppm): 1.36-1.48 (2H, m)5 1.58-1.66 (2H，m)，2.39-2.58 (3H，m)，2.89-2.98 (2H，m)，6·67 (1H，dd， J=5.6 Hz，2.4 Hz)，7.09-7.18 (3H，m)，7·38 (1H，d，J=2.4 Hz)， 7.44-7.50 〇2*H，m)，7.66 (1H，d，J=2.4 Hz)，8.15 (2H，m)， 8.38 (1H，s)，9.48 (1H，s)，10·44 (1H，s) 〇、 如下述得到中間體。 製造例201-1 4-{「心（3-氪-4-(|~(4-氟茉胺基)」變基丄胺^1^_氧某）_2-吡啶 基1胺基丨羰基-1-六ft.毗哇#酸第三丁酯 使用製造例199-2合成之原料以及對氟苯胺，以與製造例 199-3同樣之方法，得到目的物。 lH-NMR (DMSO-d6) 5 (ppm): 1.32-1.46 (1 1H, m), 1.66-1.75 (2H，m)，2·56-2·78 (3H，m)，3·88-4·〇〇 (2H，m)，6,69 (1H, dd， -311 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公爱） 1304061 、 〜- A7 ^__B7 _._ 五、發明説明（306 ) J=5.6 Hz, 2.4 Hz), 7.10-7.18 (3H5 m), 7.38 (1H5 d, J=2.4 Hz), 7.43-7.50 (2H，m)，7·64 (1H，d，J=2.4 Hz)，8.17-8.23 (2H，m)， 8·37 (1H，s)，9·45 (1H，s)，10.55 (1H，s)。 :實施例202 H4-(3-氯-4-(174-氣苯胺某）羱某1胺某}笨氧基）-2-吡 遂_基1-1-甲基-4-六氫外1：矣藉酿胺 使用N4-[4-(3-氯-4-{[(4-氟苯胺基）羰基]胺基}苯氧基）-2-吡啶基]-4-六氫吡啶幾醯胺，以與實施例199同樣之方法 得到目的物。 ^-NMR (DMSO-d6) 5 (ppm): 1.48-1.60 (2H, m), 1.62-1.70 (2H，m)，1.74-1.83 (2H，m)，2·11 (3H，s)，2.33-2.43 (1H，m)， 2.70-2.78 (2H，m)，6·68 (1H，dd，J=5.6 Hz，2.4 Hz)，7.10. 7.20 (3H，m)，7·39 (1H，d，J=2.4 Hz)，7·44-7·50 (2H，m)， 7.65 (1H, d3 J=2.4 Hz), 8.16-8.23 (2H, m), 8.33 (1H, s), 9.41 (1H，s)，10.47 (1H，s)。 實施例203 、 m-(4-丨4-K苯胺羰基）胺某i-3_氳芙蛋，某卜2-吡啶某）-2- LL-曱基-4-六氫吡啶基）乙醯脖 使用4- { 2- [(4- { 4-[(苯胺羰基）胺基]-3-氯苯氧基卜2-吡 啶基）胺基]-2-酮基乙基卜1-六氫吡啶羧酸第三丁酯，以與 實施例1 99同樣之方法，得到目的物。 !H-NMR (DMSO-d6) 5 (ppm): 1.10-1.20 (2H, m), 1.50-1.70 (3H，m)，1.72-1.80 (2H，m)，2.08 (3H，s); 2·24 (2H，d，J=6.8 Hz), 2.63-2.72 (2H, m), 6.66 (1H, d, J=5.6 Hz, 2.4 Hz), 6.97 -312 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061Line 1304061 A7 B7 V. Description of invention (305 ) (1H, d, J = 2.4 Hz), 7.61 (1H, s), 7.93 (1H, s), 8.16 (1H, d, J = 5.6 Ηζ ), 8·20 (1Η, d, J=8.8 Ηζ), 1〇·54 (1Η, s). Example 2 〇l N4-i4-(H-4-{"(4-fluoroanilino)carbonyl carbonyl 1 amine 茇 oxazolidinyl 1 - 4-hexahydropyridine # decylamine 4-{[4 -(3-chloro-4-{[(4-fluoroanilino)carbonyl]amino}phenoxy 2, phylloxyl]amino}carboxy-1-hexahydrop than biting acid The ester was dissolved in 10 ml of trifluoroacetic acid and sprinkled for 5 minutes at room temperature. Ethyl acetate and aqueous sodium hydrogencarbonate were added to make the mixture alkaline and liquid. The ethyl acetate layer was washed once with saline. Drying with magnesium sulfate and distilling off the solvent under reduced pressure to give a colorless powder 240 mg 0 lH-NMR (DMSO-d6) (5 (ppm): 1.36-1.48 (2H, m) 5 1.58-1.66 (2H, m), 2.39-2.58 (3H,m), 2.89-2.98 (2H,m),6·67 (1H,dd, J=5.6 Hz, 2.4 Hz), 7.09-7.18 (3H,m),7·38 (1H, d, J = 2.4 Hz), 7.44-7.50 〇 2*H, m), 7.66 (1H, d, J = 2.4 Hz), 8.15 (2H, m), 8.38 (1H, s), 9.48 (1H, s ), 10·44 (1H, s) 〇, an intermediate was obtained as follows. Production Example 201-1 4-{"Heart (3-氪-4-(|~(4-fluoromosynyl))) Amine^1^_oxygen)_2-pyridyl 1aminopurine carbonyl-1-hexaft.Viva# acid tert-butyl ester synthesized using the production example 199-2 The title compound and the p-fluoroaniline were obtained in the same manner as in the compound 199-3. lH-NMR (DMSO-d6) 5 (ppm): 1.32-1.46 (1 1H, m), 1.66-1.75 (2H, m),2·56-2·78 (3H,m),3·88-4·〇〇(2H,m),6,69 (1H, dd, -311 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 x 297 public) 1304061, ~- A7 ^__B7 _._ V. Description of invention (306) J=5.6 Hz, 2.4 Hz), 7.10-7.18 (3H5 m), 7.38 (1H5 d, J =2.4 Hz), 7.43-7.50 (2H,m),7·64 (1H,d,J=2.4 Hz), 8.17-8.23 (2H,m), 8·37 (1H,s),9·45 ( 1H, s), 10.55 (1H, s).: Example 202 H4-(3-chloro-4-(174-gas aniline) 羱1 amine 笨 笨 ) ) ) ) ) 遂 基 基 1 -1-Methyl-4-hexahydro outside 1: 矣N-[4-(3-chloro-4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-2 The object was obtained in the same manner as in Example 199. ^-NMR (DMSO-d6) 5 (ppm): 1.48-1.60 (2H, m), 1.62-1.70 (2H, m), 1.74-1.83 (2H, m), 2·11 (3H, s), 2.33 -2.43 (1H,m), 2.70-2.78 (2H,m),6·68 (1H,dd,J=5.6 Hz,2.4 Hz), 7.10. 7.20 (3H,m),7·39 (1H,d , J=2.4 Hz), 7.44-7·50 (2H, m), 7.65 (1H, d3 J=2.4 Hz), 8.16-8.23 (2H, m), 8.33 (1H, s), 9.41 (1H , s), 10.47 (1H, s). Example 203, m-(4-丨4-K-anilinocarbonyl)amine i-I-3_ 氲芙 egg, a certain 2-pyridine-)-2- LL-mercapto-4-hexahydropyridyl) acetamidine 4-{ 2-[(4- { 4-[(phenylaminocarbonyl)amino]-3-chlorophenoxy-2-pyridyl)amino]-2-ketoethyl b- 1-hexahydro The title compound was obtained in the same manner as in Example 1 99. !H-NMR (DMSO-d6) 5 (ppm): 1.10-1.20 (2H, m), 1.50-1.70 (3H, m), 1.72-1.80 (2H, m), 2.08 (3H, s); 24 (2H,d,J=6.8 Hz), 2.63-2.72 (2H, m), 6.66 (1H, d, J=5.6 Hz, 2.4 Hz), 6.97 -312 This paper size applies to the Chinese National Standard (CNS) A4 Specifications (210 x 297 mm) 1304061

(1H3 dd, J=7.2 Hz, 7.2 Hz), 7.14 (1H, dd3 J=8.8 Hz, 2.4 Hz), 7.28 (2H, dd, J=7.2 Hz, 7.2 Hz), 7.39 (1H, d5 J=2.4 Hz), 7.47 (2H, d, J=7.2 Hz), 7.68 (1H5 d, J=2.4 Hz), 8.16 (1H, d, J=5.6 HZ)，8·20 (1H，d，J==8·8 Hz)，8·40 (1H，s)5 9·42 (1H，s)，10.48 (1H，s)。 如下述得到中間體。 製造例203-1 4- (2- { [4_:丄4-胺基^^苯氧基）· 2_吡啶某〗胺甚卜| 7 基W-六氮吡啶#蓋第三丁酯 將2-胺基-4-(4-胺基-3 -氯苯氧基）吡淀1 ·〇 g , B〇p試劑1.9 g ’三乙胺1·2 ml，2-[1-(第三丁氧羰基）_心六氫吡啶基]乙 酸1.0 g及二甲基甲酿胺1〇 ml於6〇 °C攪:拌2小時以及於室溫 攪拌1 8小時。在反應溶液中加入水以及用乙酸乙酯萃取。 在萃取溶液中加入矽凝膠及減壓餾去溶媒，以使反應生成 物吸著於珍&lt;凝膠上。將該矽凝膠饋入充填有矽凝膠之乾燥 管柱中，以及藉由管柱層析（己烷：乙酸&amp;酯=1 : 1)精製。 得到淡褐色油狀物570 mg。 ^-NMR (DMSO-d6)(5(ppm): 0.95-1.07 (2H, m), 1.36 (9H, s), 1.53-1.62 (2H, m)3 1.30-1.43 (1H, m), 2.25 (1H, d, J=7.2 Hz), 2.55-2.75 (2H5 m), 3.80-3.92 (2H, m), 5.37 (2H, s), 6.58 (1H, dd，J=5.6 Hz，2.4 Hz)，6·80-6·90 (2H，m)，7.07 (1H, d，J=2.4 Hz), 7.61 (1H, d, J=2.4 Hz), 8.11 (1H, d, J=5.6 Hz), 10.43 (lH，s)。 ‘ 製造例203-2 313 -(1H3 dd, J=7.2 Hz, 7.2 Hz), 7.14 (1H, dd3 J=8.8 Hz, 2.4 Hz), 7.28 (2H, dd, J=7.2 Hz, 7.2 Hz), 7.39 (1H, d5 J=2.4 Hz), 7.47 (2H, d, J=7.2 Hz), 7.68 (1H5 d, J=2.4 Hz), 8.16 (1H, d, J=5.6 HZ), 8·20 (1H,d,J==8 · 8 Hz), 8·40 (1H, s) 5 9·42 (1H, s), 10.48 (1H, s). The intermediate was obtained as follows. Production Example 203-1 4-(2- { [4_:丄4-Aminophenoxyphenoxy)· 2_pyridine A certain amine| 7 base W-hexaazinidine #盖丁丁酯2 -amino-4-(4-amino-3-chlorophenoxy)pyridine 1 ·〇g , B〇p reagent 1.9 g 'triethylamine 1 · 2 ml, 2-[1-(third 1.0 g of oxycarbonyl)-heart hexahydropyridyl]acetic acid and 1 〇ml of dimethyl ketoamine were stirred at 6 ° C for 2 hours and at room temperature for 18 hours. Water was added to the reaction solution and extracted with ethyl acetate. A hydrazine gel was added to the extraction solution, and the solvent was distilled off under reduced pressure to cause the reaction product to be adsorbed on the gel. The ruthenium gel was fed into a dry column packed with a ruthenium gel and purified by column chromatography (hexane: acetic acid &amp; ester = 1 : 1). A pale brown oil 570 mg was obtained. ^-NMR (DMSO-d6) (5 (ppm): 0.95-1.07 (2H, m), 1.36 (9H, s), 1.53-1.62 (2H, m)3 1.30-1.43 (1H, m), 2.25 ( 1H, d, J=7.2 Hz), 2.55-2.75 (2H5 m), 3.80-3.92 (2H, m), 5.37 (2H, s), 6.58 (1H, dd, J=5.6 Hz, 2.4 Hz),6 ·80-6·90 (2H,m),7.07 (1H, d,J=2.4 Hz), 7.61 (1H, d, J=2.4 Hz), 8.11 (1H, d, J=5.6 Hz), 10.43 ( lH, s). ' Manufacturing Example 203-2 313 -

裝 訂Binding

本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公爱) 1304061 、--· A7 ____B7 &quot;'五、發明説明1 ~~) 甚）胺基1-3-氯笨氣基卜2-咕啶某）胺 基丄乙基卜1 -六氪吡啶羧酸第三丁酯 在4-(2-{[4-(4-胺基-3-氯苯氧基）-2-吡啶基]胺基卜2-酮 基乙基）-六氫吡啶羧酸第三丁酯570 mg，吡啶11〇 mg及 二曱基曱醯胺5 ml之溶液中，在室溫攪拌下，滴入氯甲酸 苯醋210 mg及攪拌3〇分鐘。加入水及用乙酸乙酯萃取。將 有機層用水洗淨2次及用食鹽水洗淨1次。加入矽凝膠及減 壓館去溶媒。將該矽凝膠饋入充填有矽凝膠之乾燥管拄 中，及進行管柱層析精製（己烷：乙酸乙酯=1 ·· 1，繼而用 乙酸乙醋）精製。得到為淡黃色油狀物之( 2- [(4- { 3 -氯-4-[(苯氧羰基）胺基]苯氧基}·2_吡啶基）胺基酮基乙 基卜1-六氫说啶羧酸第三丁酯440 mg。在該油狀物中加入 苯胺7 1 mg及二甲基甲酿胺5 mi並於13〇 °C授拌15分鐘。使 反應落液回到室溫，加入NH型矽凝膠及減壓餾去溶媒，以 使反應生成/物吸著於矽膠上。將該矽凝膠饋入充填有]^]^型 矽凝膠之乾燥管柱中，及進行管柱精製-〇己烷：乙酸乙酯 =1 : 1)精製。減壓餾去溶媒，得到目的物丨8〇 mg ^ H-NMR (DMS〇.d6)(5(ppm): 0.94-1.06 (2H, m), 1.36 (9H, s), 1·)3-1·61 (2H，m)，1·8〇-ΐ·92 (1H，m)，2·27 (2H，d，J=6.8 Hz)， 2.)5-2.75 (2H，m)，3.80-3.90 (2H，m)，6·67 (1H，dd，J=5.6 Hz， 2.4 Hz), 6.98 (1H, dd, 1=7.2 Hz, 7.2 Hz), 7.15 (1H, dd, J=8.8This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 public) 1304061, --- A7 ____B7 &quot; '5, invention description 1 ~ ~) even) amino 1-3-chloro stupid base咕2-咕 某 ) 胺 ) ) 胺 胺 胺 卜 卜 卜 4- 4- 4- 4- 4- 4- 4- 4- 4-(2-{[4-(4-Amino-3-chlorophenoxy)-2- a solution of pyridyl]aminobutyric 2-ketoethyl)-hexahydropyridinecarboxylic acid tert-butyl ester 570 mg, pyridine 11 〇 mg and dimethyl decylamine 5 ml, stirred at room temperature Add phenyl chloroacetate 210 mg and stir for 3 minutes. Water was added and extracted with ethyl acetate. The organic layer was washed twice with water and once with saline. Add the enamel gel and reduce the pressure to the solvent. The ruthenium gel was fed into a drying tube filled with a ruthenium gel, and subjected to column chromatography purification (hexane: ethyl acetate = 1 · 1, and then ethyl acetate). Obtained as a light yellow oil (2-[(4-{3-chloro-4-[(phenoxycarbonyl)amino)phenoxy}.2-pyridyl)amino ketoethylethyl 1- Trihydrobutyl hexahydropyridinium carboxylate 440 mg. Add 7 mg of aniline and 5 mi of dimethylamine to the oil and mix for 15 minutes at 13 ° C. Allow the reaction to fall back. At room temperature, a NH-type ruthenium gel is added and the solvent is distilled off under reduced pressure to cause the reaction product to be absorbed on the ruthenium gel. The ruthenium gel is fed into a drying column packed with a 矽-type gel. And purifying the column - hexane: ethyl acetate = 1 : 1). The solvent was distilled off under reduced pressure to give the title compound (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1·61 (2H,m),1·8〇-ΐ·92 (1H,m),2·27 (2H,d,J=6.8 Hz), 2.)5-2.75 (2H,m),3.80 -3.90 (2H,m),6·67 (1H,dd,J=5.6 Hz, 2.4 Hz), 6.98 (1H, dd, 1=7.2 Hz, 7.2 Hz), 7.15 (1H, dd, J=8.8

Hz，2·4 Hz)，7·28 (2H，dd，J=7.2 Hz，7.2 Hz)，7·39 (1H，d， J-2.4 Hz)，7.45 (2H，d，J=7.2 Hz)，7.67 〇H，s)，8.17 (1H，d， J=d.6 Hz)，8·21 (1H，d，J=8.8 Hz), 8.36 (1H，s)，9.38 (1H，s)， _______-314 - 本纸張尺度適用中國國家標準(CNS) A4^^7i〇 x 297&amp;iy 1304061 〜 - A7 _ B7 __ __ 五、發明説明（309 ) 10.50 (1H，S” 音施例204Hz, 2·4 Hz), 7·28 (2H, dd, J=7.2 Hz, 7.2 Hz), 7·39 (1H, d, J-2.4 Hz), 7.45 (2H, d, J=7.2 Hz) , 7.67 〇H, s), 8.17 (1H, d, J=d.6 Hz), 8.21 (1H, d, J = 8.8 Hz), 8.36 (1H, s), 9.38 (1H, s), _______-314 - This paper scale applies to Chinese National Standard (CNS) A4^^7i〇x 297&amp;iy 1304061 ~ - A7 _ B7 __ __ V. Invention Description (309) 10.50 (1H,S" Sound Example 204

N卜茉基- 「2-Π-甲某-4-六氤吡)乙酿H 臬卜4-吡啶基）氧1-1H-1-W哚淼醯脖 使用4- { 2_ [ (4- { [ 1 -(苯胺羰基）-iH- 5-钊哚基]氧卜2-P比啶 基）胺基]-2-酮基乙基卜1-六氫吡啶羧酸第三丁酯，以與實 施例199同樣之方式得到目的物。 lH-NMR (DMSO-d6) (5 (ppm): 1.08-1.20 (2H, m)5 1.48-1.66 (3H，m)，1.71-1.80 (2H，m)，2·07 (3H，s)，2·22 (2H，d，J=7.2 Hz)，2·62-2·69 (2H，m)，6·65 (1H，dd，Hz，2·4 Hz)， 6.77 (1H, d, J=3.6 Hz), 7.07-7.16 (2H, m), 7.38 (2H, dd3 ' J=7.2 Hz, 7.2 Hz), 7.43 (1H, d, J=2.4 Hz), 7.60-7.68 (3H, m)5 8.10-8.17 (2H，m)，8.27 (1H，d，J=8.8 Hz)，10.09 (1H，s)， 10.43 (1H，s)。 如下述得剷中間體。 f 造例 204- 1 、 {f 1-(苯胺蕤基1H-5- 4 4 甚1 氣}二1_ 吡 基）胺 11 - 2-氫乙基卜1-六氫吡啶藉醴第三丁酯 將N1-苯基- 5- [(2 -胺基-4-吡啶基）氧]-1H-1-吲哚羧醯胺 5 00 mg，2-[1-(第三丁氧幾基）-4-六氫此症基]乙酸350 mg，苯并三唑-1-基參（二甲胺基）鳞六氟磷酸鹽640 mg，三 乙胺0.4 ml及二甲基甲醯胺5 ml於60°C攪捽1小時並於室溫 攪拌19小時。在反應溶液中加入水及用-·乙酸乙酯萃取。將 有機層用水洗淨2次及用食鹽水洗淨1次。加入矽凝膠及減 -315 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜 Λ, ^ ： -- ----------^_ 五、發明説明（31〇^ 〜-一&quot; 壓餾去溶媒。將該矽凝膠饋入充填有矽凝膠之乾燥管柱 中’以及進行管柱精製（己烷：乙酸乙酯叫：1，繼而用乙 酸乙醋）。得到無色油狀物220 mg。 H-NMR (DMSO^d6) δ (ppm): 0.92-1.08 (2H, m)5 1.36 (9H5 s), 1.50-1.62 (2H, m), 1.77-1.90 (1H, m), 2.24 (2H, d, J=6.8 Hz), 2.55-2.77 (2H, m), 3.78-3.93 (2H, m), 6.66 (1H, dd, 1=5.6 Hz, 2.4 Hz), 6.77 (1H, d, J=3.6 Hz), 7.08-7.16 (2H, m), 7.35-7.46 (3H, m), 7.60-7.68 (3H5 m)3 8.10-8.18 (2H, m), 8.27 (1H，d，J=8_8 Hz)，10.09 (1H，s)，10.44 (1H，s)。 實施例205 111-苯棊-3-氰二^「（2- {i-甲基·4_六藎吡啶某）蕤某1臉 基丄-4^比啶某）氧μΐΗ-1-吲哚#醯胺 將4-{[(4-{[1-(苯胺羰基）-3-氯-1]9[-5_啕哚基]氧卜2-吡 淀基）胺基]羰基卜1-六氫吡啶羧酸第三丁酯26〇 mg溶於三 氣乙酸5 mL·、，並於室溫攪拌5分鐘。加入碳酸氫鈉水溶液及 5N氫氧化鈉水溶液，用乙酸乙酯萃取，並用硫酸鎂乾燥。 濾去乾燥劑及減壓餾去溶媒，得到N1-苯基-3-氯-5-[(2-{ [ (4-六氫吡啶基）羰基]胺基} · 4·吡啶基）氧]_ 丨哚羧 画區胺之微黃色固體2〇〇 mg。在該固體中加入甲醛（37%水溶 液）0.5 nd，三乙醯氧硼氫化鈉no mg，乙酸50 mg及四氫呋 喃5 ml並於室溫攪拌1〇分鐘。加入碳酸氫鈉水溶液及5N氫 氧化鈉水溶液，用乙酸乙酯萃取，以及將萃取液用食鹽水 洗淨1次。使如此得到之乙酸乙酯溶液通過塗敷NH型矽凝 膠之玻璃濾器。將矽凝膠用乙酸乙酯沖洗及減壓餾去溶 -316 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 -一 s A7 ____B7 五、發明説明（311 ) 媒’得到微黃色油狀物210 mg。將該油狀物從己烷及乙酸 乙醋之混合溶媒中固體化，得到90 mg粉末。 ^-NMR (DMSO-d6) 5 (ppm): 1.44-1.56 (2H, m), 1.60-1.68 (2H，m)，1.73-1.82 (2H，m)，2.09 (3H，s)，2·30-2·45 (1H，m)， 2.70-2.76 (2H，m)，6.69 (1H，dd，J=5.6 Hz，2·4 Hz)，7,14 (1H， dd, J=7.2 Hz, 7.2 Hz), 7.22 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.34- 7.42 (3H，m)，7.60-7.66 (3H，m)，8.17 (1H，d，J=5.6 Hz)， 8.33 (1H，d，J=8.8 Hz)，8·38 (1H，s)，1〇·12 (1H，s)，10.45 (1H，s)。 如下述得到中間體。 製造例205-1 5-『（2二胺_基二吡啶某）氲1 - 3-氰-1H- 1- 4哚 將5-[(2-胺基-4-吡啶基）氧卜1H-1-4丨哚1·〇 g，N-氯琥珀 醯亞胺650 mg及異丙醇20 ml於80°C攪拌25分鐘。在反應溶 液中加入τΜΐ用乙酸乙酯萃取。將此萃取液通過塗敷NH型 矽凝膠之玻璃濾器。將矽凝膠用乙酸乙酯沖洗及減壓餾去 溶媒，得到赤褐色油狀物1.3g。 'H-NMR (DMSO-d6) 5 (ppm): 5.73 (1H5 d, J=2.4 Hz), 5.82 (2H，s)，6·13 (1H，dd，J=5.6 Hz，2·4 Hz)，6·93 (1H，dd，J=8.8 Hz，2·4 Hz)，7.15 (1H，d，J=2.4 Hz)，7·48 (1H，d，J=8.8 Hz)， 7.58 (1H, d, 1=2.4 Hz), 7.75 (1H, d, J=5.6 Hz), 11.48 (1H, s) ° _ 造例 205-2 .N 卜 基 - - "2-Π-甲甲-4- 氤 ) ) ) 乙 ) ) 4- 4- 4- 4- 4- 4- 4- 4- 4- 使用 使用 使用 使用 使用 使用 使用 使用 使用 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 1 -(anilinecarbonyl)-iH- 5-indenyl]oxo 2-Ppyridyl)amino]-2-ketoethylethyl 1-hexahydropyridinecarboxylic acid tert-butyl ester Example 199 gave the desired material in the same manner. lH-NMR (DMSO-d6) (5 (ppm): 1.08-1.20 (2H, m) 5 1.48-1.66 (3H, m), 1.71-1.80 (2H, m), 2·07 (3H, s), 2·22 (2H, d, J = 7.2 Hz), 2·62-2·69 (2H, m), 6·65 (1H, dd, Hz, 2·4 Hz ), 6.77 (1H, d, J=3.6 Hz), 7.07-7.16 (2H, m), 7.38 (2H, dd3 ' J=7.2 Hz, 7.2 Hz), 7.43 (1H, d, J=2.4 Hz), 7.60-7.68 (3H, m)5 8.10-8.17 (2H,m), 8.27 (1H,d,J=8.8 Hz), 10.09 (1H,s), 10.43 (1H,s). f Example 204-1, {f 1-(aniline fluorenyl 1H-5- 4 4 1 1 gas} bis 1 -pyridyl)amine 11 - 2-hydroethyl b 1-hexahydropyridine Ester will be N1-phenyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide 5 00 mg, 2-[1-(t-butoxy) -4-hexahydrogen base] acetic acid 350 mg, benzotriazol-1-yl ginseng Dimethylamino) hexafluorophosphate 640 mg, triethylamine 0.4 ml and dimethylformamide 5 ml were stirred at 60 ° C for 1 hour and at room temperature for 19 hours. Water was added to the reaction solution. Extract with ethyl acetate. Wash the organic layer twice with water and once with saline. Add hydrazine gel and reduce -315 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 1304061 ~ Λ, ^ : -- ----------^_ V. Description of the invention (31〇^~-一&quot; Press to remove the solvent. Feed the 矽 gel into the filling干燥 干燥 之 之 矽 以及 以及 以及 以及 己烷 己烷 己烷 己烷 己烷 己烷 己烷 己烷 己烷 己烷 己烷 己烷 己烷 己烷 己烷 己烷 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Ppm): 0.92-1.08 (2H, m)5 1.36 (9H5 s), 1.50-1.62 (2H, m), 1.77-1.90 (1H, m), 2.24 (2H, d, J=6.8 Hz), 2.55- 2.77 (2H, m), 3.78-3.93 (2H, m), 6.66 (1H, dd, 1=5.6 Hz, 2.4 Hz), 6.77 (1H, d, J=3.6 Hz), 7.08-7.16 (2H, m ), 7.35-7.46 (3H, m), 7.60-7.68 (3H5 m)3 8.10-8.18 (2H, m), 8.27 (1H,d,J=8_8 Hz),10.09 (1H,s),10.44 (1H , s). Example 205 111-benzoquinone-3-cyanide^("2-{i-methyl·4_hexafluorene) 蕤一一脸基丄-4^比啶) Oxygen μΐΗ-1-吲哚#醯amine will 4-{[(4-{[1-(phenylaminocarbonyl)-3-chloro-1]9[-5_mercapto]oxy-2-pyryl)amino]carbonyl-di- 26 〇g of hexahydropyridine carboxylic acid in 26 mg of triacetic acid, and stirred at room temperature for 5 minutes. Add sodium bicarbonate solution and 5N aqueous sodium hydroxide solution, extract with ethyl acetate, and use sulfuric acid Magnesium is dried. The desiccant is filtered off and the solvent is evaporated under reduced pressure to give N1-phenyl-3-chloro-5-[(2-{[(4-hexahydropyridinyl)carbonyl]amino}. Oxygen _ carboxy carboxy group amine slightly yellow solid 2 〇〇 mg. Add formaldehyde (37% aqueous solution) 0.5 nd, sodium triethyl sulfonate no mg, acetic acid 50 mg and tetrahydrofuran 5 ml The mixture was stirred at room temperature for 1 hr. An aqueous solution of sodium hydrogencarbonate and a 5N aqueous sodium hydroxide solution were added, and extracted with ethyl acetate, and the extract was washed once with brine. Glass filter for NH type enamel gel. Rinse the gel with ethyl acetate and Distillation to dissolve -316 - This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1304061 - one s A7 ____B7 V. Invention description (311) Medium 'Get a yellowish oil 210 mg. The oil was solidified from a mixed solvent of hexane and ethyl acetate to give a powder of 90 mg. ^-NMR (DMSO-d6) 5 (ppm): 1.44-1.56 (2H, m), 1.60-1.68 (2H , m), 1.73-1.82 (2H, m), 2.09 (3H, s), 2·30-2·45 (1H, m), 2.70-2.76 (2H, m), 6.69 (1H, dd, J= 5.6 Hz, 2·4 Hz), 7, 14 (1H, dd, J=7.2 Hz, 7.2 Hz), 7.22 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.34- 7.42 (3H, m), 7.60-7.66 (3H,m), 8.17 (1H,d,J=5.6 Hz), 8.33 (1H,d,J=8.8 Hz),8·38 (1H,s),1〇·12 (1H,s ), 10.45 (1H, s). An intermediate was obtained as follows. Production Example 205-1 5-"(2diamine-ylbipyridine) 氲1 - 3-cyano-1H- 1- 4 哚5-[ (2-Amino-4-pyridyl)oxo 1H-1-4丨哚1·〇g, N-chloroammonium imine 650 mg and 20 ml of isopropanol were stirred at 80 ° C for 25 minutes. To the reaction solution, τΜΐ was added and extracted with ethyl acetate. This extract was passed through a glass filter coated with a NH type gel. The hydrazine gel was washed with ethyl acetate and the solvent was evaporated under reduced pressure to yieldd yel. 'H-NMR (DMSO-d6) 5 (ppm): 5.73 (1H5 d, J=2.4 Hz), 5.82 (2H, s), 6·13 (1H, dd, J=5.6 Hz, 2·4 Hz) ,6·93 (1H, dd, J=8.8 Hz, 2·4 Hz), 7.15 (1H, d, J=2.4 Hz), 7·48 (1H, d, J=8.8 Hz), 7.58 (1H, d, 1 = 2.4 Hz), 7.75 (1H, d, J = 5.6 Hz), 11.48 (1H, s) ° _ Example 205-2 .

Nl -笨基- 5- K2 -胺某-4-吨咬某）氣1-3 -氯-lli- 1 - p朵複Si -317 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 : A7 &quot; _____ B7 五、發明説明（312) 在5-[(2-·胺基- 4-p比淀基）氣]-3 -氯-1H-U丨嗓i3 g,氯化 鈉180 mg及二甲基甲酿胺15 ml之溶液中，於室溫下滴入異 氰酸苯酯並攪拌20分鐘。在反應溶液中加入水並用乙酸乙 酯萃取。在該萃取液中加入矽凝膠及減壓餾去溶媒。將該 矽凝膠饋入充填有矽凝膠之乾燥管柱中，以及進行管柱層 析精製（己烷：乙酸乙酯=1 : 1，繼而用乙酸乙酯）。得到淡 紅色油狀物3 8 0 mg。 lH-NMR (DMSO^d6) 5 (ppm): 5.79 (1H5 d, J=2.4.Hz)5 5.89 (2H, s), 6.16 (1H, dd, J—5.6 Hz, 2.4 Hz), 7.12-7.20 (2H m) 7·28 (1H，d，J=2.4 Hz)，7.35-7.42 (2H，m)，7·64 (2H，d，J=8.0 Hz)，7·79 (1H，d，J=5.6 Hz)，8·31 (1H，d，J=8.8 Hz)，8·35 (1H， s)，10.09 (1H，s)。 ’ 製造例205-3 kU (4- { (苯胺羰基）_- 3-氯_ 1H- 5-吲哚某t氧卜比咬基） 歷基1羰基卜1-六氤吡啶羧酸第三丁酯 、 使用N1-苯基-5_ [(2_胺基吡啶基）氧卜％氯·旧，丨·旁呆 羧醯胺，以與製造例204- 1同樣之方法得到目的物。 ^-NMR (DMSO-d6) 5 (ppm): 1.30-1.43 (1 1H, m), 1.65-1.73 (2H, m)5 2.55-2.75 (3H, m), 3.87-4.00 (2H, m)5 6.70 (1H, dd, J—5.6 Hz, 2.4 Hz), 7.14 (1H, dd, J=7.2 Hz, 7.2 Hz), 7 22 (1H dd, J=8.8 Hz, 2.4 Hz)3 7.32^7.42 (3H, m), 7.60-7.67 (3H, m), 8.17 (1H, d, J—5.6 Hz), 8.32 (1H, d, J=8.8 Hz), 8.38 (1H s) 10.12 (1H，s)，10.53 (1H，s) 〇 -318 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）Nl - Stupid - 5- K2 - Amine -4- ton bite) Gas 1-3 - Chlorine - lli - 1 - p complex Si -317 - This paper scale applies to China National Standard (CNS) A4 specification ( 210 x 297 mm) 1304061 : A7 &quot; _____ B7 V. Inventive Note (312) In 5-[(2-amino- 4-p-butylate) gas]-3-chloro-1H-U丨嗓In a solution of i3 g, 180 mg of sodium chloride and 15 ml of dimethylamine, the phenyl isocyanate was added dropwise at room temperature and stirred for 20 minutes. Water was added to the reaction solution and extracted with ethyl acetate. A hydrazine gel was added to the extract and the solvent was distilled off under reduced pressure. The ruthenium gel was fed into a dry column packed with a ruthenium gel, and column column refining was carried out (hexane: ethyl acetate = 1 : 1, followed by ethyl acetate). A pale red oil of 380 mg was obtained. lH-NMR (DMSO^d6) 5 (ppm): 5.79 (1H5 d, J=2.4.Hz)5 5.89 (2H, s), 6.16 (1H, dd, J-5.6 Hz, 2.4 Hz), 7.12-7.20 (2H m) 7·28 (1H,d,J=2.4 Hz), 7.35-7.42 (2H,m),7·64 (2H,d,J=8.0 Hz),7·79 (1H,d,J = 5.6 Hz), 8·31 (1H, d, J = 8.8 Hz), 8.35 (1H, s), 10.09 (1H, s). ' Manufacturing Example 205-3 kU (4- { (aniline carbonyl)_- 3-chloro-1H- 5-吲哚 a t-oxygen bucking base) lignin 1 carbonyl b 1-hexapyridine carboxylic acid third The title compound was obtained by the same method as in Production Example 204-1 using N-phenyl-5-[(2-aminopyridinyloxy)oxyl% chloro-anthracene. ^-NMR (DMSO-d6) 5 (ppm): 1.30-1.43 (1 1H, m), 1.65-1.73 (2H, m)5 2.55-2.75 (3H, m), 3.87-4.00 (2H, m)5 6.70 (1H, dd, J-5.6 Hz, 2.4 Hz), 7.14 (1H, dd, J=7.2 Hz, 7.2 Hz), 7 22 (1H dd, J=8.8 Hz, 2.4 Hz) 3 7.32^7.42 (3H , m), 7.60-7.67 (3H, m), 8.17 (1H, d, J-5.6 Hz), 8.32 (1H, d, J=8.8 Hz), 8.38 (1H s) 10.12 (1H, s), 10.53 (1H,s) 〇-318 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

訂Order

線 1304061 A7 B7 五、發明説明（313) 實施例206 基[2·Γ2•酮某四氤 _ 1Η· 1- g比咯基）-4-吡啶基1氧丨笨基）_ 將N-(4-氟苯基）-N，-(4-{[2-(4-氯丁胺基）-4-吡啶基]氧} 苯基）脲56 mg，碳酸鉀46 mg及二甲基甲醯胺2 ml於150 °C 攪拌15分鐘。加入水及乙酸乙酯以萃取·，將此萃取液通過 塗敷碎凝膠之玻璃濾器。將矽凝膠用乙酸乙酯沖洗及將有 機層減塵条鶴。在殘餘物中加入乙酸乙酯及己烷並濾取析 出來之固體。得到微褐色粉末2丨mg。 lH-NMR (DMSO-d6) 5 (ppm): 1&lt;98 (2H, tt5 J=7.6 Hz, 7.6 Hz), 2.50 (2H, t, J=7.6 Hz), 3.95 (2H, t, J=7.6 Hz), 6.70 (1H, d, J=5.6 Hz)，7.05-7.15 (4H，m)，7·45 (2H，dd，J=8.4 Hz，5.2Line 1304061 A7 B7 V. INSTRUCTIONS (313) EXAMPLE 206 BASE [2·Γ2•Ketone 氤4氤·1Η·1-g-pyryl)-4-pyridyl 1 oxindole) _ N-( 4-fluorophenyl)-N,-(4-{[2-(4-chlorobutylamino)-4-pyridyl)oxy}phenyl)urea 56 mg, potassium carbonate 46 mg and dimethylformamidine 2 ml of the amine was stirred at 150 ° C for 15 minutes. Water and ethyl acetate were added to extract, and the extract was passed through a glass filter of a gelatin gel. The enamel gel was rinsed with ethyl acetate and the organic layer was dust-removed. Ethyl acetate and hexane were added to the residue and the precipitated solid was filtered. A fine brown powder of 2 丨 mg was obtained. lH-NMR (DMSO-d6) 5 (ppm): 1 &lt;98 (2H, tt5 J=7.6 Hz, 7.6 Hz), 2.50 (2H, t, J=7.6 Hz), 3.95 (2H, t, J=7.6 Hz), 6.70 (1H, d, J=5.6 Hz), 7.05-7.15 (4H, m), 7·45 (2H, dd, J=8.4 Hz, 5.2

Hz), 7.52 (2H, d3 J-9.2 Hz), 7.84 (1H, s), 8.22 (1H, d, J=5.6Hz), 7.52 (2H, d3 J-9.2 Hz), 7.84 (1H, s), 8.22 (1H, d, J=5.6

Hz)，8·77 (1H，s)，8·83 (1H，s)。 如下述得測中間體。 製造例206- 1 · lzJi2-(4-氯丁疫吡啶某1羞}苯脸 將2-胺基-4-(4-硝基苯氧基）吡啶3〇〇 mg ,心氯丁基氯化 物0.18 m卜二乙胺〇·77 ml，二甲基甲醯胺i ml及四氫呋喃} ml於至攪拌1〇分鐘，在反應溶液中加入矽凝膠及減壓餾 去溶媒，以使反應生成物吸著於矽凝膠上。將該矽凝膠饋 入充填有碎凝膠之乾燥管柱中，以及進行管柱精製（己烷： 乙酸乙酯=3:1,繼而2:1，繼而l:i&gt;。減壓鶴去溶媒， 氯化銨600 在得到之殘餘物15〇 mg中加入鐵粉3〇〇Hz), 8·77 (1H, s), 8·83 (1H, s). The intermediate was measured as described below. Production Example 206- 1 · lzJi2-(4-chlorobutylpyrazine pyridine 1 y} benzoic acid 2-amino-4-(4-nitrophenoxy)pyridine 3 〇〇mg, heart chloride butyl chloride 0.18 m of diethylamine 〇·77 ml, dimethylformamide i ml and tetrahydrofuran} ml are stirred for 1 minute, a hydrazine gel is added to the reaction solution, and the solvent is distilled off under reduced pressure to obtain a reaction product. Sorption on the gel. The crucible gel is fed into a dry tube column filled with crushed gel, and the column is refined (hexane: ethyl acetate = 3:1, then 2:1, then l :i&gt;. Decompression crane to solvent, ammonium chloride 600 Add iron powder to the residue of 15 〇mg

13040611304061

五、發明説明（ A7 B7 314 ) mg ’ DMF 2 m卜乙酵1 ml及水1 m卜並於100°C攪拌20分 鐘。經碎藻土過濾，在濾液中加入水，及用乙酸乙酯萃 取。將有機層用氯化銨水溶液洗淨5次後用硫酸鎂乾燥。濾 去乾燥劑及減壓餾去溶媒，得到為油狀物之目的物丨J 〇 (DMSO-d6) 5 (ppm)： 1.95 (2H, tt, J=6.8 Hz, 6.8 Hz), 2.48 (2H，t，J=6.8 Hz)，3·62 (2H，t，J=6.8 Hz)，5.10 (2H，br s)，6.55 (1H，dd，J=5.6 Hz，1·2 Hz)，6·59 (2H，d，J=8.4 Hz)， 6·79 (2H，d，J=8.4 Hz), 7·57 (1H，d, J=1.2 Hz)，8·09 (1H，d， 1=5.6 Hz)。 製造例2 0 6 - 2 將4- { [2-(4-氯丁胺基）-4-吡啶基]氧}苯胺loo mg，異氰 酸對氟苯酯4)·〇37 ml及四氫呋喃3 ml於室溫攪摔25分鐘。在 反應溶液中加入水以及用乙酸乙酯萃取。《、在萃取溶液中加 入NH型矽凝膠及減壓餾去溶媒，以使反應生成物吸著於矽 凝膠上。將該矽凝膠饋入充填有NH型矽凝膠之乾燥管柱 中’以及進行管柱精製（己烷：乙酸乙酯=1 ·· !，繼而乙酸 乙酯，繼而乙酸乙酯：甲酵=10 :丨）。減壓餾去溶媒，得到 為白色固體之目的物56 mg。 lH-NMR (DMSO-d6) 5(ppm): 1.95 (2H, tt, J=7.2 Hz, 7.2 Hz), 2.46 (2H, t, J-7.2 Hz), 3.62 (2H, t, J=7/2 Hz), 6.63 (1H d J=5.6 Hz)，7.04-7.16 (4H，m)，7·40-7·48 (2H，m)，7.51 (2H，d，V. INSTRUCTIONS (A7 B7 314 ) mg ' DMF 2 m Ethyl acetate 1 ml and 1 m water and stirred at 100 ° C for 20 minutes. It was filtered through celite, water was added to the filtrate, and extracted with ethyl acetate. The organic layer was washed 5 times with an aqueous solution of ammonium chloride and dried over magnesium sulfate. The desiccant was filtered off and the solvent was evaporated under reduced pressure to give the title compound (yield: DMSO-d6) 5 (ppm): 1.95 (2H, tt, J = 6.8 Hz, 6.8 Hz), 2.48 (2H) ,t,J=6.8 Hz),3·62 (2H,t,J=6.8 Hz), 5.10 (2H,br s),6.55 (1H,dd,J=5.6 Hz,1·2 Hz),6· 59 (2H,d,J=8.4 Hz), 6·79 (2H,d,J=8.4 Hz), 7·57 (1H,d, J=1.2 Hz),8·09 (1H,d, 1= 5.6 Hz). Production Example 2 0 6 - 2 4- { [2-(4-Chlorobutylamino)-4-pyridyl]oxy}aniline loo mg, p-fluorophenyl isocyanate 4)·〇37 ml and tetrahydrofuran 3 Mol was stirred for 25 minutes at room temperature. Water was added to the reaction solution and extracted with ethyl acetate. Further, an NH type hydrazine gel is added to the extraction solution, and the solvent is distilled off under reduced pressure to cause the reaction product to be adsorbed on the hydrazine gel. Feeding the ruthenium gel into a dry column packed with NH-type ruthenium gel' and performing column purification (hexane: ethyl acetate = 1 · ·, then ethyl acetate, then ethyl acetate: methyl leaven) =10 :丨). The solvent was evaporated under reduced pressure to give a white crystals (yield: 56 mg). lH-NMR (DMSO-d6) 5 (ppm): 1.95 (2H, tt, J = 7.2 Hz, 7.2 Hz), 2.46 (2H, t, J-7.2 Hz), 3.62 (2H, t, J=7/ (2H, d)

裝 訂Binding

線 -320 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 、- A7 ____B7 五、發明説明（315 ) J=8.8 Ηζ)，7·62 (1H，s)，8·15 (1H，d，卜5·6 Hz)，8.71 (1H，s)， 8.76 (1H，s)，10.52 (1H，br s) 〇 實施例207 ϋζΙΚ 2-琴:丁嫁疾胺吨宜二氧笨某1 - n，- (2-遠唑甚、月辱 將4-(2-¼ 丁垸談胺p比咬-4-基）氧苯胺130 mg，N-( 2-口塞 唑基）胺基曱酸苯酯110 mg及二甲基亞颯3 mls80°C攪摔3〇 分鐘。在反應液中加入水及乙酸乙酯並萃取。將乙酸乙醋 層用氯化按水落液洗淨5次後，用硫酸鎂乾燥。濾去乾燥劑 及減壓餾去溶媒，在殘餘物中加入乙酸乙酯及濾取析出之 固體。得到130 mg淡褐色固體。 lH-NMR (DMSO-d6) 5 (ppm): 1.68 (1H, m), 1.80-1.93 (1H, m)，1.95-2.10 (2H，m)，2.05-2.18 (2H，m)，3·25-3.35 (1H，m)， 6.64 (1H，d，J=5.6 Hz)，7.06-7.17 (3H，m)，7·36 (1H，d，J=l.6 Hz)，7·56 (2H，d，J=8.0 Hz)，7.66 (1H，s)，8.14 (1H，d，J=5.6 Hz), 9·15 (LH，br s)，10.29 (1H，s)。 製造例207- 1 .、 N1 -環丁烷羰基-N W4- (4-硝基苽蓋.基）-2-吡啶基1 - 1 -環丁 烷羧醯胺 將2 -胺基- 4- (4 -硝基苯氧基）p比淀1〇 g，環丁基氯〖I g, 三乙胺1.9 ml及四氫呋喃20 ml於室溫攪拌40分鐘。加入水 及乙酸乙酯並萃取後。將萃取液減壓蒸餾，以及殘餘物藉 由充填有NH型矽凝膠之乾燥管柱（己烷：乙酸乙酯=1 : υ 精製。將所得者再用矽凝膠層析（己烷：乙酸乙酯=4 ·· 1， 繼而3 : 1)精製。最初被溶出者為目的物。得到無色油狀物 -321 - 本纸張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 裝 訂Line-320 - This paper size applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) 1304061, - A7 ____B7 V. Invention description (315) J=8.8 Ηζ), 7·62 (1H, s) ,8·15 (1H,d,Bu 5·6 Hz), 8.71 (1H, s), 8.76 (1H, s), 10.52 (1H, br s) 〇 Example 207 ϋζΙΚ 2- Qin: Ding Tons of dioxane stupid 1 - n,- (2- far-azole, vaginal will be 4-(2-1⁄4 垸 垸 胺 p 比 比 咬 -4- -4- -4- -4- -4- -4- -4- -4- 110 mg of azolylamine phenyl phthalate and 3 ml of dimethyl hydrazine at 80 ° C for 3 minutes. Water and ethyl acetate were added to the reaction solution and extracted. The ethyl acetate layer was chlorinated. The aqueous solution was washed 5 times, and dried over magnesium sulfate. The dried solvent was evaporated, and the solvent was evaporated to dryness, and ethyl acetate was added to the residue, and the precipitated solid was collected by filtration to give 130 mg of pale brown solid. DMSO-d6) 5 (ppm): 1.68 (1H, m), 1.80-1.93 (1H, m), 1.95-2.10 (2H, m), 2.05-2.18 (2H, m), 3·25-3.35 (1H ,m), 6.64 (1H,d,J=5.6 Hz), 7.06-7.17 (3H,m),7·36 (1H,d,J=l.6 Hz),7·56 (2H,d,J =8.0 Hz), 7.66 (1H, s), 8.14 ( 1H, d, J = 5.6 Hz), 9·15 (LH, br s), 10.29 (1H, s). Production Example 207- 1 ., N1 -cyclobutanecarbonyl-N W4- (4-nitroindole)盖))-2-pyridyl 1 - 1 -cyclobutane carboxy decylamine 2-amino-4-(4-nitrophenoxy)p ratio 1 〇g, cyclobutyl chloride 〖I g , 1.9 ml of triethylamine and 20 ml of tetrahydrofuran were stirred at room temperature for 40 minutes. After adding water and ethyl acetate and extracting, the extract was distilled under reduced pressure, and the residue was dried by a dry column packed with NH-type hydrazine gel. (Hexane:ethyl acetate = 1: υ Purification. The obtained product was purified by hydrazine gel chromatography (hexane: ethyl acetate = 4 ··1, then 3:1). Get colorless oil -321 - This paper size applies to Chinese National Standard (CNS) Α4 size (210 X 297 mm) Binding

線 1304061 A7 B7 五、發明説明（316) 720 mg 〇 】Η-ΝΜΙΙ (DMSO-d6) 5 (ppm): 1.62-1.96 (8H，m)，2.10-2.23 (4H，m)，3.35-3.45 (2H，m)，7·20 (1H，d，J=5.6 Hz), 7.23 (1H， s)，7.40 (2H，d，J=9.2 Hz)，8.33 (2H，d，J=9.2 Hz)，8.49 (ih, d，J=5.6 Hz)。 被第二個溶出者為2-環丁羰胺基-(4-硝基苯氧基）吡啶。 得到白色結晶560 mg。 lH-NMR (DMSO-d6) (5 (ppm): 1.66-1.80 (1H, m), 1.80-1.94 (1H，m)，1.98-2.20 (4H，m)，3.26-3.36 (1H，m)，6·83 (1H，d， J=5.6 Hz)，7·38 (2H，d，J=9.2 Hz)，7·81 (1H，s)，8.27 (1H，d， J=5.6 Hz)，8.31 (2H，d，J=9.2 Hz)。 製造例207-2 生-(4-胺基苯氧基）-2-環丁烷羰胺某毗冷 將N1-環丁烷羰基-Nl-[4-(4-硝基苯氧基）-2-吡啶基]· ；μ 環丁垸複酸。胺720 mg，鐵粉1·4 g，氯化按2·4 g，二曱基甲 醯胺52 ml，乙醇2 ml及水2 ml於1〇〇°C攪拌15分鐘。經矽藻 土過濾’加入乙酸乙酯並萃取。將有機層用氯化按水溶液 洗淨5次後，用硫酸鍰乾燥。濾去乾燥劑及減壓r餘去溶媒， 在殘餘物中加入乙酸乙酯及己烷並濾取析出之固體。得到 130 mg固體。 丨 H-NMR (DMS〇-d6) 5 (ppm): 1·68-1.80 (1H，m)，1.80」93 (1H，m)，1·96-2·19 (4H，m)，3.23-3·34 (1H，m)，5·1〇 (2H，br s)，6.55 (1H, d，J=5.6 Hz)，6.59 (2H，d，J=8.4 Hz)，6.79 (2¾ d，J=8.4 Hz)，7·61 (1H，s)，8.07 (1H，d，J=5.6 Hz)，10.22 (旧 -322 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 發明説明（317 br s)。 實施例208 111:』4-{「（環丙胺基）蕤某1胺基卜3-氨茇氫甚1二^症某1-1-環丙烷#醯胺 將2-胺基-4-(4-胺基-3-氯苯氧基）p比續：2·6 g，環丙羰基氯 2·3 g，三乙胺4.6 ml及四氫呋喃30 ml於室溫攪拌1〇分鐘。 加入水及用乙酸乙酯萃取，然後用硫酸鎂乾燥。濾去乾燥 劑及減壓餾去溶媒，得到褐色油狀物3.69 g。將如此所得油 狀物中之900 mg與三乙胺〇·37 ml及四氫呋喃1〇 ml一起授 拌，並於室溫下滴入氯甲酸苯酯〇·3 ml。揽拌15分鐘後，加 入環丙胺1 ml並再攪拌22小時。在反應溶液中加入石夕凝膠 及減壓餾去溶媒，以使反應生成物吸著於矽凝膠上。將該 矽凝膠饋入充填有矽凝膠之乾燥管柱中，以及進行管柱層 析精製（己烷：乙酸乙酯=1 : 1，繼而乙酸乙酯）。得到為褐 色固體之目的物38 mg。 lH-NMR (DMSO-d6) δ (ppm): 0.40-0.52 (2H, m)? 0.6〇^〇 7〇 (2H，m)，0.70-0.85 (4H，m)，1.9 卜2.00 (1H，m)，2,50-2 70 (1H，m)，6.67 (1H，dd，J=5.6 Hz，2·8 Hz), 7.11 (iH，dd J=8.4 Hz，2.8 Hz)，7.17 (1H，d，J=2.8 Hz)，7·33 (1H，d，J=2.8 Hz), 7.61 (1H, d5 J=2.8 Hz), 7.94 (1H, s), 8.18 (1H, d, J=5 6 Hz)，8·20 (1H，d，J = 8.4 Hz)，1〇·84 (1H，s)。 如下述得到中間體。 _ i告例 2 0 8 -1 2 -胺基-4-( 4 -胺基-3-氯笨氣某）外 -323 -Line 1304061 A7 B7 V. INSTRUCTIONS (316) 720 mg Η-Η-ΝΜΙΙ (DMSO-d6) 5 (ppm): 1.62-1.96 (8H, m), 2.10-2.23 (4H, m), 3.35-3.45 ( 2H,m),7·20 (1H,d,J=5.6 Hz), 7.23 (1H, s), 7.40 (2H,d,J=9.2 Hz), 8.33 (2H,d,J=9.2 Hz), 8.49 (ih, d, J = 5.6 Hz). The second eliminator was 2-cyclobutylaminoamino-(4-nitrophenoxy)pyridine. A white crystal of 560 mg was obtained. lH-NMR (DMSO-d6) (5 (ppm): 1.66-1.80 (1H, m), 1.80-1.94 (1H, m), 1.98-2.20 (4H, m), 3.26-3.36 (1H, m), 6·83 (1H,d, J=5.6 Hz), 7.38 (2H,d,J=9.2 Hz), 7·81 (1H,s), 8.27 (1H,d, J=5.6 Hz), 8.31 (2H, d, J = 9.2 Hz). Production Example 207-2 -(4-Aminophenoxy)-2-cyclobutanecarbonylamine, a V-N-cyclobutanecarbonyl-Nl-[4 -(4-Nitrophenoxy)-2-pyridyl]· ; μ cyclobutanic acid. 720 mg of amine, 1.4 g of iron powder, 2.6 g of chlorinated, dimercaptocarboxamide 52 ml, 2 ml of ethanol and 2 ml of water were stirred at 1 ° C for 15 minutes. Filtered through diatomaceous earth 'Add ethyl acetate and extract. The organic layer was washed with chlorinated aqueous solution for 5 times, then with barium sulfate. Drying. The desiccant was removed by filtration, and the solvent was evaporated, and ethyl acetate and hexane were added to the residue, and the precipitated solid was collected by filtration to obtain 130 mg of solid. 丨H-NMR (DMS 〇-d6) 5 (ppm) ): 1.68-1.80 (1H,m), 1.80"93 (1H,m),1·96-2·19 (4H,m), 3.23-3·34 (1H,m),5·1〇 (2H, br s), 6.55 (1H, d, J = 5.6 Hz), 6.59 (2H, d, J = 8.4 Hz), 6.79 (23⁄4 d, J = 8.4 Hz), 7.61 (1H, s), 8.07 (1H, d, J = 5.6 Hz), 10.22 (old-322 - this paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 Description of invention (317 br s). Example 208 111: 』4-{"(cyclopropylamino) hydrazine 1 amino group - 3 - amino hydrazine hydrogen 1 1-2 1-1 - cyclopropane # decylamine 2-amino group - 4-(4-Amino-3-chlorophenoxy)p ratio: 2·6 g, 2-4 g of cyclopropylcarbonyl chloride, 4.6 ml of triethylamine and 30 ml of tetrahydrofuran were stirred at room temperature for 1 hr. After adding water and extracting with ethyl acetate, it was dried over magnesium sulfate. The desiccant was filtered off and the solvent was evaporated under reduced pressure to give 3.69 g of brown oil. 37 ml and 1 〇ml of tetrahydrofuran were mixed together, and 3 ml of phenyl chloroformate was added dropwise at room temperature. After 15 minutes of stirring, 1 ml of cyclopropylamine was added and stirred for another 22 hours. Stone was added to the reaction solution. The solvent was distilled off under reduced pressure to cause the reaction product to be adsorbed on the ruthenium gel. The ruthenium gel was fed into a dry column packed with a ruthenium gel, and column column refining was carried out (hexane: ethyl acetate = 1 : 1, then ethyl acetate). The object was obtained as a brown solid, 38 mg. lH-NMR (DMSO-d6) δ (ppm): 0.40-0.52 (2H, m)? 0.6〇^〇7〇(2H,m), 0.70-0.85 (4H,m),1.9 2.00 (1H,m ), 2, 50-2 70 (1H, m), 6.67 (1H, dd, J = 5.6 Hz, 2·8 Hz), 7.11 (iH, dd J = 8.4 Hz, 2.8 Hz), 7.17 (1H, d , J=2.8 Hz),7·33 (1H,d,J=2.8 Hz), 7.61 (1H, d5 J=2.8 Hz), 7.94 (1H, s), 8.18 (1H, d, J=5 6 Hz ), 8·20 (1H, d, J = 8.4 Hz), 1〇·84 (1H, s). The intermediate was obtained as follows. _ i 告例 2 0 8 -1 2 -Amino-4-(4-amino-3-chloro-formaldehyde) outside -323 -

裝 訂Binding

線 1304061 〜 … A7 _ B7 _._ 五、發明説明（318) 將為公知化合物之2-胺基-4-氯说啶5.0 g，4-胺基-3-氯 紛g’氯化制（60% ’在油中）及一甲基亞石風$ 〇 m 1在丨6 0 C 攪拌9.5小時。加入水，及用乙酸乙酯萃取。將萃取液用水 洗淨5次。令萃取液通過塗敷矽凝膠之玻璃濾器。將矽凝膠 用乙酸乙酯洗出，將乙酸乙酯層合併及減壓餾去溶媒，得 到濃紫色固體5.1 g。 lH-NMR (DMSO-d6)5(ppm): 5.32 (2H, s)5 5.72 (1H, s), 5.86 (2H，bs)，6.07 (1H，d，J=6.4 Hz)，6·83 (2H，s)，7.01 (1H，s)， 7·72 (1H，d，J=6.4 Hz)。 實施例209 溴-4-(4-{K環丙胺基）羰基1胺基卜3-1茉氫某）-2- i唉基瑗丙烷#醯胺 將Nl-[ 5-溴-4-(4-胺基-3-氯苯氧基）-2-吡啶基]-N1-環丙 羰基-1-環丙烷羧醯胺67 mg，吡啶52 mg及二甲基曱醯胺5 ml冷卻至〇弋，然後加入氯甲酸苯酯54 mg。40分鐘後，加 入環丙羰基氯80 mg並於60°C檀拌20分鐘、回到室溫後，加 入水及用乙酸乙酯萃取。在萃取溶液中加入矽凝膠及減壓 館去溶媒。將該矽凝膠饋入充填有矽凝膠之乾燥管柱中， 以及藉由管柱層析（己燒：乙酸乙酯=1 :丨）精製。在殘餘物 中加入曱醇，得到為白色固體之目的物丨〗mg。 lH-NMR (DMSO-d6) (5 (ppm): 0.40 (2H, br s), 0.65 (2H, m), 0.72 (4H, br s), 1.90 (1H, br s), 2.55 (1H, br s), 7.11 (1H, d, J=9.2 Hz), 7.19 (1H, s), 7.38 (1H, s), 7.56 (1H, s), 7.96 (1H, s)，8.22 (1H，d，J=9.2 Hz)，8·42 (1H，s)，10.94 (1H，s)。 -324 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐)&quot;&quot;&quot;&quot;&quot;'' 一 1304061 _ _ A7 __— B7 五、發明説明（^ -- 如下述得到中間體。 製造例209-1 L胺基二1 臭ζΛζίΑζΜ^^ - 3-氣芡氫某）吡啶 將2-胺基-4-(4-胺基-3-氣苯氧基）吡啶！·〇 g，氺溴琥始 醯亞胺0·78 g及異丙醇1〇 ml於回流下攪拌15分鐘。回到室 溫後，加入水及用乙酸乙酯萃取。在萃取溶液中加入矽凝 膠及減壓餾去溶媒。將該矽凝膠饋入充填有矽凝膠之乾燥 管柱中，以及用管柱層析（己烷··乙酸乙酯=2 : 1，繼而又： 1，繼而乙酸乙酯）精製。得到為褐色油狀物之目的物4〇〇 mg 〇 H-NMR (DMSO-d6) 5 (ppm): 5·39 (2H，br s)，5.68 (1H，s) 6·06 (2H，br s)，6·85 (1H，s)，6·86 (1H，d，J=2.4 Hz)，7.09 (1H，d，J=2.4 Hz)，7.90 (1H，s)。 製造例209-2 U5-溴胺基-3-f‘笨氣某）-2-毗啶甚l-Nl-蹲 基-1 -環丙烷#醯胺 ·、 在2-胺基-3'&gt;臭-4-(4-胺基-3-氯苯氧基）ρ比淀400 mg，三 乙胺0·53 ml及四氫咬喃5 ml之溶液中，於室溫及攪掉下， 加入環丙羰基氣260 mg。40分鐘後，在反應溶液中加入今 凝膠及減壓餾去溶媒。將該矽凝膠饋入充填有矽凝膠之乾 燥管柱中，以及用管柱層析（己烷：乙酸乙酯=2 : 1，繼而 1 : 1，繼而乙酸乙酯）精製。得到目的物67 mg。 lH-NMR (DMSO-d6) 5 (ppm): 0.66-1.00 (8H, m), 1.85-1.96 (2H, m), 5.45 (2H, br s), 6.77 (1H, s)3 6.84 ( 1H, d, J=8.8 Hz), -325 ^ 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（320 6.92 (1H，dd，J=8.8 Ηζ，2.8 Hz)，7.17 (1H，d，J=2.8 Hz)，8.66 (lH，s)〇 . _實施例2 10 这丄-「(3_^5ά氯-4·丨「（環丙胺基）羰基1胺基}苯氧茱2-毗 矣基1-1-環丙烷羧醯胺 在Nl-[4-(4 -胺基-3,5-二氯苯氧基）-2〇比淀基]-&gt;^1-環丙 羰基-1·環丙烷羧醯胺96 mg，吡啶0.076 ml及二甲基甲醯胺 5 ml之溶液中，於室溫下加入氯甲酸苯酯11() mg。攪摔3〇 分鐘後，加入環丙胺0.5 ml並於70°C加溫10分鐘。回到室溫 後，加入水及用乙酸乙酯萃取。在萃取溶液中加入♦凝膠 及減歷:餾去溶媒。將該矽凝膠饋入充填有矽凝膠之乾燥管 柱中，以及用管柱層析（乙酸乙酯）精製。在殘餘物中加入 曱醇使之固體化，得到為淡褐色固體之目的物4.8 mg。 lH-NMR (DMSO-d6) δ (ppm): 0.42 (2H, s)5 0.57-0.66 (2H, m), 0.70-0.83 (IfH，m)，1·92-2·01 (1H，m)，2.43-2.53 (1H，m)， • 6.62 (1H，s)，6·71 (1H，d，Hz)，7,39、(2H，s)，7.69 (1H， s)，7·89 (1H，s)，8·22 (1H，d，J=5.6 Hz)，10.89 (1H, s)。 如下述得到中間體。 製造例210-1 2-胺基·4..:.(4-胺基-3,5·二氯笨氧基）说奋 將2-胺基-4-(心胺基-3-氯苯氧基）吡啶7〇〇 mg，N-氯琥 珀醯亞胺0.44 g及異丙醇1〇 mi於8〇°c攪拌1小時。回到室溫 後，加入水及用乙酸乙酯萃取。在萃取；·溶液中加入矽凝膠 及減壓餾去溶媒。將該矽凝膠饋入充填有矽凝膠之乾燥管 ____ - 326 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公董)一 '----- 1304061 - A7 B7 五、發明説明（321 ) 柱中，以及用管柱層析（乙酸乙酯）精製。得到褐色油狀物 120 mg 0 ^-NMR (DMSO-d6) (5 (ppm): 5.47 (2H5 br s)5 5.73 (1H, d, J=2.4 Hz)，5.90 (2H，br s)，6.09 (1H，dd，J=5.6 Hz，2·4 Hz)， 7.13 (2H，s)，7·75 (1H，d，J=5.6 Hz)。 製造例210-2 胺基-3,5-二氛茉氳某&gt;&gt;-2-吡啶基^Nl-瑷1¾淼其-l-環丙烷羧醯胺 在2-胺基-4-(4-胺基-3,5-二氯苯氧基）吡啶120 mg，三乙 胺0.19 ml及四氫呋喃5 ml之溶液中，於室溫及攪掉下，加 入環丙談基氯93 mg ^ 20分鐘後，在反應溶液中加入碎凝膠 及減壓餾去溶媒β將該矽凝膠饋入充填有矽凝膠之乾燥管 柱中，以及用管柱層析（乙酸乙酯）精製。得到褐色油狀物 120 mg 〇 'H-NMR (D1VISO-d6) (5 (ppm): 0.82-0.98 (8H, m), 1.86-1.96 (2H，m)，5.55 (2H，br s)，6·95 (1H，dd，J、=5.6 Hz，2.4 Hz)， 7.03 (1H, d, J=2.4 Hz), 7.24 (2H, s)3 8.3 8 ( 1H, d, J=5.6 Hz)。 實施例2 1 1 m-環丙基-5-π 2-丨二（環丙蕤某）胺基1-4-毗啶基}氣）_ 1Η· 吲哚#醯胺 在Ν1-環丙基-5-[(2 -胺基- 4-t7比淀基）氧]嗓幾酿 胺100 mg及三乙胺49 mg溶於四氫呋喃乏溶液中，於〇它下 加入環丙羰基氯51 mg。攪拌20分鐘後，在反應溶液中加入 __—- 327 - 本纸張尺度適用中國g家標準(CNS) A4規格(21Gx 297公爱) &quot; &quot;&quot; 1304061Line 1304061 ~ ... A7 _ B7 _._ V. Description of the invention (318) 2-Amino-4-chloropyridinium, which is a known compound, is 5.0 g, 4-amino-3-chloroindole 60% 'in oil) and monomethyl sapite $ 〇m 1 was stirred at 丨6 0 C for 9.5 hours. Water was added and extracted with ethyl acetate. The extract was washed 5 times with water. The extract was passed through a glass filter coated with a gel. The hydrazine gel was washed with ethyl acetate, and the ethyl acetate layer was combined, and the solvent was evaporated under reduced pressure to give a crude purple solid (5.1 g). lH-NMR (DMSO-d6) 5 (ppm): 5.32 (2H, s)5 5.72 (1H, s), 5.86 (2H, bs), 6.07 (1H, d, J = 6.4 Hz), 6·83 ( 2H, s), 7.01 (1H, s), 7·72 (1H, d, J = 6.4 Hz). Example 209 Brom-4-(4-{K-cyclopropylamino)carbonyl 1-amino-bu 3-1-hydrogen hydrazide -2-i-hydrazinylpropane #N-[5-bromo-4-() 4-amino-3-chlorophenoxy)-2-pyridyl]-N1-cyclopropylcarbonyl-1-cyclopropanecarboxamide 67 mg, pyridine 52 mg and dimethyl decylamine 5 ml cooled to 〇弋, then add phenyl chloroformate 54 mg. After 40 minutes, 80 mg of cyclopropanecarbonyl chloride was added and the mixture was placed at 60 ° C for 20 minutes. After returning to room temperature, water was added and extracted with ethyl acetate. The ruthenium gel and the decompression chamber were added to the extraction solution to remove the solvent. The hydrazine gel was fed into a dry column packed with a hydrazine gel, and purified by column chromatography (hexane: ethyl acetate = 1: hydrazine). The sterol was added to the residue to give the title compound as a white solid. lH-NMR (DMSO-d6) (5 (ppm): 0.40 (2H, br s), 0.65 (2H, m), 0.72 (4H, br s), 1.90 (1H, br s), 2.55 (1H, br s), 7.11 (1H, d, J=9.2 Hz), 7.19 (1H, s), 7.38 (1H, s), 7.56 (1H, s), 7.96 (1H, s), 8.22 (1H, d, J =9.2 Hz), 8.42 (1H, s), 10.94 (1H, s) -324 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)&quot;&quot;&quot;&quot;&quot;'' A 1304061 _ _ A7 __- B7 V. Description of the invention (^ -- an intermediate obtained as follows. Production example 209-1 L-amino 2 odor ζΛζ ΑζΜ ^ ^^ - 3- gas hydrazine hydrogen) pyridine 2-Amino-4-(4-amino-3-phenphenoxy)pyridine!·〇g, 氺bromosuccinimide 0·78 g and isopropanol 1〇ml were stirred under reflux for 15 minutes. After returning to room temperature, water is added and extracted with ethyl acetate. The ruthenium gel is added to the extraction solution and the solvent is distilled off under reduced pressure. The ruthenium gel is fed into a dry column packed with ruthenium gel, and Purification by column chromatography (hexane·ethyl acetate = 2:1, and then: 1, and then ethyl acetate) to give the title compound as a brown oil. D6) 5 (pp m): 5·39 (2H, br s), 5.68 (1H, s) 6·06 (2H, br s), 6·85 (1H, s), 6·86 (1H, d, J = 2.4 Hz ), 7.09 (1H, d, J = 2.4 Hz), 7.90 (1H, s). Production Example 209-2 U5-bromoamino-3-f' stupid)-2-pyridinium l-Nl- Mercapto-1 -cyclopropane #醯amine·, in 2-amino-3'&gt; odor-4-(4-amino-3-chlorophenoxy) ρ, 400 mg, triethylamine In a solution of 53 ml and tetrahydrocyanate 5 ml, 260 mg of cyclopropylcarbonyl gas was added at room temperature with stirring. After 40 minutes, the gel was added to the reaction solution and the solvent was distilled off under reduced pressure. The hydrazine gel was fed into a dry column packed with a hydrazine gel, and purified by column chromatography (hexane: ethyl acetate = 2: 1, then 1:1, then ethyl acetate). The objective compound was obtained in 67 mg. lH-NMR (DMSO-d6) 5 (ppm): 0.66-1.00 (8H, m), 1.85-1.96 (2H, m), 5.45 (2H, br s), 6.77 (1H, s)3 6.84 ( 1H, d, J=8.8 Hz), -325 ^ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Invention description (320 6.92 (1H, dd, J=8.8 Ηζ, 2.8 Hz), 7.17 (1H, d, J = 2.8 Hz), 8.66 (lH, s) 〇. _ Example 2 10 This 丄-"(3_^5άchloro-4·丨"(cyclopropylamino)carbonyl 1 Amino-phenoxy oxime 2-pyridyl 1-1-1-cyclopropanecarboxamide in Nl-[4-(4-amino-3,5-dichlorophenoxy)-2 hydrazide-based]- &gt;^1-cyclopropanecarbonyl-1·cyclopropanecarboxamide 96 mg, pyridine 0.076 ml and dimethylformamide 5 ml solution, add phenyl chloroformate 11 () mg at room temperature. After 3 minutes, add 0.5 ml of cyclopropylamine and warm at 70 ° C for 10 minutes. After returning to room temperature, add water and extract with ethyl acetate. Add ♦ gel and subtraction in the extraction solution: distill off The oxime gel is fed into a dry column packed with ruthenium gel and purified by column chromatography (ethyl acetate), and sterol is added to the residue to solidify it. Object of light brown solid 4.8 mg. lH-NMR (DMSO-d6) δ (ppm): 0.42 (2H, s)5 0.57-0.66 (2H, m), 0.70-0.83 (IfH, m), 1.92 -2·01 (1H,m),2.43-2.53 (1H,m), • 6.62 (1H,s),6·71 (1H,d,Hz),7,39,(2H,s), 7.69 ( 1H, s), 7·89 (1H, s), 8.22 (1H, d, J = 5.6 Hz), 10.89 (1H, s). Intermediate was obtained as follows. Production Example 210-1 2-Amine ·4..:(4-Amino-3,5.dichlorooctyloxy) says 2-amino-4-(nonylamino-3-chlorophenoxy)pyridine 7〇〇mg, N-chlorosuccinimide 0.44 g and isopropanol 1 〇mi were stirred at 8 ° C for 1 hour. After returning to room temperature, water was added and extracted with ethyl acetate. And distilling off the solvent under reduced pressure. The ruthenium gel is fed into a drying tube filled with ruthenium gel ____ - 326 - This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 dongdong)--- --- 1304061 - A7 B7 V. Inventive Note (321) Column, and purified by column chromatography (ethyl acetate). Obtained as a brown oil 120 mg 0^-NMR (DMSO-d6) (5 (ppm): 5.47 (2H5 br s)5 5.73 (1H, d, J=2.4 Hz), 5.90 (2H, br s), 6.09 (1H, dd, J = 5.6 Hz, 2·4 Hz), 7.13 (2H, s), 7·75 (1H, d, J = 5.6 Hz). Production Example 210-2 Amino-3,5-II氲茉氲&gt;&gt;-2-pyridyl^Nl-瑷13⁄4淼-l-cyclopropanecarboxamide in 2-amino-4-(4-amino-3,5-dichlorophenoxy a solution of 120 mg of pyridine, 0.19 ml of triethylamine and 5 ml of tetrahydrofuran at room temperature with stirring, adding 93 mg of cyclopropenyl chloride for 20 minutes, adding crushed gel to the reaction solution and reducing The hydrazine gel was fed to a dry column packed with a hydrazine gel and purified by column chromatography (ethyl acetate) to obtain a brown oil 120 mg 〇'H-NMR (D1VISO) -d6) (5 (ppm): 0.82-0.98 (8H, m), 1.86-1.96 (2H, m), 5.55 (2H, br s), 6.95 (1H, dd, J, =5.6 Hz, 2.4 Hz), 7.03 (1H, d, J=2.4 Hz), 7.24 (2H, s)3 8.3 8 (1H, d, J=5.6 Hz). Example 2 1 1 m-cyclopropyl-5-π 2 -丨二(环丙蕤)Amino 1-4-alridinyl} gas)_ 1Η· 吲哚#醯amine in Ν1-cyclopropyl-5 -[(2-Amino-4-t7-butylated)oxy]indoleamine 100 mg and triethylamine 49 mg are dissolved in tetrahydrofuran-depleted solution, and cyclopropenylcarbonyl chloride 51 mg is added thereto under stirring. After a minute, add __-- 327 to the reaction solution. This paper scale applies to the Chinese g standard (CNS) A4 specification (21Gx 297 public) &quot;&quot;&quot; 1304061

五、發明說明（322 ) A7 B7 矽凝膠及減壓餾去溶媒，以使矽凝膠吸著。將該矽凝膠饋 =无填有矽凝膠之乾燥管柱中，以及進行管柱層析精製（己 心·乙酸乙酯=1 : 1 ,繼而乙酸乙酯）。在殘餘物中加入 水’得到為白色固體之目的物19 mg。 H-NMR (DMSO-d6) &lt;5 (ppm): 〇.57^0.63 (2H, m)5 0.68-0.75 (2H，m)，0.83-0.96 (6H，m)，1.86-1.94 (2H，m)，2.73-2.80 ⑽，m)，6.66 (1H，d，J=3.6 Hz)，6·9ΐ (1H，d，卜5 6 Hz)，6 98 UH，d，J=2.4 Hz)，7·08 (1H，dd，J=9.2 Hz，2.4 Hz)，7.41 (1H， d，J=2.4 Hz)，7·87 (1H，d，J=3.6 Hz)，8.26·8·32 (2H，m)，8·38 UH，d，J=5.6 Hz)。 如下述得到中間體。 M 211-1 胺基-4-吡啶基）氧1 - 1 Η- 4丨唤 將2-胺基-4-氯吡啶2.0 g，5- #基啕哚4· lg，氫化鈉 (60°/〇，在油、中）ι·25 g及二甲基甲醯胺2〇 mi於i6〇°C攪拌9.5 小時。加入水及用乙酸乙酯萃取，用矽凝·艰層析（己烷：乙 酸乙酯=1 : 1，繼而乙酸乙酯）精製。將溶媒減壓餾去，在 殘餘物中加入少量乙酸乙酯以及濾取固體。得到淡褐色固 體 490 mg。 ^-NMR (DMSO-d6) 5 (ppm): 5.72 (1H, d, J=2.0 Hz), 5.78 (2H，br s)，6.10 (1H，d，J=5.6 Hz)，6.41 (1H，d，J=2.0 Hz)， 6·82 (1H，d，J=8.4 Hz)，7.25 (1H，s)，7.36-7.44 (2H，m)，7.73 (1H，d，J=5.6 Hz)，11.15 (1H，s)。 · 製造例2 11 - 2 -328 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐〉V. INSTRUCTIONS (322) A7 B7 矽 gel and vacuum distillation to remove the solvent to smear the ruthenium gel. The ruthenium gel was fed into a dry column without a ruthenium gel, and subjected to column chromatography purification (hearts, ethyl acetate = 1 : 1 , followed by ethyl acetate). Water was added to the residue to give the object 19 mg as a white solid. H-NMR (DMSO-d6) &lt;5 (ppm): 〇.57^0.63 (2H, m)5 0.68-0.75 (2H, m), 0.83-0.96 (6H, m), 1.86-1.94 (2H, m), 2.73-2.80 (10), m), 6.66 (1H, d, J = 3.6 Hz), 6·9 ΐ (1H, d, 卜 5 6 Hz), 6 98 UH, d, J = 2.4 Hz), 7 · 08 (1H, dd, J = 9.2 Hz, 2.4 Hz), 7.41 (1H, d, J = 2.4 Hz), 7·87 (1H, d, J = 3.6 Hz), 8.26·8·32 (2H, m), 8·38 UH, d, J = 5.6 Hz). The intermediate was obtained as follows. M 211-1 Amino-4-pyridyl)oxy 1 - 1 Η- 4 将 2-amino-4-chloropyridine 2.0 g, 5-#yl啕哚4· lg, sodium hydride (60°/ 〇, in oil, medium) ι·25 g and dimethylformamide 2〇mi were stirred at i6 ° C for 9.5 hours. Water was added and extracted with ethyl acetate, and purified by EtOAc (EtOAc:EtOAc) The solvent was distilled off under reduced pressure, and a small amount of ethyl acetate was added to the residue and the solid was collected by filtration. Obtained a light brown solid 490 mg. ^-NMR (DMSO-d6) 5 (ppm): 5.72 (1H, d, J = 2.0 Hz), 5.78 (2H, br s), 6.10 (1H, d, J = 5.6 Hz), 6.41 (1H, d , J=2.0 Hz), 6·82 (1H, d, J=8.4 Hz), 7.25 (1H, s), 7.36-7.44 (2H, m), 7.73 (1H, d, J=5.6 Hz), 11.15 (1H, s). · Manufacturing Example 2 11 - 2 -328 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂Binding

線 1304061 〜 A7 B7 五、發明説明（323) N1-環丙基胺基-4-吡啶基）氣1·1Η-1-叫丨哚藉醯胺 在溶解有5-[(2-胺基-4-吡啶基）氧]-1Η- 1-吲哚150 mg之 二甲基甲醯胺中，於室溫下加入氫化鈉（60%，在油中）28 mg並攪拌5分鐘後冷卻至0°C，加入N-環丙基胺基甲酸苯酯 124 mg並揽拌30分鐘。加入水以及用乙酸乙酯萃取。將有 機層用水洗淨3次以及用氯化銨水溶液洗淨1次後，加入碎 凝膠及減壓餾去溶媒。將該矽凝膠饋入充填有碎凝膠之乾 燥管柱中，以及用管柱層析（己烷：乙酸乙酯==1 : 1 ,繼而 乙酸乙酯）精製。得到2·4 g無色粉末。 lH-NMR (DMSO-d6) 5 (ppm): 0.57-0.64 (2H5 m)5 0.68-0.76 (2H, m), 2.72-2.79 (1H, m), 5.74 (1H, d, J=2.4 Hz), 5.83 (2H5 br s)5 6.12 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.64 (1H, d, J=3.6 Hz), 7.01 (1H, dd, J=9.2 Hz, 2.4 Hz)5 7.32 (1H, d, J=2.4 Hz), 7.75 (1H, d, J—5.6 Hz), 7.84 (1H, d, J=3.6 Hz), 8.24 (1H s) 8·25 (1H，d，.J=9.2 Hz)。 ’ 實施例212 ' Nl -環丙基-5-(丨2- 環丙羰基）胺某1 - 4-毗畦卷丨氣）· 1H_卜 4哚瘦醯胺 將犯-環丙基-5-({2-[二（環丙羰基）胺基]_4_吡啶基}氧）· 1H-1 - Η卜木&amp;龜胺190 mg，氯化铵660 mg，二甲基甲酿胺5 ml，水5 ml及乙醇5 ml於100°C攪掉1小時。加入水及乙酸 乙酯並萃取，然後用水洗淨6次。用硫酸鎂乾燥，濾去乾燥 劑後減壓館去溶媒。在殘餘物中加入乙-·酸乙酯使之固化及 濾取。得到白色粉末66 mg。Line 1304061 ~ A7 B7 V. Description of the invention (323) N1-cyclopropylamino-4-pyridyl) gas 1·1Η-1- 丨哚 丨哚 醯 醯 在 在 在 在 在 在 在 在 在4-pyridyl)oxy]-1Η- 1-吲哚 150 mg of dimethylformamide, sodium hydride (60% in oil) 28 mg was added at room temperature and stirred for 5 minutes and then cooled to 0. At ° C, 124 mg of N-cyclopropylaminocarbamate was added and stirred for 30 minutes. Water was added and extracted with ethyl acetate. The organic layer was washed three times with water and once with an aqueous solution of ammonium chloride, and then the gel was added and the solvent was distilled off under reduced pressure. The hydrazine gel was fed into a dry column packed with a pulverized gel, and purified by column chromatography (hexane: ethyl acetate = 1:1, followed by ethyl acetate). 2,4 g of a colorless powder was obtained. lH-NMR (DMSO-d6) 5 (ppm): 0.57-0.64 (2H5 m)5 0.68-0.76 (2H, m), 2.72-2.79 (1H, m), 5.74 (1H, d, J=2.4 Hz) , 5.83 (2H5 br s)5 6.12 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.64 (1H, d, J=3.6 Hz), 7.01 (1H, dd, J=9.2 Hz, 2.4 Hz)5 7.32 (1H, d, J = 2.4 Hz), 7.75 (1H, d, J - 5.6 Hz), 7.84 (1H, d, J = 3.6 Hz), 8.24 (1H s) 8·25 (1H, d,. J = 9.2 Hz). 'Example 212 'Nl -cyclopropyl-5-(indol-2-cyclopropylcarbonyl)amine 1 - 4-pyrene oxime) · 1H_b 4 哚 醯 醯 将 环 -cyclopropyl-5 -({2-[bis(cyclopropylcarbonyl)amino]]4_pyridinyl}oxy)· 1H-1 - eucalyptus &amp; melamine 190 mg, ammonium chloride 660 mg, dimethyl ketoamine 5 5 ml of water, 5 ml of water and 5 ml of ethanol were stirred at 100 ° C for 1 hour. Water and ethyl acetate were added and extracted, and then washed 6 times with water. Dry with magnesium sulfate, filter off the desiccant and remove the solvent from the decompression chamber. Ethyl ethyl acetate was added to the residue to solidify and filter. A white powder of 66 mg was obtained.

裝 訂Binding

線 -329 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公爱） 1304061Line -329 - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 public) 1304061

AT ____B7 ___ 五、發明説明（324 ) 'H-NMR (DMSO-d6) (5 (ppm): 0.57-0.64 (2H, m)) 〇.66-0.78 (6H, m), 1.88-1.98 (1H, m), 2.72-2.80 (1H3 m)? 6.63-6.69 (2H，m)，7.04 (1H，d，J=8.8 Hz)，7·36 (1H，s)，7 56 (1H，s)， 7·87 (1H，d，J=3.6 Hz)，8.14 (1H，d，J=5.6 Hz)，8 26 (1H，d， J=8.8 Hz)，8.28 (1H，s)，10.55 (1H，s)。 實施例2 1 3AT ____B7 ___ V. INSTRUCTIONS (324 ) 'H-NMR (DMSO-d6) (5 (ppm): 0.57-0.64 (2H, m)) 〇.66-0.78 (6H, m), 1.88-1.98 (1H , m), 2.72-2.80 (1H3 m)? 6.63-6.69 (2H,m),7.04 (1H,d,J=8.8 Hz),7·36 (1H,s),7 56 (1H,s), 7·87 (1H,d,J=3.6 Hz), 8.14 (1H,d,J=5.6 Hz), 8 26 (1H,d, J=8.8 Hz), 8.28 (1H, s), 10.55 (1H, s). Example 2 1 3

Nl-%：丙基-5 -丨 f2v(2,5 -二酮某四 fc-1 Η1 洛某）* 4· ?比淀 基1乳丨- 丨嗓我酿胺（實施例213 - A) N1 - 3衣丙基-5 - {「2-(二乙酿胺基）-4- π比淀基丄氢^ n 1 _ g弓丨嗓 羧醯胺（皆施钏213-B) N1-環丙摹-5- Π 2·(乙酿脸幕、-4_ 口比咬基Ί氧} - iH-1- Θ卜朵藉 醯胺（實施例213-C) 將N1-環丙基-5-[(2-胺基-4-吡啶基）氧]-1H-卜峭哚羧醯 胺830 mg，琥珀酸酐270 mg及甲苯30 ml回流30分鐘。在該 反應溶液中1口入乙酸酐50 ml及乙酸鈉82 mg並於80°C攪拌 15分鐘。將溶媒減壓餾去，將殘餘物用多^凝膠層析（乙酸乙 酯）精製。第2個被溶出者為N1-環丙基-5-{[2-(2,5-二酮基 四氫-1 Η- 1 -吡咯基）-4-吡啶基]氧} - 1H- ：! - 4哚羧醯胺β得 到無色粉末440 mg。 (實施例213-A) ^-NMR (DMSO-d6) 5 (ppm): 0.57-0.63 (2H, m), 0.70-0.75 (2H，m)，2.70-2.80 (1H，m)，2·71 (4H，s)，6.66 (1H，d，J=3.6Nl-%: propyl-5-丨f2v (2,5-dione, a certain four fc-1 Η1 洛)* 4· 比 基 1 丨 丨 - 丨嗓 酿 酿 (Example 213 - A) N1 - 3 propyl-5 - {"2-(diethylamino)-4- π ratio 丄 丄 hydrogen ^ n 1 _ g 丨嗓 carboxy carbamide (both 钏 213-B) N1- Cyclopropanil-5- Π 2·(B, -4, -4, -4, -4, -4, -4, -4, -4, -4, Ί, Ί, Ί, Ί, Ί, Ί, }, }, }, }, N, N -[(2-Amino-4-pyridyl)oxy]-1H-b-glycolcarboxamide 830 mg, succinic anhydride 270 mg and toluene 30 ml were refluxed for 30 minutes. Into the reaction solution, acetic anhydride 50 was added in one portion. Mol and sodium acetate 82 mg were stirred at 80 ° C for 15 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by chromatography (ethyl acetate). The second was dissolved by N1-cyclopropane. 5-5-{[2-(2,5-dionetetrahydro-1 Η-1 -pyrrolidinyl)-4-pyridyl]oxy} - 1H- :! - 4 carboxy carbamide 得到β gives a colorless powder 440 mg. (Example 213-A) ^-NMR (DMSO-d6) 5 (ppm): 0.57-0.63 (2H, m), 0.70-0.75 (2H, m), 2.70-2.80 (1H, m), 2·71 (4H, s), 6.66 (1H, d, J=3.6

Hz)，6·76 (1H，d，J=2.4 Hz)，7.03 (1H，dd，J二5.6 Hz，2.4 Hz)， 7.10 (1H, dd, J=9.2 Hz, 2.4 Hz), 7.43 (1H, d, J=2.4 Hz), 7.87 -330 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐)Hz),6·76 (1H,d,J=2.4 Hz), 7.03 (1H, dd, J 5.6 Hz, 2.4 Hz), 7.10 (1H, dd, J=9.2 Hz, 2.4 Hz), 7.43 (1H , d, J=2.4 Hz), 7.87 -330 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

訂Order

線 1304061 … A7 ____B7___ 一 五、發明説明（325 ) (1H，d，J=3.6 Hz)，8,29 (1H，s)，8·30 (1H，d，J=9.2 Hz), 8.42 (1H，d，J=5.6 Hz)。 • 第1個被溶出者為N1 -環丙基-5 - {[ 2-(二乙醯胺基）_ ‘咐 啶基]氧} - 1Η-1-吲哚幾醯胺與Ν1-環丙基- {[2-(乙醯胺 基）-4- ρ比嗓基]氧} -1 η- 1 - 嗓致酿胺之混合物。將該丨昆合 物用碎凝膠層析（氯仿··甲醇==5 0 : 1)精製。最初被溶出者 為Ν1-環丙基-5 - { [2-(二乙醯胺基）-4-吡啶基]氧卜1Η- 1叫丨 哚羧醯胺。得到45 mg白色粉末 (實施例213-B) W-NMR (DMSO-d6) 5 (ppm): 0.57-0.63 (2H，m)，〇.70-0.75 (2H，m)，2·13 (6H，s)，2.74-2.80 (1H，m)，6·66 (1H，d，J=3.6Line 1304061 ... A7 ____B7___ 1-5, invention description (325) (1H, d, J = 3.6 Hz), 8, 29 (1H, s), 8 · 30 (1H, d, J = 9.2 Hz), 8.42 (1H , d, J = 5.6 Hz). • The first dissolved is N1 -cyclopropyl-5 - {[ 2-(diethylguanidinyl)_ 'acridinyl]oxy} - 1Η-1-吲哚 醯 醯 and Ν 1-cyclopropyl Base - a mixture of {[2-(ethylamino)-4- ρ hydrazino]oxy} -1 η- 1 - hydrazine. The guanidine complex was purified by gel-gel chromatography (chloroform·methanol ==50:1). The initial dissolution was Ν1-cyclopropyl-5 - {[2-(diethylammonium)-4-pyridyl)oxybenzoquinone-1 丨 哚 carboxy carbamide. Obtained 45 mg of white powder (Example 213-B) W-NMR (DMSO-d6) 5 (ppm): 0.57-0.63 (2H, m), 〇.70-0.75 (2H, m), 2·13 (6H , s), 2.74-2.80 (1H, m), 6.66 (1H, d, J = 3.6

Hz), 6.96 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.99 (1H, d, J=2.4 Hz), 7.09 (1H，dd，J=9.2 Hz, 2.4 Hz)，7.43 (1H，d，J=2.4 Hz)，7.87 (1H, d, J=3.6 Hz), 8.28 (1H, s), 8.30 (1H, d, J=9.2 Hz), 8.38 (1H，d，J=5T6 Hz)。 第2個被溶出者為Nl -環丙基-5- { [2-( i醯胺基）-4-吡啶 基]氧} - 1H- 1-吲哚羧醯胺。從乙酸乙酯及己烷中固體化， 得到28 mg β (實施例213-C) lH-NMR (DMSO-d6) (5 (ppm): 0.57-0.63 (2H, m), 0.70-0.75 (2H, m), 2.00 (3H, s), 2.72-2.80 (1H, m), 6.62 (1H, d, J=5.6Hz), 6.96 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.99 (1H, d, J=2.4 Hz), 7.09 (1H, dd, J=9.2 Hz, 2.4 Hz), 7.43 (1H, d , J = 2.4 Hz), 7.87 (1H, d, J = 3.6 Hz), 8.28 (1H, s), 8.30 (1H, d, J = 9.2 Hz), 8.38 (1H, d, J = 5T6 Hz). The second dissolved was Nl-cyclopropyl-5-{[2-(i-amino)-4-pyridyl]oxy}-1H- 1-indolecarboxamide. Solidified from ethyl acetate and hexane to give 28 mg (Example 213-C) lH-NMR (DMSO-d6) (5 (ppm): 0.57-0.63 (2H, m), 0.70-0.75 (2H , m), 2.00 (3H, s), 2.72-2.80 (1H, m), 6.62 (1H, d, J=5.6

Hz，2.4 Hz), 6·65 (1H，d，J=3.6 Hz)，7.04 (1H，dd，J=9.2 Hz， 2.4 Hz)，7.36 (1H，d，J=2.4 Hz)，7·60 (ΪΗ，s)，7.87 (1H，d， J=3.6 Hz), 8.13 (1H, d, J=9.2 Hz), 8.25-8.30 (2H, m), 10.47 -331 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公爱） 1304061 A7 Β7· 五、發明説明（326 ) (1H，十 實施例214 Μ1ζ,·¥丙基〇二乙胺某]蕤某}胺基)· 4·吡啶甚1 氲} - 1H- 1-吲哚4¾—醯胺 將N1-環丙基-5_[(2·胺基·‘吡啶基）氧]·丨沁^吲哚羧醯 胺400 mg ’異氰酸2·氯乙酯150 mg及四氫呋喃5 nU,於80 C授摔1 ·5小時。回到室溫後，加入矽凝膠及減壓餾去溶 媒°將琢碎凝膠饋入充填有矽凝膠之乾燥管柱中，以及用 管柱層析（己垸：乙酸乙酯: 1，繼而乙酸乙酯）精製。得 到280 mg無色粉末。 H-NMR (DMSO-d6) δ (ppm): 0.57-0.63 (2H，m)，0.70-0.75 (2H，m)，2.73·2·80 (1H，m)，3.42 (2H，q，J=6.0 Hz)，3·61 (2H， t，J=6.0 Hz)，6·52 (1H，dd，J=5.6 Hz，2·4 Hz)，6·65 (1H，d， J=3.6 Hz), 6.85 (1H? d, J=2.4 Hz), 7.04 (1H3 dd, J=8.8 Hz 2.4 Hz), 7.?5 (1H, d, J=2.4 Hz), 7.86 (1H, d, J=3.6 Hz), 8.04 (1H, d5 J=5.6 Hz), 8.27 (1H, s), 8.28 (1H, 3, J=8.8 Hz), 8.34 (1H，bi: s)，9.19 (1H，s) e 實施例2 1 5 ^二(2-氟乙基）-5-({2-丨（環丙羰基）脖11-4-毗啶^^^ 1 Η- 1 - 4丨嗓義酿胺 在溶解有Ni-(2-氟乙基）-5-[(2-胺基-4-毗啶基）氧卜1;^ 1-吲哚羧醯胺400 mg及三乙胺0.53 ml之四氫呋喃溶液中， 於室溫加入環丙羰基氯330 mg。攪拌15分鐘後，回到宣溫 後，加入水及乙酸乙酯並萃取。將萃取液用硫酸鍰乾燥^ , -332 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）Hz, 2.4 Hz), 6·65 (1H, d, J=3.6 Hz), 7.04 (1H, dd, J=9.2 Hz, 2.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.60 (ΪΗ, s), 7.87 (1H, d, J = 3.6 Hz), 8.13 (1H, d, J = 9.2 Hz), 8.25-8.30 (2H, m), 10.47 -331 This paper scale applies to Chinese national standards ( CNS) A4 specification (210 x 297 public) 1304061 A7 Β7· V. Description of invention (326) (1H, ten embodiment 214 Μ1ζ, · propyl hydrazine diethylamine) 蕤 } an amine) · 4· Pyridine 1 氲} - 1H- 1-吲哚43⁄4 - decylamine N1-cyclopropyl-5_[(2.amino]'pyridyl)oxy]·丨沁^吲哚carboxamide 400 mg Cyanate 2·chloroethyl ester 150 mg and tetrahydrofuran 5 nU were dropped at 80 C for 1.5 hours. After returning to room temperature, the ruthenium gel was added and the solvent was distilled off under reduced pressure. The mashed gel was fed into a dry column packed with ruthenium gel and chromatographed with column chromatography (hexane: ethyl acetate: 1 , then ethyl acetate) refined. 280 mg of a colorless powder was obtained. H-NMR (DMSO-d6) δ (ppm): 0.57-0.63 (2H, m), 0.70-0.75 (2H, m), 2.73·2·80 (1H, m), 3.42 (2H,q,J= 6.0 Hz), 3·61 (2H, t, J=6.0 Hz), 6·52 (1H, dd, J=5.6 Hz, 2·4 Hz), 6·65 (1H, d, J=3.6 Hz) , 6.85 (1H? d, J=2.4 Hz), 7.04 (1H3 dd, J=8.8 Hz 2.4 Hz), 7.?5 (1H, d, J=2.4 Hz), 7.86 (1H, d, J=3.6 Hz), 8.04 (1H, d5 J=5.6 Hz), 8.27 (1H, s), 8.28 (1H, 3, J=8.8 Hz), 8.34 (1H, bi: s), 9.19 (1H, s) e Implementation Example 2 1 5 ^ bis(2-fluoroethyl)-5-({2-丨(cyclopropylcarbonyl) neck 11-4-pyridinyl^^^ 1 Η- 1 - 4 丨嗓 酿 胺 在Ni-(2-fluoroethyl)-5-[(2-amino-4-pyridyl)oxybenzoate 1; ^ 1-indolecarboxamide 400 mg and triethylamine 0.53 ml in tetrahydrofuran solution, Add 330 mg of cyclopropylcarbonyl chloride at room temperature. After stirring for 15 minutes, return to Xuanwen, add water and ethyl acetate and extract. The extract is dried with barium sulfate. -332 - This paper scale applies to Chinese national standards. (CNS) A4 size (210 X 297 mm)

裝 訂Binding

線 1304061 二 … Λ7 . _________ Β7 五、發明説明（327 ) 繼而通過塗敷NH型矽凝膠之玻璃濾器。減壓餾去溶媒，得 到490 mg油狀物。在該殘餘物中，加入氯化銨，二甲 基甲酿胺10 ml，水10 ml及乙醇1〇 mi，並於ll〇°C攪拌15 小時。回到室溫後，加入水及用乙酸乙酯萃取。在萃取溶 液中加入矽凝膠及減壓餾去溶媒，以吸著於矽凝膠上。將 該矽凝膠饋入充填有矽凝膠之乾燥管柱中，以及進行管柱 層析精製（乙酸乙醋）。在殘餘物中加入乙酸乙醋及己燒使 之固體化，得到為白色固體之目的物丨8〇 mg。 ^-NMR (DMSO-d6) (5 (ppm): 0.64-0.80 (4H, m), 1.88-1.97 (1H，m)，3·50-3·65 (2H，m)，4·52 (1H，t，J=4.8 Hz)，4·64 (1H， t，J=4.8 Hz), 6·65 (1H，dd，J=5.6 Hz，2.4 Hz)，6.69 (1H，d， J=3.6 Hz), 7.05 (1H, dd, J-8.8 Hz, 2.4 Hz), 7.38 (1H, d, J=2.4 Hz), 7.57 (1H5 d, J=2.4 Hz), 7.95 (1H5 d, J=3.6 Hz), 8.14 (1H，d，J=5.6 Hz)，8·27 (1H，d，J=8.8 Hz)，8·47 (1H，t， J=5.6 Hz)，ΤΌ·77 (1H，s)。 如下述得到中間體。 '、 製造例215-1Line 1304061 II ... Λ7. ______ Β7 V. Inventive Note (327) This is followed by application of a glass filter of NH-type enamel gel. The solvent was evaporated under reduced pressure to give 490 mg of oil. To the residue, ammonium chloride, 10 ml of dimethylamine, 10 ml of water and 1 〇m of ethanol were added, and stirred at ll ° C for 15 hours. After returning to room temperature, water was added and extracted with ethyl acetate. A ruthenium gel was added to the extraction solution and the solvent was distilled off under reduced pressure to adsorb on the ruthenium gel. The ruthenium gel was fed into a dry column packed with a ruthenium gel, and subjected to column chromatography (acetic acid acetate). Ethyl acetate was added to the residue and the mixture was evaporated to give a white solid. ^-NMR (DMSO-d6) (5 (ppm): 0.64-0.80 (4H, m), 1.88-1.97 (1H, m), 3·50-3·65 (2H, m), 4·52 (1H ,t,J=4.8 Hz),4·64 (1H, t,J=4.8 Hz), 6·65 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.69 (1H, d, J=3.6 Hz) ), 7.05 (1H, dd, J-8.8 Hz, 2.4 Hz), 7.38 (1H, d, J=2.4 Hz), 7.57 (1H5 d, J=2.4 Hz), 7.95 (1H5 d, J=3.6 Hz) , 8.14 (1H, d, J = 5.6 Hz), 8.27 (1H, d, J = 8.8 Hz), 8.47 (1H, t, J = 5.6 Hz), ΤΌ·77 (1H, s). The intermediate was obtained as follows. ', Manufacturing Example 215-1

Nl-m乙_基）-5-「胺某比啶某）氣卜1H_ ^㈣哚崧醯 ϋ. 在5-[(2-胺基-4-吡啶基）氧卜1Η-1 •峭哚2 〇 g溶於二甲基 甲醯胺30 ml之溶液中，於室溫下加入氫化鈞（6〇%，在油 中）360 mg。攪拌5分鐘後，在冰浴冷卻下，加入N-(2-氟乙 基）胺基甲酸苯酯1.8 g。回到室溫及攪拌3〇分鐘後，加入水 及用乙酸乙酯萃取。使該萃取液通過塗敷矽凝膠之玻璃濾 -333 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐；Γ --- ' 1304061Nl-m B-yl)-5-"amine some than pyridine" gas Bu 1H_ ^ (four) 哚嵩醯ϋ. In 5-[(2-amino-4-pyridyl)oxybu 1Η-1 • 哚2 〇g is dissolved in dimethylformamide 30 ml solution, add hydrazine hydride (6 〇% in oil) 360 mg at room temperature. After stirring for 5 minutes, add N- while cooling in an ice bath. (2-fluoroethyl) phenyl carbamate 1.8 g. After returning to room temperature and stirring for 3 minutes, water was added and extracted with ethyl acetate. The extract was passed through a glass-coated glass filter-333 - This paper size applies to the Chinese National Standard (CNS) Α 4 specification (210 X 297 mm; Γ --- ' 1304061

器。、將如此得到之乙酸乙酯層用碳酸氫鈉水溶液洗淨丨次及 用硫酸鎂乾燥。濾去乾燥劑，得到微褐色粉末193g。 H-NMR (DMSO-d6) 5 (ppm): 3.52-3.64 (2H，m)，4.52 (1H，t， J=4.8 Hz), 4.64 (1H, t, J=4.8 Hz), 5.75 (1H, d, J=2.4 Hz), 5.82 (2H，br s)，6.12 (1H，dd，J=5.6 Hz，2.4 H2)，6·68 (1H，d， J=3.6 Hz), 7.02 (1H, dd5 J=8.8 Hz, 2.4 Hz), 7.33 (1H,. d, J=2.4 Hz)，7·76 (1H，d，J=5.6 Hz)，7.92 (1H，d，J=3.6 Hz)， 8·26 (1H，d，J=8.8 Hz)，8·44 (1H，t，J=5.2 Hz)。 實施例21 6基丄氧卜1 Η-1 - θ卜朵# gj脸 在落解有5 - (4- { [2- (2-酮基四氫-1H- 1-吡咯基卜4-吡淀基] 氧} - 1H-1-啕哚130 mg之二甲基甲醯胺溶液中，於室溫下加 入氫化鈉（60%，在油中）19 mg，繼而加入N-環丙基胺基甲 本酯8 2垃名。授拌10分鐘後，加入水以及用乙酸乙醋萃 取。在萃取液中加入水以及用乙酸乙酯萃取。在萃取溶液 中加入矽凝膠及減壓餾去溶媒，以吸著於矽凝膠上。將該 矽凝膠饋入充填有矽凝膠之乾燥管柱中，以及進行管柱層 析精製（己燒·乙酸乙醋=1 : 1 ’繼而乙酸乙g旨）。在殘餘物 中加入乙酸乙g旨及己垸以使之固體化，得到為白色固體之 目的物25 mg。 ]H-NMR (DMSO-d6) 5 (ppm): 0.58-0.63 (2H, m), 0.68-0.75 (2H, m), 1.97 (2H, tt, J=6.4 Hz, 6.4 Hz)； 2.47 (2H, t, J=6.4 Hz)，2·73-2·80 (1H，m)，3.94 (2H，t，J=6.4 Hz)，6·65 (1H，d， -334 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）Device. The ethyl acetate layer thus obtained was washed with a sodium hydrogencarbonate aqueous solution and dried over magnesium sulfate. The desiccant was filtered off to give 193 g of a brown powder. H-NMR (DMSO-d6) 5 (ppm): 3.52-3.64 (2H, m), 4.52 (1H, t, J = 4.8 Hz), 4.64 (1H, t, J = 4.8 Hz), 5.75 (1H, d, J=2.4 Hz), 5.82 (2H, br s), 6.12 (1H, dd, J=5.6 Hz, 2.4 H2), 6.68 (1H, d, J=3.6 Hz), 7.02 (1H, dd5 J=8.8 Hz, 2.4 Hz), 7.33 (1H,. d, J=2.4 Hz), 7·76 (1H,d,J=5.6 Hz), 7.92 (1H,d,J=3.6 Hz), 8· 26 (1H, d, J = 8.8 Hz), 8.44 (1H, t, J = 5.2 Hz). Example 21 6 丄 丄 卜 1 Η - - - - - g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g Addition of sodium hydride (60% in oil) to 19 mg, followed by the addition of N-cyclopropylamine, in an aqueous solution of oxa}-1H-1-indole 130 mg in dimethylformamide After the mixture was stirred for 10 minutes, water was added and extracted with ethyl acetate. Water was added to the extract and extracted with ethyl acetate. The hydrazine gel was added to the extraction solution and distilled off under reduced pressure. The solvent is adsorbed on the ruthenium gel. The ruthenium gel is fed into a dry column packed with ruthenium gel, and subjected to column chromatography purification (hexane, acetic acid ethyl acetate = 1 : 1 ' and then acetic acid B. The addition of ethyl acetate to the residue was carried out to solidify to give the title compound as a white solid 25 mg.]H-NMR (DMSO-d6) 5 (ppm): 0.58-0.63 (2H, m), 0.68-0.75 (2H, m), 1.97 (2H, tt, J=6.4 Hz, 6.4 Hz); 2.47 (2H, t, J=6.4 Hz), 2·73-2·80 ( 1H,m),3.94 (2H,t,J=6.4 Hz),6·65 (1H,d, -334 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm)

裝 訂Binding

線 1304061 A7 B7 五、發明説明（329) j=3.6 Hz), 6.71 (1H, dd, J=5.6 Hz, 2.4 Hz), 7.04 (1H3 dd, j=8.8 Hz, 2..4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.81 (1H, d, J=2.4Line 1304061 A7 B7 V. Description of invention (329) j=3.6 Hz), 6.71 (1H, dd, J=5.6 Hz, 2.4 Hz), 7.04 (1H3 dd, j=8.8 Hz, 2..4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.81 (1H, d, J=2.4

Hz)，7·86 (1H，d，J=3.6 Hz)，8.22 (1H，d，J=5.6 Hz)，8.27 (1H， br s)，8·28 (1H，d，J=8.8 Hz)。 如下述得到中間體。 i告例 2 1 6 _ 1 hXlr { _基四輯,〗·吡咯某毗啶某·j氲1Η· —1 - 4 哚 在N1-環丙基-5-[(2-胺基-4-吡啶基）氧]-1H-1-峋哚羧醯 胺1 ·0 g，二乙胺1 · 1 ml及四氫咳喃20 ml溶液中，於室溫加 入4-溴丁基氯0.8 ml。攪拌20分鐘後，加入水及用乙酸乙酯 萃取。將萃取液通過塗敷矽凝膠之玻璃濾器。在如此得到 之油狀物中，加入4-羥基六氫吡啶95〇 mg，碳酸鉀丨.7 g及 二甲基甲醯胺10 ml，並於70°C攪拌20分鐘。加入水及用乙 酸乙酯萃取&quot;，在萃取溶液中加入矽凝膠及減壓餾去溶媒， 以吸著於矽凝膠上。將該矽凝膠饋入充瑱有矽凝膠之乾燥 管柱中，以及進行管柱層析精製（己烷··乙酸乙酯=1 : 1， 繼而乙酸乙醋）。最初被溶出者為目的物。得到13 0 mg白色 固體。 'H-NMR (DMSO-d6) δ (ppm): 1.97 (2H, tt, J=6.4 Hz, 6.4 Hz), 2.46 (2H, t, J=6.4 Hz), 3.93 (2H, t, J=6.4 Hz), 6.42 (1H, s), 6.66 (1H, d3 J=5.6 Hz), 6.85 (1H, d, J=8.8 Hz), 7.29 (1H, s), 7.42 (1H, s), 7.44 (1H, d, J=8.8 Hz), 7.8Ό (1H, s), 8.18 (1H, d，J=5.6 Hz)，11·05 (1H，s)。 _ - 335 - 本紙張尺度遴用中國國家標準(CNS) A4規格（210 x 297公釐） 裝 訂Hz),7·86 (1H,d,J=3.6 Hz), 8.22 (1H,d,J=5.6 Hz), 8.27 (1H, br s),8·28 (1H,d,J=8.8 Hz) . The intermediate was obtained as follows. i 告例2 1 6 _ 1 hXlr { _ base four series, 〗 〖pyrrole a certain pyridyl · j氲1 Η · — 1 - 4 哚 in N1-cyclopropyl-5-[(2-amino-4- Pyridyl)oxy]-1H-1-indolecarboxamide 1 · 0 g, diethylamine 1 · 1 ml and tetrahydrogenethane 20 ml solution, 0.8 ml of 4-bromobutyl chloride was added at room temperature. After stirring for 20 minutes, water was added and extracted with ethyl acetate. The extract was passed through a glass filter coated with a gel. To the oil thus obtained, 4-hydroxyhexahydropyridine 95 mg, potassium carbonate 丨.7 g and dimethylformamide 10 ml were added, and stirred at 70 ° C for 20 minutes. Water was added and extracted with ethyl acetate. The hydrazine gel was added to the extraction solution and the solvent was distilled off under reduced pressure to absorb the hydrazine gel. The ruthenium gel was fed into a dry column packed with a ruthenium gel, and subjected to column chromatography purification (hexane·ethyl acetate = 1: 1, followed by ethyl acetate). The person who was originally dissolved was the target. This gave 130 mg of a white solid. 'H-NMR (DMSO-d6) δ (ppm): 1.97 (2H, tt, J=6.4 Hz, 6.4 Hz), 2.46 (2H, t, J=6.4 Hz), 3.93 (2H, t, J=6.4 Hz), 6.42 (1H, s), 6.66 (1H, d3 J=5.6 Hz), 6.85 (1H, d, J=8.8 Hz), 7.29 (1H, s), 7.42 (1H, s), 7.44 (1H , d, J = 8.8 Hz), 7.8 Ό (1H, s), 8.18 (1H, d, J = 5.6 Hz), 11.05 (1H, s). _ - 335 - This paper is sized with Chinese National Standard (CNS) A4 size (210 x 297 mm)

線 1304061 _ A7 _____B7 __ 五、發明説明（330^ ' 第2個被溶出者為5- [(2- {[ 4- (4-羥基六氫吡啶基）丁醯基] 胺基卜4-吡啶基）氧]4哚。得到52〇 mg&amp;褐色油狀物。 W-NMR (DMS〇-d6) 5 (ppm): 1.25-1.35 (2H，m)，1.55-1.67 (4H, m), 1.85-1.95 (2H, m), 2.17 (2H, t, J=6.8 Hz), 2.28 (2H? t, J=6.8 Hz), 2.57-2.67 (2H, m), 3.15 (1H, d, J=3.6 Hz), 3.30-3.42 (1H，m)，4.48 (1H，d，J=3.6 Hz)，6.42 (1H，s)，6.57 (1H，dd，J=5.6 Hz，2.4 Hz)，6·85 (1H，dd，J=8.8 Hz，2.4 Hz)， 7.29 (1H，d，J=2.4 Hz)，7.40-7.43 (2H，m)，7·60 (1H，d，J=2.4 Hz)，8.09 (1H，d，Hz)，1〇·37 (1H，s)，11.23 (1H，s)。 實施例217 1^_(心『6-贰基-7-(3'二乙胺丙氧某&gt;)_4_喹味氫1_2_氣苯某）-3-(4-氣芙某）胧 將6-氰基-4-{4-[4-氟苯胺羰基]胺基氟苯氧基}喹啉-7_醇鈉鹽480 mg溶於二曱基甲醯胺5 mi ,加入碳酸鉀35〇 mg及3-氯疔二乙胺204 mg ,並於65它加熱攪拌7小時。放 冷後加入水，用乙酸乙酯及四氫呋喃萃、取，減壓餾去溶 媒，將殘餘物用NH矽凝膠層析（乙酸乙酯-甲酵系）精製， 得到135 mg標題化合物。 h-NMR 光譜（DMSO-d6)5(ppm): 〇·96 (6H，t J=7〇 Hz) 1.93 (2H, quint, J=7.0 Hz), 2.45-2.53 (4H, m)&gt; 2.61 (2H t J=7.0 Hz)，4·32 (2H，t，J=7.0 Hz)，6.62 (ih，d，J=5 3 Hz) 7.10-7.19 (3H，m)，7.41 (1H，dd，J=12.3 Hz，Γ=2·8 Hz)， 7.46-7.52 (2H, m), 7.60 (1H, s)5 8.25 (1H3 t, J=9.〇 Hz), 8.68 (1H，d，J=2.0 Hz)，8·76-8·78 (2H，m)，9.16 (ih，s)。 ’ -336 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) ' ------ 1304061Line 1304061 _ A7 _____B7 __ V. Description of the invention (330^ ' The second dissolved is 5-[(2- {[ 4- (4-hydroxyhexahydropyridyl)butanyl]amino-4-pyridyl) Oxygen] 4 哚. Obtained 52 〇 mg &amp; brown oil. W-NMR (DMS 〇-d6) 5 (ppm): 1.25-1.35 (2H, m), 1.55-1.67 (4H, m), 1.85-1.95 (2H, m, 2.17 (2H, t, J=6.8 Hz), 2.28 (2H? t, J=6.8 Hz), 2.57-2.67 (2H, m), 3.15 (1H, d, J=3.6 Hz) , 3.30-3.42 (1H, m), 4.48 (1H, d, J = 3.6 Hz), 6.42 (1H, s), 6.57 (1H, dd, J = 5.6 Hz, 2.4 Hz), 6.85 (1H, Dd, J = 8.8 Hz, 2.4 Hz), 7.29 (1H, d, J = 2.4 Hz), 7.40-7.43 (2H, m), 7·60 (1H, d, J = 2.4 Hz), 8.09 (1H, d, Hz), 1〇·37 (1H, s), 11.23 (1H, s). Example 217 1^_(heart "6-mercapto-7-(3'diethylaminepropoxy)&gt; _4_ 苯味氢1_2_气苯苯)-3-(4-气芙) 66-Cyano-4-{4-[4-fluoroanilinecarbonyl]aminofluorophenoxy}quinoline- 7-alcohol sodium salt 480 mg was dissolved in dimercaptocarhamamine 5 mi, and 35 mg of potassium carbonate and 204 mg of 3-chloroindole diethylamine were added, and the mixture was stirred under heating for 7 hours at 65. After cooling, water was added. Ethyl acetate and four The title compound was purified by EtOAc (EtOAc-EtOAc). Ppm): 〇·96 (6H, t J=7〇Hz) 1.93 (2H, quint, J=7.0 Hz), 2.45-2.53 (4H, m)&gt; 2.61 (2H t J=7.0 Hz), 4· 32 (2H, t, J = 7.0 Hz), 6.62 (ih, d, J = 5 3 Hz) 7.10-7.19 (3H, m), 7.41 (1H, dd, J = 12.3 Hz, Γ = 2·8 Hz ), 7.46-7.52 (2H, m), 7.60 (1H, s)5 8.25 (1H3 t, J=9.〇Hz), 8.68 (1H,d,J=2.0 Hz),8·76-8·78 (2H,m), 9.16 (ih, s). ’ -336 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) ' ------ 1304061

如下述合成中間體 製造例217 J - [ 7- 基）脲 在製造例8得到之7_节氧基-6-氰基-4-(3·氟4胺基苯氧 基）喹啉6·95 g中，加入甲苯210 ml及乙腈20 ml ,並加熱回 /；，ϋ在其中’加入異氰酸4-氟苯酯2.67 ml，並加熱回流！小 時。放冷後，遽取析出之固體及減壓乾燥，得到標題化合 物 7.45 g。 lH-NMR 光譜（DMSO-d6)5(ppm): 5·49 (2H，s)，6·61 (1H，d， J=5.4 Hz)，7·05-7·57 (11H，m)，7.54 (1H，s)，8·24 (1H，t，9·5 Hz), 8.63 (1H, s), 8.72 (1H, d, J=5.4 Hz), 8.77 (1H, s)5 9.10 (1H，S)。 製造例217-2 氰基- 4-(本「4-氟茉胺蕤某l胺某-3-氣笨氣基 鈉鹽 ' 將1-(4-[7-芊氧基-6-氰基喹啉-4-基氧]-2-氟苯基）-3-(4-氟苯基）脲1.7 g，三氟乙酸17 ml及硫代苯甲醚1.7 ml之混合 物在使用油浴下，於70 °C加熱攪拌20小時。反應終了後， 將反應液濃縮，以及加入飽和碳酸氫鈉水溶液及曱醇，攪 拌30分鐘以及濾取析出之固體。將得到之固體減壓乾燥， 得到標題化合物1.15 g。 iH-NMR 光譜（DMS〇-d6)5(ppm): 6·62*(1Η，d，J=5.3 Hz)， 7.18-7.68 (7H, m), 8.24 (1H, t, J=8.5 Hz), 8.70-8.86 (3H, m),Production Example 217 J-[7-yl)urea as described below. 7-Pentoxy-6-cyano-4-(3·fluoro-4-aminophenoxy)quinoline 6 obtained in Production Example 8. In 95 g, add 210 ml of toluene and 20 ml of acetonitrile, and heat back to the mixture; and then add '2.67 ml of 4-fluorophenyl isocyanate in it and heat it back! Hours. After allowing to cool, the precipitated solid was taken and dried under reduced pressure to give the title compound 7.45 g. lH-NMR spectrum (DMSO-d6) 5 (ppm): 5·49 (2H, s), 6.61 (1H, d, J = 5.4 Hz), 7·05-7·57 (11H, m), 7.54 (1H, s), 8·24 (1H, t, 9·5 Hz), 8.63 (1H, s), 8.72 (1H, d, J=5.4 Hz), 8.77 (1H, s)5 9.10 (1H , S). Production Example 217-2 Cyano- 4- (This 4-(4-fluoromethylamine hydrazine) is a 1-(7-decyloxy-6-cyano group) a mixture of quino-4-yloxy]-2-fluorophenyl)-3-(4-fluorophenyl)urea 1.7 g, 17 ml of trifluoroacetic acid and 1.7 ml of thioanisole in an oil bath The mixture was heated and stirred at 70 ° C for 20 hours. After the reaction was completed, the reaction mixture was concentrated, and a saturated aqueous solution of sodium hydrogencarbonate and decyl alcohol were added, and the mixture was stirred for 30 minutes, and the precipitated solid was collected by filtration. 1.15 g. iH-NMR spectrum (DMS〇-d6) 5 (ppm): 6·62*(1Η,d,J=5.3 Hz), 7.18-7.68 (7H, m), 8.24 (1H, t, J= 8.5 Hz), 8.70-8.86 (3H, m),

-337 -_____ 本纸張尺度適用中國國家標举(CNS) A4規格(210 x 297公爱）-337 -_____ This paper size applies to China National Standard (CNS) A4 specification (210 x 297 public)

裝 訂Binding

線 l3〇4〇6i 、 A7 〜^^__ B7 ___ 五、發明説明（332 ) 9·20 (1H，s)。 f施例2 1 8 教某-7-Γ3-嚙福啉-4-丙氫某V4-4啉氧卜2-氟苯 H3-(4·氣苽甚 使用6-氰基-4-(4-[4-氟苯胺羰基]胺基-3-氟苯氧基）喹 啉-7-醇鈉鹽450 mg，二甲基甲醯胺5 ml，碳酸鉀328 mg及 (3-氯丙基）嗎福啉1 94 mg，以與實施例2 17同樣之方法得 到標題化合物205 mg ^ 光譜（DMS〇-d6)5(ppm)·· 2·01 (2H，quint，J=6.9 Hz)， 2.36-2.44 (4H, m)5 2.48-2.54 (2H, covered by DMSO peak), 3.58 (4H, t, J=4.0 Hz), 4.35 (2H, t, J=6.9 Hz), 6.64 (1H, d, J=5.3 Hz), 7.10-7.19 (3H, m), 7.41 (1H, dd, J=2.9, 12.3 Hz), 7.44-7.52 (2H，m)3 7·63 (1H，s)，8.25 (1H，t，J=8.9 Hz)，8.64 (1H，d，J=2.0 Hz)，8.74-8.78 (2H，m)，9.20 (1H，s)。 f施例219 IJL·4·『6-氰茱-7- (3 -二乙胺某丙氣基）-4、奎g株氲1 - 2-最宏 基卜3-茉基服 將6-氰基-4-(4-[4-苯胺羰胺基]-3-苯氧基）喳啉-7-醇鈉 鹽179 mg溶於二甲基曱醯胺2 ml中，然後加入碳酸_135 mg及3-氯丙基二乙胺79 mg，並於65-75 °C加熱攪拌整夜。 放冷後加入水，用乙酸乙酯及四氫呋喃萃取，藉硫酸麵乾 燥，減壓餾去溶媒，將殘餘物用NH矽凝膠管柱層析（乙酸 乙酯-甲醇系）精製，得到標題化合物6〇 mg。 H-NMR 光譜（DMSO-ds) 5 (ppm): 0·94 (6H，t，J=7,2 Hz) ___ - 338 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱) -- 1304061 A7 B7 五、發明説明（333 ) 1.92 (2H, quint, J=7.2 Hz), 2.43-2.55 (4H, m, covered by DMSO peak), 2.60 (2H, t, J=7.2 Hz), 4.42 (2H, t, J=7.2 Hz), 6.62 (1H, d, J=5.〇 Hz), 6.98 (1H, t, J=7.2 Hz), 7.12-7.18 (1H, m)5 7.29 (2H, t5 J-7.2 Hz), 7.40 (1H5 dd, J=11.9 Hz3 J^2.8 Hz), 7.46 (2H, d, J=7.2 Hz), 7.59 (1H, s), 8.26 (1H, t, J-9.〇 Hz)，8.67 (1H，s)，8·72.8·78 (2H，m), 9.16 (1H, s)。 如下述合成中間體e 举造例219_ 11^(4丄7二；氧基氰基-4-喹啉氧卜2-氯芡某彳·3·苯莘％將製造例8得到之7-芊氧基-6-氰基-4- (3-氟-4-胺基苯氧 基）喹啉1.90 g加至甲苯60 ml及乙腈30 ml中，並加熱回 &gt;;fu。在其中’加入異氰酸苯酯0.76 ml，並加熱回流1小時。 放冷後，濾取析出之固體及減壓乾燥，得到標題化合物 1.65 g。 iH-NMR 光譜（DMSO-d6)&lt;5(ppm): 5.45 (2H，s)，6.62 (1H，d， J=5.4 Hz)，6.95-7.57 (12H，m)，7·71 (1H，s)，8·27 (1H，t，9.2 Hz)，8.66 (1H，s)，8·74 (1H，d，J=5.4 Hz)，8.78 (1H，s)，9·〇9 (1H，s) 〇 製造例219-2 6-¾基- 4-(4-[4-笨胺藏胺基1-3 -氣笨氣基）醆 使用1-(4-[7-芊氧基-6-氰基-4」峻啉氧]-2-氟苯基）_3-苯 基勝1.64 g，三氟乙酸16 ml及硫代苯甲醚1.6 ml之混合物在 使用油浴下，於65-72t加熱攪摔14小時。反應終了後，將 反應液濃縮，以及加入飽和碳酸氫鈉水溶液及甲醇，攪拌 -339 - 本畝張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 — A7 ____B7_-_ 五、發明説明（334 ) 30分鐘以及濾取析出之固體。將得到之固體減壓乾燥，得 到標題化合物1.35 g。 1H-NMR 光譜（DMSO-d6)5(PPm): 6·41 (1H，d，J=5.1 Hz)， 6.98 (1H，t，J=7.1 Hz)，7·11 (1H，d，J=7.1 Hz)，7·20-7·40 (4H， m), 7.45 (2H, d, J=7.1 Hz), 8.24 (1H, t, J=8.0 Hz), 8.55 (1H, s)，8·57 (1H，d，J=5.1 Hz)，8·66 (1H，s)，9.10 (1H，s)。 i施例220 1^(_4-『6-氰基-7-(3-嗎_福啉-4-丙氫某&gt;)-4-4啉氫1-2-最.茇 基卜3-苽某脲 使用6-氰基-4-(4-[4-苯胺羰胺基]-3-苯氧基）喹啉-7-醇 鈉鹽505 mg，二曱基甲醯胺5 m卜碳酸鉀3 80 mg及4-(3 -氯 丙基）嗎福啉195 mg，以與實施例217同樣之方法得到標題 化合物301 mg。 iH-NMR 光譜（DMSO-d6)5(ppm): 1·99 (2H，quint，J=6.8 Hz)， 2.33-2.52 (4Ή, m), 2.48-2.54 (2H, covered by DMSO peak), 3.58 (4H，t，J=4.2 Hz)，4.32 (2H，t，J=6.8、Hz)，6·62 (1H，d， J&quot;=5.3 Hz), 6.98 (1H, t, J-7.2 Hz), 7.12-7.48 (6H, m), 7.60 (1H, s), 8.26 (1H, t, J=8.5 Hz), 8.64 (1H, d, J=1.5 Hz), 8.72^ 8·78 (2H，m)，9.06 (1H，s)。 f施例221 U 4- (6-氰基-7二f 3二(：甲胺基）丙氣基1 - 4- g奋说氣）苯篡1 -Κ··(4-氣苽某）脲 使用6-氰基-4-(4-[(4-氟苯胺）羰基]胺基苯氧基）喹啉-7· 醇鈉鹽100 mg，以與實施例7同樣之方法得到標題化合物2〇 ____- 340 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（335 ) mg 〇 iH-NMR 光譜（DMSO-d6)5(ppm): ι·97 (2H，quint，J=7.1 Hz)， 2.18 (6H, s), 2.42 (2H, t, J=7.1 Hz), 4.32 (2H, t, J=7.1 Hz), 6.54 (1H, d, J=5.6 Hz), 7.05-7.65 (9H, m), 8.63 (1H, d, J=5.6 Hz)，8·76 (1H，s)，8·80 (1H，s)，8.88 (1H，s)。 實施例222 包:.（[(么.7-二甲氧基4：_#-4-基氳&gt;)毗啶-2-某&gt;)-&gt;^苽某蛛 將5-( 6,7-二甲氧基4淋-4-基氧）吡啶-2-基胺（29.7 mg， 0 · 100 mmol)及異氰酸苯酉旨（13·1 mg，〇. 11 〇 mmol)在二甲基 甲醯胺（1 ml)中，於室溫攪摔18小時。將反應液在乙酸乙 酉旨與水間分溶，將有機層用水及飽和食鹽水洗淨，用無水 硫酸鍰乾燥’滤除乾燥劑及將滤液減壓蒸餘。將得到之粗 生成物付諸於麥凝膠管柱層析（溶出液，乙酸乙醋：甲醇 =20 : 1)，將包含目的物之溶出份濃縮，懸浮於乙酸乙酯， 將其用己烷稀釋及濾取結晶，用己烷洗淨後，藉由通風乾 燥，得到為無色結晶之標題化合物（30.4 mg，0.073 mmol， 73%) ° iH-NMR 光譜（DMS〇-d6)5(ppm): 3·95 (3H，s)，3.96 (3H，s)， 6·53 (1Η，d，J=5.4 Ηζ)，7.00-7.06 (1Η，m)，7.28-7.35 (2Η，m)， 7.41 (1H, s)5 7.50-7.56 (3H, m), 7.76-7.82 (2H, m)5 8.30- 8·33 (1H, m)，8.49 (1H，d，J=5.4 Hz)，9·56 (1H，s)，10.04 (1H， s)。 如下述合成中.間體。 舉i告例222-1 -341 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） 裝 訂Line l3〇4〇6i, A7~^^__ B7 ___ V. Description of invention (332) 9·20 (1H, s). fExample 2 1 8 teach a -7-Γ3-campfos-4-propanol V4-4 porphyrin 2-bromobenzene H3-(4· gas 苽 even use 6-cyano-4-(4 -[4-Fluoroanilinecarbonyl]amino-3-fluorophenoxy)quinolin-7-ol sodium salt 450 mg, dimethylformamide 5 ml, potassium carbonate 328 mg and (3-chloropropyl) The title compound 205 mg ^ spectrum (DMS〇-d6) 5 (ppm)·· 2·01 (2H, quint, J=6.9 Hz), 2.36, was obtained in the same manner as in Example 2 17. -2.44 (4H, m)5 2.48-2.54 (2H, covered by DMSO peak), 3.58 (4H, t, J=4.0 Hz), 4.35 (2H, t, J=6.9 Hz), 6.64 (1H, d, J=5.3 Hz), 7.10-7.19 (3H, m), 7.41 (1H, dd, J=2.9, 12.3 Hz), 7.44-7.52 (2H,m)3 7·63 (1H, s), 8.25 (1H , t, J = 8.9 Hz), 8.64 (1H, d, J = 2.0 Hz), 8.74 - 8.78 (2H, m), 9.20 (1H, s) f Example 219 IJL · 4 · "6-Cyanide -7-(3-diethylamine, a propane group)-4, quinegrin 氲1 - 2-the most macro group, 3- mercapto, 6-cyano-4-(4-[4-aniline carbonylamine 179 mg of 3-phenyloxy)porphyrin-7-ol sodium salt is dissolved in 2 ml of dimethylguanamine, then _135 mg of carbonic acid and 79 mg of 3-chloropropyldiethylamine are added, and Stir at 65-75 °C overnight After cooling, water was added, and the mixture was extracted with ethyl acetate and EtOAc. EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHH 6〇mg. H-NMR spectrum (DMSO-ds) 5 (ppm): 0·94 (6H, t, J=7, 2 Hz) ___ - 338 - This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 public ) -- 1304061 A7 B7 V. Description of invention (333 ) 1.92 (2H, quint, J=7.2 Hz), 2.43-2.55 (4H, m, covered by DMSO peak), 2.60 (2H, t, J=7.2 Hz), 4.42 (2H, t, J=7.2 Hz), 6.62 (1H, d, J=5.〇Hz), 6.98 (1H, t, J=7.2 Hz), 7.12-7.18 (1H, m)5 7.29 (2H, t5 J-7.2 Hz), 7.40 (1H5 dd, J=11.9 Hz3 J^2.8 Hz), 7.46 (2H, d, J=7.2 Hz), 7.59 (1H, s), 8.26 ( 1H, t, J-9.〇Hz), 8.67 (1H, s), 8·72.8·78 (2H, m), 9.16 (1H, s). For the synthesis of the intermediate e, the following example: 219_11^(4丄7; oxycyano-4-quinolineoxy-2-chloroindole 3·3·benzoquinone % 7-芊 obtained in Production Example 8 1.90 g of oxy-6-cyano-4-(3-fluoro-4-aminophenoxy)quinoline was added to 60 ml of toluene and 30 ml of acetonitrile, and heated back to &gt;; fu. To the phenyl isocyanate, 0.76 ml, and heated under reflux for 1 hour. After cooling, the solid which crystallised was filtered and dried under reduced pressure to give the title compound 1.65 g. iH-NMR spectrum (DMSO-d6) &lt;5 (ppm): 5.45 (2H, s), 6.62 (1H, d, J = 5.4 Hz), 6.95-7.57 (12H, m), 7·71 (1H, s), 8.27 (1H, t, 9.2 Hz), 8.66 (1H, s), 8.74 (1H, d, J = 5.4 Hz), 8.78 (1H, s), 9·〇9 (1H, s) 〇 Manufacturing Example 219-2 6-3⁄4 Base - 4-( 1-[4-[7-decyloxy-6-cyano-4"sulfanyloxy]-2-fluorophenyl _3-Phenyl wins 1.64 g, a mixture of 16 ml of trifluoroacetic acid and 1.6 ml of thioanisole is stirred and heated for 14 hours at 65-72 t using an oil bath. After the reaction is finished, the reaction solution is concentrated, and Add saturated sodium bicarbonate solution and methanol, stir -339 - The standard of the acre is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 — A7 ____B7_-_ V. Inventive Note (334) 30 minutes and the precipitated solid is collected by filtration. The obtained solid is dried under reduced pressure. The title compound was obtained in 1.35 g. 1H-NMR spectrum (DMSO-d6) 5 (PPm): 6·41 (1H,d,J=5.1 Hz), 6.98 (1H,t,J=7.1 Hz),7·11 ( 1H,d,J=7.1 Hz),7·20-7·40 (4H, m), 7.45 (2H, d, J=7.1 Hz), 8.24 (1H, t, J=8.0 Hz), 8.55 (1H , s), 8.57 (1H, d, J = 5.1 Hz), 8.66 (1H, s), 9.10 (1H, s). Example 220 1^(_4-『6-Cyano-7 -(3-?_Forphyrin-4-propanol&gt;)-4-4 porphyrin hydrogen 1-2-most. 茇 卜 苽 苽 苽 脲 脲 脲 脲 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用 使用- phenylaminocarbonylamino]-3-phenoxy)quinolin-7-ol sodium salt 505 mg, dimethylformamide 5 m potassium carbonate 3 80 mg and 4-(3-chloropropyl) The title compound 301 mg was obtained in the same manner as Example 217. iH-NMR spectrum (DMSO-d6) 5 (ppm): 1·99 (2H, quint, J=6.8 Hz), 2.33-2.52 (4Ή, m), 2.48-2.54 (2H, covered by DMSO peak), 3.58 (4H,t,J=4.2 Hz), 4.32 (2H,t,J=6.8,Hz),6·62 (1H,d, J&quot;=5.3 Hz), 6.98 (1H, t, J-7.2 Hz) , 7.12-7.48 (6H, m), 7.60 (1H, s), 8.26 (1H, t, J=8.5 Hz), 8.64 (1H, d, J=1.5 Hz), 8.72^ 8·78 (2H,m ), 9.06 (1H, s). fExample 221 U 4-(6-Cyano-7dif 3 bis(:methylamino)propenyl 1 - 4-g 说 )) benzoquinone 1 -Κ··(4-gas 苽) The title compound 2 was obtained in the same manner as in Example 7 using the title compound (yield of 6- cyano-4-(4-[(4-fluoroaniline) carbonyl)aminophenoxy)quinolin-7-propoxide as a sodium salt. 〇____- 340 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (335 ) mg 〇iH-NMR spectrum (DMSO-d6) 5 (ppm) : ι·97 (2H, quint, J=7.1 Hz), 2.18 (6H, s), 2.42 (2H, t, J=7.1 Hz), 4.32 (2H, t, J=7.1 Hz), 6.54 (1H, d, J=5.6 Hz), 7.05-7.65 (9H, m), 8.63 (1H, d, J=5.6 Hz), 8·76 (1H, s), 8·80 (1H, s), 8.88 (1H , s). Example 222:: ([(m.7-dimethoxy 4:_#-4-ylhydrazine)] pyridin-2-some&gt;)-&gt;^苽A spider will be 5-(6 ,7-dimethoxy-4-phospho-4-yloxy)pyridin-2-ylamine (29.7 mg, 0 · 100 mmol) and phenyl isocyanate (13·1 mg, 〇. 11 〇mmol) In dimethylformamide (1 ml), it was stirred at room temperature for 18 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and saturated brine, and dried with anhydrous sulphate. The desiccant was filtered off and the filtrate was evaporated under reduced pressure. The obtained crude product was subjected to a gel column chromatography (eluent, ethyl acetate: methanol = 20:1), and the dissolved fraction containing the desired product was concentrated, suspended in ethyl acetate, and used. The title compound (30.4 mg, 0.073 mmol, 73%) was obtained as a colorless crystals eluted with hexanes. ): 3·95 (3H, s), 3.96 (3H, s), 6·53 (1Η, d, J=5.4 Ηζ), 7.00-7.06 (1Η, m), 7.28-7.35 (2Η, m), 7.41 (1H, s)5 7.50-7.56 (3H, m), 7.76-7.82 (2H, m)5 8.30- 8·33 (1H, m), 8.49 (1H, d, J=5.4 Hz), 9· 56 (1H, s), 10.04 (1H, s). The synthesis is as follows. For example, the paper size is applicable to the Chinese National Standard (CNS) A4 specification (21〇x 297 mm).

線 1304061 A7 B7 五、發明説明（336 ) 2，承_· _ ό _ 口比 - 3 · 5?» 將2-氯-3-#至基外ti症（5.00 g，38·6 mmol)及琪化納（5.79 g，38.6 mmol)溶於二甲基甲醯胺（70 ml)，於冰冷下加入氯 胺T(l〇.9 g，38,6 mmol)後，於室溫攪拌1小時。反應後加 入2N鹽酸水溶液（19.3 ml，38.6 mmol)後，在乙酸乙g旨及水 間分溶，將有機層用水及飽和食鹽水洗淨，用無水硫酸鎂 乾燥，濾除乾燥劑及將濾液減壓蒸餾。將得到之粗生成物 付諸於矽凝膠管柱層析（溶出液，乙酸乙酯：己烷=i : 2)，將含目的物之溶出份濃縮，得到為無色結晶之標題化 合物（9.00 g，35.2 mmol，91%) ° !H-NMR 光譜（CDCl3)5(ppm): 5·61 (1H，br s)，7·02 (1H，d， J=8.2 Hz)，7.56 (1H，d，J=8.2 Hz) 〇 製造例222-2 4 - (2 -氣-6 -埃叶b咬-3 -基氣）-6，7 -二甲氣邊喊 將4-氯-6,7-二甲氧基峻淋（2.23@，1〇.〇111111〇1)，2-氯-6·&quot; 琪吡啶-3-醇（2.55 g，22·0 mmol)及二異丙基乙胺（1.29 g , 10.0 mmol)在二甲基甲醯胺（5 ml)中，於130°C加熱攪拌3小 時。將反應液在乙酸乙酯-四氫呋喃混合溶劑與水間分溶， 將有機層用水及飽和食鹽水洗淨，用無水硫酸鍰乾燥，遽 除乾燥劑及將濾液減壓蒸餾。將得到之粗生成物付諸於碎 凝膠管柱層析（溶出液，乙酸乙酯：己烷=3 :丨），將包含 目的物之溶出份濃縮，懸浮於乙酸乙酯，將其用己烷稀釋 及滤取結晶.，用.己垸洗淨後，藉由通風乾燥，得到為無色 結晶之標題化合物（2.16g，4.88 mmol，49%)。 -342 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂Line 1304061 A7 B7 V. Description of invention (336) 2, bearing _· _ ό _ mouth ratio - 3 · 5?» 2-chloro-3-# to extrabasic ti (5.00 g, 38·6 mmol) and Chihua Na (5.79 g, 38.6 mmol) was dissolved in dimethylformamide (70 ml), chloroamine T (1 〇.9 g, 38, 6 mmol) was added under ice-cooling, and stirred at room temperature for 1 hour. . After the reaction, a 2N aqueous solution of hydrochloric acid (19.3 ml, 38.6 mmol) was added, and then the mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. Vacuum distillation. The obtained crude product was subjected to hydrazine gel column chromatography (eluent, ethyl acetate:hexane = i: 2), and the fractions of the desired product were concentrated to give the title compound (9.00) as colorless crystals. g,35.2 mmol,91%) °H-NMR spectrum (CDCl3) 5 (ppm): 5·61 (1H, br s), 7·02 (1H, d, J = 8.2 Hz), 7.56 (1H, d, J = 8.2 Hz) 〇 Manufacturing Example 222-2 4 - (2 - gas-6 - Eye b bit-3 - base gas) - 6,7 - Dimethyl gas shouting 4-chloro-6,7 -Dimethoxy sulfonate (2.23@,1〇.〇111111〇1), 2-chloro-6·&quot; pyridine-3-ol (2.55 g, 22.0 mmol) and diisopropylethylamine (1.29 g, 10.0 mmol) was stirred and heated at 130 ° C for 3 hours in dimethylformamide (5 ml). The reaction mixture was partitioned between ethyl acetate-tetrahydrofuran mixed solvent and water, and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then evaporated and evaporated. The obtained crude product was subjected to a gel column chromatography (eluent, ethyl acetate:hexane = 3: hydrazine), and the fractions containing the desired product were concentrated, suspended in ethyl acetate, and used. The title compound (2.16 g, 4.88 mmol, 49%) was obtained. -342 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm).

線 I3〇4〇61 A7、 B7 -—— --—— -- --------- 五、發明説明（337 ) 1H-NMR 光譜（CDCl3)(5(ppm): 4.05 (3H，s)，4·06 (3H，s)， 6.39 (1Η, d, J=5.2 Hz), 7.20 (1H, d, J=8.2 Hz), 7.45 (1H, s), 7.48 (1H, s), 7.75 (1H, d, J=8.2 Hz), 8.55 (1H, d, J=5.2 Hz)。 製造例222-3 6-氳-5-( 6T7-二甲氣4啉基氧）吡啶 將二苯甲酮亞胺（1.67g，9.21 mmol)及第三丁氧化鈉（885 mg，9.21 mmol)在甲苯（40 ml)中，於氮氣流及80°c加熱攪 掉1小時後，加入4-(2-氯-6-埃p比咬-3-基氧）·6,7-二甲氧4 啉（3.72 g，8.40 mmol)，參（二亞芊丙酮）二鈀（0)(86·9 mg，0.084 mmol)及消旋-2,2·-貳（二苯基膦）-ΐ，ι，-聯莕（157 mg，0.252 mmol)，然後於90°C加熱攪拌6小時。反應終了 後，將反應混合物經矽藻土過濾，將濾液付諸於矽凝膠管 柱層析（溶出液，乙酸乙酯：己烷==3 : 1 )，將包含目的物 之溶出份濃縮，得到黃色油狀物（1·98 g)。將得到之黃色油 狀物（1.98 g)溶於乙醇（20 ml)，加入1N鹽酸水溶液（5 ml) 並於室溫攪拌1小時。反應終了後，將反應液用5N氫氧化鈉 水溶液（1 ml)中和後，在乙酸乙酯與水間分溶，將有機層 用水及飽和食鹽水洗淨，用無水硫酸鍰乾燥，；慮除乾燥劑 及減壓餾去溶媒。將得到之粗生成物付諸於矽凝膠管柱層 析（溶出液’乙酸乙酯），將包含目的物之溶出份濃縮，得 到為無色結晶之標題化合物（506 mg，1.53 mmol，1 8%)。 1H-NMR 光譜（ CDCl3)5(ppm): 4·06 (3H，s)，4·〇7 (3H，s)， 4.71 (2H, s), 6.34 (1H, d, J=5.2 Hz), 6.53 (1H, d, J=8.8 Hz), 343 - 本紙張尺度通用中國國家標準(CNS) A4規格(210 x 297公釐)Line I3〇4〇61 A7, B7 -—— --—— -- --------- V. Description of the invention (337 ) 1H-NMR spectrum (CDCl3) (5 (ppm): 4.05 (3H ,s),4·06 (3H,s), 6.39 (1Η, d, J=5.2 Hz), 7.20 (1H, d, J=8.2 Hz), 7.45 (1H, s), 7.48 (1H, s) , 7.75 (1H, d, J = 8.2 Hz), 8.55 (1H, d, J = 5.2 Hz). Production Example 222-3 6-氲-5-(6T7-dimethyl gas 4 phenyloxy)pyridine will be two The benzophenone imine (1.67 g, 9.21 mmol) and the third sodium butoxide (885 mg, 9.21 mmol) in toluene (40 ml) were stirred in a nitrogen stream at 80 ° C for 1 hour, then added 4- (2-Chloro-6-Ep-to-bito-3-yloxy)·6,7-Dimethoxy- 4 porphyrin (3.72 g, 8.40 mmol), ginseng (dipyridinium acetonide) dipalladium (0) (86· 9 mg, 0.084 mmol) and racemic-2,2·-indole (diphenylphosphine)-indole, ι,- hydrazine (157 mg, 0.252 mmol), then stirred at 90 ° C for 6 hours. After that, the reaction mixture was filtered through celite, and the filtrate was applied to a gel column chromatography (eluent, ethyl acetate:hexane ==3:1). Yellow oil (1·98 g). Yellow oil (1) .98 g) Dissolved in ethanol (20 ml), added 1N aqueous hydrochloric acid (5 ml) and stirred at room temperature for 1 hour. After the reaction was finished, the reaction mixture was neutralized with 5N aqueous sodium hydroxide (1 ml). The ethyl acetate was partitioned between water and water, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the obtained crude product was poured into a gel. Column chromatography (eluent < EtOAc), EtOAc (EtOAc: EtOAc (EtOAc) Ppm): 4·06 (3H, s), 4·〇7 (3H, s), 4.71 (2H, s), 6.34 (1H, d, J=5.2 Hz), 6.53 (1H, d, J=8.8 Hz), 343 - Common Chinese National Standard (CNS) A4 specification (210 x 297 mm)

裝Loading

1304061 A7 —------ B7 五、發明説明（338 ) 7.37 (1H, d, J=8.8 Hz), 7.43 (1H, s), 7.59 (1H, s), 8.50 (1H, d，J=5.2 Hz.)。 盤造例222-4 MU：二一甲氧基4嗒某iWk珐葚fe 將6-氯-5-(6,7-二曱氧喹啉-4-基氧）吡啶-2-基胺（5〇〇 mg ’ L.51 mmol)懸浮於甲醇（2〇 ml)，四氫呋喃（10 mi)及三 乙胺（3 ml)之混合溶媒中，加入鈀/碳（3〇〇 mg)，在氫氣蒙 氣下於室溫攪拌15小時。藉由矽藻土過濾濾去觸媒，用乙 醇洗淨後，將濾液減壓蒸餾。將得到之粗生成物付諸於矽 凝膠管柱層析（溶出液，乙酸乙酯），將包含目的物之溶出 份濃縮，懸浮於乙酸乙酯，將其用己烷稀釋及濾取結晶， 用己烷洗淨後，藉由通風乾燥，得到為無色結晶之標題化 合物（138 mg，0·465 mmol，31%)。 iH-NMR 光譜（CDCl3)5(ppm)·· 4.05 (3H，s)，4·07 (3H，s)， 4.52 (2H, s), 6.42 (1H, d, J=5.2 Hz), 6.61 (1H, d5 J=8.8 Hz), 7.32 (1H，dd，J=2.8, 8·8 Hz)，7·42 (1H，s)，7·57 (1H，s)，8.04 (1H，d，J=2.8 Hz)，8·49 (1H，d，J=5.2 Hz)。 實施例223 U 5-(6,7-二甲氧基4啉-4-某氳）吡啶-2-某VΝ’-基）脲 將製造例222-4得到之5-(6,7-二甲氧基喹啉-‘基氧），比 咬-2-基胺（44.5 mg，0.1 50 mmol)及異氰酸4-氟苯醋（22 6 mg，0.165 .mm.ol)，以與實施例222同樣之手法，得到為無 色結晶之標題化合物（50.9 mg，117 mmol，78% )。 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（339 ) lH-NMR 光譜（DMSO-d6)5(ppm): 3.94 (3H，s)，3.95 (3H，s)， 6.53 (1H, d? J=5.2 Hz), 7.13-7.20 (2H, m), 7.41 (1H, s)3 7.51-7.57 (3H, m), 7.74-7.82 (2H, m)5 8.30-8.33 (1H, m), 8.49 (1H，d，J=5.2 Hz)，9·55 (1H，s)，10.09 (1H，s)。 實施例224 N-(5-{6,7-二甲氳基崦淋-4·某氲）吡哇-2-基-N，-(違唑- 2- 基）脲1304061 A7 —------ B7 V. INSTRUCTIONS (338 ) 7.37 (1H, d, J=8.8 Hz), 7.43 (1H, s), 7.59 (1H, s), 8.50 (1H, d, J =5.2 Hz.).盘例例222-4 MU: Di-methoxy-4-oxime iWk珐葚fe 6-chloro-5-(6,7-dioxaquinolin-4-yloxy)pyridin-2-ylamine ( 5〇〇mg 'L.51 mmol) was suspended in methanol (2 〇ml), tetrahydrofuran (10 mi) and triethylamine (3 ml) in a mixed solvent, palladium/carbon (3 〇〇mg) was added in hydrogen Stir at room temperature for 15 hours under a monsoon atmosphere. The catalyst was filtered off through celite, washed with ethanol, and the filtrate was distilled under reduced pressure. The obtained crude product was subjected to hydrazine gel column chromatography (eluent, ethyl acetate), and the fractions containing the objective substance were concentrated, suspended in ethyl acetate, diluted with hexane and filtered to crystallize. The title compound (138 mg, 0. 465 mmol, 31%) was obtained. iH-NMR spectrum (CDCl3) 5 (ppm) · 4.05 (3H, s), 4·07 (3H, s), 4.52 (2H, s), 6.42 (1H, d, J = 5.2 Hz), 6.61 ( 1H, d5 J=8.8 Hz), 7.32 (1H, dd, J=2.8, 8·8 Hz), 7·42 (1H, s), 7·57 (1H, s), 8.04 (1H, d, J =2.8 Hz), 8·49 (1H, d, J = 5.2 Hz). Example 223 U 5-(6,7-Dimethoxy-4-oxo-4-anthracene)pyridine-2-one VΝ'-yl)urea 5-(6,7-di) obtained in Production Example 222-4 Methoxyquinoline-'oxyl), butyl-2-ylamine (44.5 mg, 0.1 50 mmol) and 4-fluorophenyl acetonate (22 6 mg, 0.165 .mm.ol) The title compound (50.9 mg, 117 mmol, 78%). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (339) lH-NMR spectrum (DMSO-d6) 5 (ppm): 3.94 (3H, s), 3.95 (3H, s), 6.53 (1H, d? J = 5.2 Hz), 7.13-7.20 (2H, m), 7.41 (1H, s)3 7.51-7.57 (3H, m), 7.74-7.82 (2H, m)5 8.30-8.33 (1H, m), 8.49 (1H, d, J = 5.2 Hz), 9·55 (1H, s), 10.09 (1H, s). Example 224 N-(5-{6,7-dimethylmercapto-indole-4·anthracene)pyrho-2-yl-N,-(offazole-3-yl)urea

將製造例222-4得到之5-(6,7-二甲氧基喹啉-4-基氧）吡 啶-2-基胺（44.5 mg，0.150 mmol)及〃塞峻-2-基胺基甲酸苯 酯（39.6 mg，0.180 mmol)在二甲基亞艰（1 mi)中，於 85°C 攪拌2小時。將反應液在乙酸乙酯與水間分溶，將有機層用 水及飽和食鹽水洗淨，用無水硫酸鎂乾燥，濾除乾燥劑及 將濾液減壓蒸餾。將得到之粗生成物付諸於矽凝膠管柱層 析（溶出液，乙酸乙酯：甲醇=30: 1)，將包含目的物之溶 出份濃縮，懸浮於乙酸乙酯，將其用己烷稀釋及濾取結 晶，用己烷洗淨後，藉由通風乾燥，得到為無色結晶之標 題化合物（46.7 mg，0.110 mmol，74%)。 W-NMR 光譜（DMSO-d6)5(ppm): 3·95 (3H，s)，3.96 (3H，s)， 6.53 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=3.4 Hz), 7.41 (1H, s)3 7.43 (1H3 d, J=3.4 Hz), 7.54 (1H, s)? 7.80-7.86 (2H, m), 8.36猶8·39 (1H，m)，8.49 (1H，d，J=5.2 Hz)，9·92 (1H，br s)， 11·55 (1H，br s)〇 如下述合成中間體。 塑造例224-1 -345 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（340 邊唾-2 -基胺基甲酸笨g旨 將 2-胺基嘍唑（5.01 g，50.0 mmol)及吡啶（7.91 g , 1〇〇 mmol)落於二甲基甲醯胺（50 ml)，於冰冷下加入氯甲酸苯 酯（8·22 g，52.5 mmol)後，於室溫攪拌丨小時。將反應液在 乙酸乙g旨-四氫呋喃混合溶劑與水間分溶，將有機層用水及 飽和食鹽水洗淨，用無水硫酸鎂乾燥，濾除乾燥劑及將濾 液減壓条餾。在得到之粗生成物中加入乙酸乙酯，繼而加 入己燒，然後濾取析出之結晶，藉由通風乾燥，得到為無 色結晶之標題化合物（l〇.6g，48.1 mm〇l，96%)。 H-NMR 光譜（0〇(：13)5咖111):6.97(1^(1，1=3.4 112)，7.24-7.32 (3H，m)，7.40-7.46 (2H，m)，7.52 (1H，d，J=3.4 Hz)， 13.19 (1H，s)。 實施例225 Μ-(6-氯-5-(6,7-二甲氲某4淋-4-某氣）吡啶-2-某）芡 基脲 將製造例222-3得到之6-氣-5-(6,7-二甲氧基喹啉-4-基氧） 口比咬-2·基胺（33.2 mg，〇·1〇〇 mmol)及異氰酸苯酯（13.1 mg，0·11〇 mm〇l)在二甲基甲醯胺（lml)中，於6(rc加熱攪 拌2小時。將反應液在乙酸乙酯與水間分溶，將有機層用水 及飽和食鹽水洗淨，用無水硫酸鎂乾燥，濾除乾燥劑及將 遽液減壓蒸餾。將得到之粗生成物付諸於矽凝膠管柱層析 (溶出液，乙酸乙酯），將包含目的物之溶出份濃縮，懸浮 於乙酸乙酯，將其用己烷稀釋及濾取結晶，用己烷洗淨 後’藉由通風乾燥，得到為無色結晶之標題化合物（丨7.5 -346 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂 線 1304061 A7 B7 五、發明説明（341 ) mg，0.039 mmol，39%) 〇 iH-NMR 光譜（DMSO-d6)d(ppm): 3·96 (6H，s)，6.50 (1H，d， J=5.2 Hz)，7·01-7·07 (1H，m)，7·30-7·37 (2H，m)，7.43 (1H， s)，7.46-7.51 (2H，m)，7·54 (1H，s)，7.94-8.00 (2H，m)，8.49 (1H，d，J=5.2 Hz)，9.29 (1H，br s)，9.75 (1H，br s)。 實施例226 二甲氧皋4啉基硫吩_2_基-ν’-笨基脲 將5-(6,7-二甲氧基喹啉-4-基硫）嘍吩-2-基胺（89.0 mg， 0.280 mmol)及異氰酸苯酯（36.6 mg，0·307 mmol)在二甲基 甲酿胺（1 ml)中，於室溫攪拌丨小時。將反應液在乙酸乙酯 與水間分溶’將有機層用水及飽和食鹽水洗淨，用無水硫 酸鎂乾燥，濾除乾燥劑及將濾液減壓蒸餾。將得到之粗生 成物付諸於矽凝膠管柱層析（溶出液，乙酸乙酯：甲醇 =50 : 1 )，將包含目的物之溶出份濃縮，懸浮於乙酸乙酯， 將其用己烷稀釋及濾取結晶，用己烷洗淨後，藉由通風乾 燥’得到為無色結晶之標題化合物（6〇 〇 mg，0.137 mmol , 48%) 〇 i-NMR 光譜（DMSO_d6)5(ppm): 3 95 (3H，s), 3 % (3H，s)， 6·70 (1H，d，J=3.6 Hz)，6.74 (1H，d, J=4.8 Hz)，6·98-7.〇3 (1H，m)，7·26-7·36 (4H，m)，7.40 (1H，s)，7.43-7.50 (2H，m)， 8·48 (1H，d，J=4.8 Hz)，9.02 (1H，br s)，10.27 (1H，br s)。 如下述合成中間體。 盥造例 甲乳幕林-4-硫嗣5-(6,7-Dimethoxyquinolin-4-yloxy)pyridin-2-ylamine (44.5 mg, 0.150 mmol) obtained from Preparation 222-4 Phenyl formate (39.6 mg, 0.180 mmol) was stirred in dimethyl argon (1 mi) at 850C for 2 h. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained crude product was subjected to hydrazine gel column chromatography (eluent, ethyl acetate:methanol = 30:1), and the fractions containing the objective substance were concentrated, suspended in ethyl acetate, and used for The title compound (46.7 mg, 0.110 mmol, 74%) was obtained. W-NMR spectrum (DMSO-d6) 5 (ppm): 3·95 (3H, s), 3.96 (3H, s), 6.53 (1H, d, J = 5.2 Hz), 7.20 (1H, d, J= 3.4 Hz), 7.41 (1H, s)3 7.43 (1H3 d, J=3.4 Hz), 7.54 (1H, s)? 7.80-7.86 (2H, m), 8.36 still 8. 39 (1H, m), 8.49 (1H, d, J = 5.2 Hz), 9.92 (1H, br s), 11·55 (1H, br s), such as the following synthetic intermediates. Molding Example 224-1 -345 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of invention (340 sialyl-2-aminocarbamic acid stupid g -Aminocarbazole (5.01 g, 50.0 mmol) and pyridine (7.91 g, 1 mmol) were added to dimethylformamide (50 ml), and phenyl chloroformate (8·22 g, After 52.5 mmol), the mixture was stirred at room temperature for </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> And the filtrate is subjected to a vacuum distillation. The obtained crude product is added with ethyl acetate, followed by the addition of hexane, and the crystals are separated by filtration, and dried to give the title compound (1 g. , 48.1 mm 〇l, 96%). H-NMR spectrum (0 〇 (: 13) 5 coffee 111): 6.97 (1^(1,1=3.4 112), 7.24-7.32 (3H, m), 7.40- 7.46 (2H, m), 7.52 (1H, d, J = 3.4 Hz), 13.19 (1H, s). Example 225 Μ-(6-chloro-5-(6,7-dimethylhydrazine) 4-a gas) pyridin-2-one) guanyl urea will be produced in the production example 222-3 6-gas-5-(6,7-dimethoxyquinolin-4-yloxy) benzoate (33.2 mg, 〇·1〇〇mmol) and phenyl isocyanate (13.1 mg, 0·11〇mm〇l) in dimethylformamide (1 ml), stir at 2 (rc for 2 hours). Dissolve the reaction solution between ethyl acetate and water, and use the organic layer with water. The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated, evaporated, evaporated. The concentrate containing the desired product was concentrated, suspended in ethyl acetate, diluted with hexanes and filtered, crystallised, washed with hexanes, and then dried by air to give the title compound as colorless crystals (丨7.5 - 346 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) Gutter 1304061 A7 B7 V. Description of invention (341 ) mg, 0.039 mmol, 39%) 〇iH-NMR spectrum (DMSO-d6) d(ppm): 3·96 (6H, s), 6.50 (1H, d, J=5.2 Hz), 7·01-7·07 (1H, m), 7·30-7·37 (2H, m ), 7.43 (1H, s), 7.46-7.51 (2H, m), 7·54 (1H, s), 7.94-8 .00 (2H, m), 8.49 (1H, d, J = 5.2 Hz), 9.29 (1H, br s), 9.75 (1H, br s). Example 226 Dimethoxyindole 4 phenylthiophene-2-yl-v'-stupyl urea 5-(6,7-dimethoxyquinolin-4-ylthio)porphen-2-ylamine (89.0 mg, 0.280 mmol) and phenyl isocyanate (36.6 mg, 0. 307 mmol) were stirred in dimethylamine (1 ml) at rt. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained crude product was subjected to hydrazine gel column chromatography (eluent, ethyl acetate:methanol = 50:1), and the fractions containing the objective substance were concentrated, suspended in ethyl acetate, and used for The title compound (6 〇〇 mg, 0.137 mmol, 48%) was obtained as a colorless crystals. : 3 95 (3H, s), 3 % (3H, s), 6·70 (1H, d, J = 3.6 Hz), 6.74 (1H, d, J = 4.8 Hz), 6·98-7.〇 3 (1H,m),7·26-7·36 (4H,m), 7.40 (1H,s), 7.43-7.50 (2H,m), 8·48 (1H,d,J=4.8 Hz), 9.02 (1H, br s), 10.27 (1H, br s). The intermediate is synthesized as follows.盥造例甲甲幕林-4-嗣

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1304061 A7 B7 五、發明説明（342 )1304061 A7 B7 V. Description of invention (342 )

將WO 9717329記載之6,7 -二甲氧基- lH-β奎琳-4-酮（10.3 g，50.0 mmol)，五硫化二磷（26.7 g，60.0 mmol)及碳酸氫 鈉（26.7 g，3 18 mmol)懸浮於二乙二醇二甲屬（1〇〇 mi)中， 並於8(TC加熱攪摔2小時。使反應液回到室溫後，注入冰水 (1000 ml)，濾取析出之結晶及用水洗淨後，藉由通風乾燥 得到為黃色結晶之標題化合物（8· 19g，37·〇 mmol，74%)。 h-NMR 光譜（DMS〇-d6)5(ppm): 3·87 (3H，s)，3·91 (3H，s)， 7.07 (1Η, s), 7.19 (1H, d, J=6.8 Hz), 7.74 (1H, d5 J=6.8 Hz), 8.11 (1H，s)，12.76 (1H，br s)。 鳃造例226-2 6.7-二甲氣基，奎啉-4-(5-硝基達吩-2-基硫h杏嗾6,7-Dimethoxy-lH-β quinolin-4-one (10.3 g, 50.0 mmol), phosphorus pentasulfide (26.7 g, 60.0 mmol) and sodium hydrogencarbonate (26.7 g, 3 18 mmol) as described in WO 9717329 Suspended in diethylene glycol dimethyl genus (1 〇〇mi), and stirred at 8 (TC heating for 2 hours. After returning the reaction solution to room temperature, inject ice water (1000 ml), and filter it out. The title compound (8·19 g, 37·〇mmol, 74%) was obtained as a yellow crystal. mp NMR (DMS 〇-d6) 5 (ppm): 3·87 (3H, s), 3·91 (3H, s), 7.07 (1Η, s), 7.19 (1H, d, J=6.8 Hz), 7.74 (1H, d5 J=6.8 Hz), 8.11 (1H, s ), 12.76 (1H, br s). 鳃例226-2 6.7-Dimethyl group, quinolin-4-(5-nitrodaphen-2-ylsulfide h apricot

將 6，7 --—甲乳基-1Η -峻嚇· - 4 -硫嗣（2·21 g ’ 1〇·〇 mmol)， 2-溴-5-硝基β塞吩（2.29 g，11.0 mmol)及碳酸卸（2.07 g， 15 ·0 mmol)在二甲基甲醯胺（30 ml)中，於室溫攪拌1小時。 將反應液在乙酸乙酯與水間分溶，將有機層用1N氫氧化#3 水溶液，水及飽和食鹽水洗淨後，用無水硫酸鎂乾燥，；慮 除乾燥劑及將濾液減壓蒸餾。將得到之粗生成物付諸於碎 凝膠管柱層析（溶出液，乙酸乙酯：己烷=3: 1)，將包含 目的物之溶出份濃縮，得到為黃色結晶之標題化合物 (1.93g，5·54 mmol，55%)。 W-NMR 光譜（CDCl3)5 (ppm): 4.04 (3H，s)，4.06 (3H，s)， 7.10 (1H，d，J=4.8 Hz)，7.22 (1H，d，J=4.4 Hz)，7.37 (1H，s)， 7·46 (1H，s)，7·89 (1H，d，J=4.4 Hz)，8.60 (1H，d，J=4.86,7 ---methyllacyl-1 Η - 吓 - · - 4 - thiopurine (2 · 21 g ' 1 〇 · 〇 mmol), 2-bromo-5-nitro β thiophene (2.29 g, 11.0 Methyl acetate (2.07 g, 15 · 0 mmol) was stirred in dimethylformamide (30 ml). The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with a 1N aqueous solution of EtOAc (3), water and brine, and dried over anhydrous magnesium sulfate. . The obtained crude product was subjected to a gel column chromatography (eluent, ethyl acetate:hexane = 3:1), and the fractions of the desired product were concentrated to give the title compound (1. g, 5·54 mmol, 55%). W-NMR spectrum (CDCl3) 5 (ppm): 4.04 (3H, s), 4.06 (3H, s), 7.10 (1H, d, J = 4.8 Hz), 7.22 (1H, d, J = 4.4 Hz), 7.37 (1H, s), 7·46 (1H, s), 7.89 (1H, d, J = 4.4 Hz), 8.60 (1H, d, J = 4.8

Hz) 〇 -348 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 343 五、發明説明（ 例 226- 3 基硫岭-2_ 某脖 將6,7-二甲氧基_4-( 5-硝基，塞吩-2-基硫）喹啉（1.39 g， 4.00 mmol)，鐵（1·12 g，2〇 〇 _〇1)及氯化銨（2 18 g，4〇 〇 mmol)懸斤在乙醇（32 ml) -水（8 mi)之混合液中，於8(rc加 熱攪拌5分鐘。反應終了後，將反應混合物經矽藻土過濾， 用乙酸乙酯洗出。將有機層用水及飽和食鹽水洗淨，用無 水硫酸鎂乾燥後，濾除乾燥劑及將濾液減壓蒸餾。將得到 之粗生成物付諸於矽凝膠管柱層析（溶出液，乙酸乙酯：己 烷=3 · 1 )，將包含目的物之溶出份濃縮，得到為黃褐色結 晶之標題化合物（1.93g，5.54 mmol，55%)。 W-NMR 光 lf(CDCl3)(5(ppm): 4 〇4 (3H，s)，4 〇6 (3H，s)， 4.15 (2H，s)，6.21 (1H，d，J=3.8 Hz)，6·87 (1H，d，J=5.0 Hz)， 7.04 (1H，d，J=3.8 Hz)，7·31 (1H，s)，7.40 (1H，s)，8.47 (1H， d，J=5.0 Hz) o 實施例227 N- 5-( 6:1:二甲乳基崎淋-4-某硫）違吩-2-基）-N，- (4-氣笨某） 將5-(6,7-二甲氧基喹啉-4-基硫）嘍吩基胺（3 18 mg， 0.100 mmol)及異氰酸 4-氟苯醋（15·1 mg，0.110 mm〇i)，以 與實施例226同樣之手法，得到為無色結晶之標題化合物 (29.3 mg，64.3 mmol，64%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 3·94 (3H，s)，3.97 (3H，s)， 6.70 (1H, d, J—4.0 Hz), 6.74 (1H, d, 1==5.2 Hz), 7.10-7.18 -349 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 x 297公釐） 1304061 A7 B7 五、發明説明（344 ) (2H，m)，7.31 (1H，s)，7·33 (1H，d，J=4.0 Hz)，7.39 (1H，s)， 7.45-7.51 (2H, m), 8.48 (1H, d, J=5.2 Hz), 9.05 (1H, br s)3 10.29 (1H，br s) 〇 實施例228 N-(5-(6,7-二―甲氧基4啉-4-基硫）遠吩举「苯 基）脲- 將5-(6,7-«—甲氧基峻淋-4-基硫）p塞吩-2-基胺（6 4 · 0 m g， 0.200 mmol)及異氰酸 4-氟苯 S 旨（15·1 mg，0.110 mmol)，以 與實施例226同樣之手法，得到為淡褐色結晶之標題化合物 (62·0 mg，0.136 mmol，68%)。 iH-NMR光譜（DMSO-d6)5(ppm)·· 3·95 (3H，s)，3·97 (3H，s)， 6.72 (1Η，d，J=3.6 Ηζ)，6·75 (1Η，d，J=4.6 Ηζ)，6·80-6·85 (1H，m)，7.17-7.21 (1H，m)，7.29-7.36 (3H，m)，7·40 (1H，s)， 7.42-7.48 (1H，m)，8·48 (1H，d，J=4.6 Hz)，9·18 (1H，br s)， 10.27 (1H，br s) 〇 實施例229 基苯基）-Ν·-(5-(6,7-二甲氧基林-4-基硫）g菜吩― 2-基）脲 將5-( 6,7-二甲氧基喹啉-4-基硫）喳吩-2-基胺（64 mg， 0·200 mmol)及異氰酸 3-氰基苯酯（31·7 mg，0·220 mmol)， 以與實施例226同樣之手法，得到為淡褐色結晶之標題化合 物（60.0 mg，0.130 mmol，65%)。 !H-NMR 光譜（DMSO-d6)(5 (ppm): 3.95 (3H，s)，3.97 (3H，s)， 6.73-6.77 (2H，m)，7·31 (1H，s)，7.34 (1H，d，J=4.0 Hz)，7.40 -350 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 裝 訂 絲 1304061 A7 B7 五、發明説明（345 ) (1H，s)，7·44-7·48 (1H，m)，7.49-7.54 (1H，m)，7.71-7.75 (1H， m)，7·94-7·96 (1H，m)，8·48 (1H，d, J=4.8 Hz)，9.30 (1H，brs)，10.40 (1H，br s)。實施例230N-(5:丄二甲氧基4生二硫）。盡 基）脲· 將5-(6,7-二曱氧基喹啉-4_基硫）噻吩-2-基胺（31.81^, 0.100 mmol)及噻唑-2-基胺基曱酸苯酯（33 〇 ^ , 0el50 mmol)在二曱基亞颯（1 mi)中，於85它攪摔2小時。將反應 液在乙酸乙酯與水間分溶，將有機層用水及飽和食鹽水洗 平，用無水硫酸鎂乾燥，濾除乾燥劑及將濾液減壓蒸餾。 將得到之粗生成物付諸於矽凝膠管柱層析（溶出液，乙酸乙 醋·甲醇=20 : 1) ’將包含目的物之溶出份濃縮，懸浮於 乙酸乙酯’將其用己烷稀釋及濾取結晶，$己烷洗淨後， 藉由通風乾燥，得到為無色結晶之標題化合物（25 6 mg , 0.058 mmol，58%) 〇 h-NMR光譜（DMSO-d6)(5(Ppm): 3.95 (3H，s)，3 97 (3H s) 6.74 (1H, d, J=5.0 Hz), 6.75-6.80 (1H, m), 7.〇；.7.1〇 (1H&gt; mi, 7.32 (1H, s), 7.34 (1H, d, J=4.0 Hz), 7.36-7.39 (1H, m), 7.40 (1H，s)，8·48 (1H，d，J=5.0 Hz)。 實施例231Hz) 〇-348 - This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 343 V. Invention description (Example 226-3) Sulfur ridge-2_ A neck will be 6,7- Dimethoxy- 4-(5-nitro, cephen-2-ylthio)quinoline (1.39 g, 4.00 mmol), iron (1·12 g, 2〇〇_〇1) and ammonium chloride ( 2 18 g, 4 〇〇mmol), in a mixture of ethanol (32 ml)-water (8 mi), stirred at 8 (rc for 5 minutes). After the reaction was completed, the reaction mixture was filtered through celite. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was evaporated under reduced pressure. The crude product was applied to a gel column. The title compound (1.93 g, 5.54 mmol, 55%) was obtained. Lf(CDCl3)(5(ppm): 4 〇4 (3H,s), 4 〇6 (3H,s), 4.15 (2H,s), 6.21 (1H,d,J=3.8 Hz),6·87 (1H,d,J=5.0 Hz), 7.04 (1H,d,J=3.8 Hz),7·31 (1H,s), 7.40 (1H, s), 8.47 (1H, d, J = 5.0 Hz) o Example 227 N- 5-(6:1: dimethyl thiopyranyl-4- thio) 违-2-yl)- N,-(4-gas phenyl) 5-(6,7-dimethoxyquinolin-4-ylthio)phosphenylamine (3 18 mg, 0.100 mmol) and 4-fluorobenzene isocyanate The title compound (29.3 mg, 64.3 mmol, 64%) was obtained. (ppm): 3·94 (3H, s), 3.97 (3H, s), 6.70 (1H, d, J—4.0 Hz), 6.74 (1H, d, 1==5.2 Hz), 7.10-7.18 -349 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of invention (344) (2H, m), 7.31 (1H, s), 7·33 (1H, d , J=4.0 Hz), 7.39 (1H, s), 7.45-7.51 (2H, m), 8.48 (1H, d, J=5.2 Hz), 9.05 (1H, br s)3 10.29 (1H, br s) Example 228 N-(5-(6,7-di-methoxy-4-phenyl-4-ylthio) far-named "phenyl" urea - 5-(6,7-«-methoxy淋-4-ylthio)p-cephen-2-ylamine (6 4 · 0 mg, 0.200 mmol) and 4-fluorobenzene isocyanate (15·1 mg, 0.110 mmol), Example 226 in the same way of embodiments, to give pale brown crystals of the title compound (62 · 0 mg, 0.136 mmol, 68%). iH-NMR spectrum (DMSO-d6) 5 (ppm)············································ ,d,J=4.6 Ηζ),6·80-6·85 (1H,m),7.17-7.21 (1H,m), 7.29-7.36 (3H,m),7·40 (1H,s), 7.42 -7.48 (1H,m),8·48 (1H,d,J=4.6 Hz),9·18 (1H,br s), 10.27 (1H,br s) 〇Example 229 phenyl)-Ν· -(5-(6,7-dimethoxylin-4-ylthio)g-phen-2-yl)urea 5-(6,7-dimethoxyquinolin-4-ylsulfonyl) Phen-2-ylamine (64 mg, 0·200 mmol) and 3-cyanophenyl isocyanate (3·7 mg, 0·220 mmol) were obtained as pale brown in the same manner as in Example 226. The title compound was crystallized (60.0 mg, 0.130 mmol, 65%). !H-NMR spectrum (DMSO-d6) (5 (ppm): 3.95 (3H, s), 3.97 (3H, s), 6.73-6.77 (2H, m), 7·31 (1H, s), 7.34 ( 1H,d,J=4.0 Hz), 7.40 -350 - This paper scale is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) Binding wire 1304061 A7 B7 V. Invention description (345 ) (1H, s ),7·44-7·48 (1H,m), 7.49-7.54 (1H,m),7.71-7.75 (1H, m),7·94-7·96 (1H,m),8·48 ( 1H, d, J = 4.8 Hz), 9.30 (1H, brs), 10.40 (1H, br s). Example 230N-(5: fluorene dimethoxy 4 disulfide). -(6,7-dimethoxyoxyquinolin-4-ylthio)thiophen-2-ylamine (31.81^, 0.100 mmol) and thiazol-2-ylaminophosphonate (33 〇^, 0el50 mmol In the diterpene (1 mi), it was stirred for 2 hours at 85. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The obtained crude product was subjected to a gel column chromatography (eluent, ethyl acetate, methanol = 20:1). The concentrate containing the target substance was concentrated, suspended in ethyl acetate, and used to be used. The title compound (25 6 mg, 0.058 mmol, 58%) was obtained as a colorless crystal. Ppm): 3.95 (3H, s), 3 97 (3H s) 6.74 (1H, d, J=5.0 Hz), 6.75-6.80 (1H, m), 7.〇;.7.1〇(1H&gt; mi, 7.32 (1H, s), 7.34 (1H, d, J = 4.0 Hz), 7.36-7.39 (1H, m), 7.40 (1H, s), 8.48 (1H, d, J = 5.0 Hz). 231

装 訂Binding

線 N-(5-(6,7-二甲氣某4啉-4-某硫） 醯笨基）脹- 基）-Ν’-Γ3- f 碏 將5-(6,7-二甲氧基峻淋-4-基硫）喧吩 2-基胺（64.0 mg， -351 - 本紙張尺度適用中國國家標準(CMS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（346 ) 0.200 mmol)及（3 -甲磺醯苯基）胺基甲酸酯（87·4 mg，0.300 mmol)，以與實施例230同樣之手法，得到為淡褐色結晶之 標題化合物（61.0 mg，0.118 mmol，59%)。 W-NMR 光譜（DMSO-d6)5(PPm): 3.20 (3H，s)，3·95 (3H，s)， 3·97 (3Η，s)，6.75 (1Η，d，J=4.8 Hz), 6.76 (1Η，d，J=4.0 Ηζ)， 7.32 (4H, s), 7.35 (1H, d, J=4.0 Hz), 7.40 (1H, s)5 7.53-7.60Line N-(5-(6,7-dimethyl gas 4 4 -4- thio) 醯 基 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Kejun -4--4-yl thio) porphin 2-ylamine (64.0 mg, -351 - This paper scale applies to Chinese National Standard (CMS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (346 The title compound (61.0 mg, m.p.), m. 0.118 mmol, 59%). W-NMR spectrum (DMSO-d6) 5 (PPm): 3.20 (3H, s), 3·95 (3H, s), 3·97 (3Η, s), 6.75 (1Η, d, J=4.8 Hz) , 6.76 (1Η,d,J=4.0 Ηζ), 7.32 (4H, s), 7.35 (1H, d, J=4.0 Hz), 7.40 (1H, s)5 7.53-7.60

(2H，m)，7.70-7.74 (1H，m)，8·13-8·16 (1H，m)，8·48 (1H，d， J=4.8 Hz)，9.40 (1H，br s)，10.35 (1H，br s)。 實施例232 义（5-(6,7-二曱氫某4啉-4-基硫）4吩-2-基）-：^彳2-#1^ 基笨基）脲 將（5-(6,7-二甲氧基喹啉-4-基硫）噻吩-2-基）胺基甲酸苯 酉旨（43.9 mg，0.100 mmol)及 2-胺基爷醇（24.6 mg，0.200 mmol)，以與實施例230同樣之手法，得到為無色結晶之標 題化合物（27.0 mg，0.058 mmol，58%)。(2H,m), 7.70-7.74 (1H,m),8·13-8·16 (1H,m),8·48 (1H,d, J=4.8 Hz), 9.40 (1H,br s), 10.35 (1H, br s). Example 232 (5-(6,7-dihydrogen 4 phenanthyl-4-ylthio) 4 phen-2-yl)-:^彳2-#1^ phenyl) urea (5-( 6,7-Dimethoxyquinolin-4-ylthio)thiophen-2-yl)carbamic acid benzoquinone (43.9 mg, 0.100 mmol) and 2-aminosityl alcohol (24.6 mg, 0.200 mmol), The title compound (27.0 mg, 0.058 mmol, 58%) was obtained.

iH-NMR 光譜（DMSO-d6)6(PPni): 3·94 (3H，s)，3·96 (3H，s)， 4·54 (2Η，d，J=5.6 Ηζ)，5·51 (1Η，t，J=5.6 Ηζ)，6.65 (1Η，d， J=4.0Hz)，6.74(lH，d，J=4.8Hz)，7.02-7.07 (lH，m)，7.22-7·27 (1H，m)，7·28-7·34 (3H，m)，7·39 (1H，s)，7.80-7.84 (1H， m)，8.46-8.50 (2H，m)，10.89 (1H，br s)。 如下述合成中間體。 製造例232- 1 (5-(6,7-士甲氧某4啉-4-基硫）遠吩-2-某）胺基甲酸笨酯 將5-(6,7-二甲氧基喹啉-4-基硫）喹吩-2-基胺（696 mg， 352 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（347 2.00 mmol)及吡啶（174mg，2.20 mmo丨）溶於四氫呋喃（1〇 ml)-二曱基甲醯胺（5 ml)之混合溶媒中，於冰冷下加入氯 甲酸苯酯（329 mg，2.10 mmol)後，於室溫攪拌1小時。將 反應液在乙酸乙酯與水間分溶，將有機層用水及飽和食鹽 水洗淨，用無水硫酸鎂乾燥，濾除乾燥劑及將濾液減壓蒸 餾。在得到之粗生成物中加入乙酸乙酯，繼而加入己燒， 濾取析出之結晶，藉由通風乾燥，得到為黃褐色結晶之標 題化合物（720 mg，1.64 mmol，82%)。 絮 1H-NMR 光譜（CDCl3)5(ppm)·· 4·08 (3H，s)，4.09 (3H，s)， 6.86-6.92 (2Η，m)，7.10-7.16 (2Η，m)，7·20-7·26 (2Η，m)， 7.34 (1H，s)，7.36-7.41 (2H，m)，7.80-7.85 (1H，m)，8·35 (1H， d，J=5.6 Hz)，8·75 (1H，br s)。 實施例233 5-(6,7-二曱氣基4啉-4-某硫）唼吩-2-基Ν'η-淼甲 基笨基）脲 以與實施例230同樣之手法，從製造例232- 1得到之（5. (6,7-二甲氧基喹啉-4-基硫）噻吩-2-基）胺基甲酸苯酯（43.9 mg，0.100 mm〇l)及 3-胺基苄醇（24.6 mg，0.200 mmol)，得 到為淡褐色結晶之標題化合物（25.0 mg ’ 0·054 mmol， 54%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 3·95 (3H，s)，3·97 (3H，s)5 (46 (2H，d，J=5.6 Hz)，5.19 (1H，t，Hz)，6·70 (1H，d， J=4.〇 Hz), 6.75 (1H, d, J=4.8 Hz), 6.93-6.97 (1H, m)5 7.21-7·26 (1H，m)，7.30-7.34 (3H，m)，7·40 (1H，s)，7.43-7.46 (1H， -353 - 本故張尺度通用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（348 ) m)，8·48 (1H，d，J=4.8 Hz)，8.97 (1H，s)。 實施例234 N-( 5-(6,7-二曱氣某4啉-4-基硫吩-2-基）-Ν’-(4-羥i 基笨基）脲 以與實施例230同樣之手法，從（5-(6,7-二甲氧基4啉-4-基硫）嘍吩-2-基）胺基甲酸苯酯（43.9 mg，〇·1〇〇 mmol)及4-胺基节醇（224 mg，1.82 mmol)，得到為淡黃色結晶之標題 化合物（27.0 mg，0.058 mmol，58%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 3·94 (3H，s)，3·97 (3H，s)， 4·42 (2Η，d，J=5.6 Ηζ)，5.07 (1Η，t，J=5.6 Ηζ)，6.69 (1Η，d， J=4.0 Hz), 6.75 (1H, d, J=5.0 Hz), 7.21-7.26 (2H, m), 7.30-7·34 (2H，m)，7.38-7.43 (3H，m)，8.47 (1H，d，J=5.0 Hz)， 8.88 (1H，s)，10.13 (1H，s) 〇 實施例23 5 K2-(6,7-二甲氣某4啉-4-某硫唑-5-基W-笨基脲 將2-(6,7-二甲氧基峻淋-4-基硫）u基嗅-5 -基胺（64·0 mg， 0.200 mmol)及異氰酸苯酯（26·2 mg，0.220 mmol)在二甲基 甲醯胺（lml)中，於室溫攪捽15小時。將反應液在乙酸乙酯 與水間分溶，將有機層用水及飽和食鹽水洗淨，用無水硫 酸鎂乾燥，濾除乾燥劑及將濾液減壓蒸餾。將得到之粗生 成物付諸於矽凝膠管柱層析（溶出液，乙酸乙酯··甲醇 =30 : 1)，將包含目的物之溶出份濃縮，懸浮於乙酸乙酯， 將其用己垸·稀釋及濾取結晶，用己烷洗淨後，藉由通風乾 燥’得到為無色結晶之標題化合物（53.2 mg，0.121 mmol， _____- 354 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A? … _ _ B7 五、發明説明（349 ) 60%) 0 iH-NMR 光譜（DMSO-d6)5(ppm): 3·94 (3H，s)，3·95 (3H，s)， 6.98-7.05 (2Η, m), 7.26-7.34 (2H, m), 7.39 (1H, s)3 7.43-7·47 (3H，m)，7.64 (1H，s)，8.55 (1H，d，J=4.8 Hz)，9_10 (1H， s)，10.29 (1H，br s) 〇 如下述合成中間體。 主j i告例23 5- 1 i.7-二甲氧基·4-(5-硝基p塞唑-2-某硫）崦啉 將 6,7-二甲氧基-1H-喹啉-4-硫酮（2·21 g，10.0 mmol)懸 浮於二甲基甲醯胺（30 ml)，於0°C加入2-溴-5-硝基噻唑 (2·30 g，11·〇 mmol)後，於室溫攪拌1小時。將反應液在乙 酸乙酯與1N氫氧化鈉水溶液間分溶，將有機層用水及飽和 食鹽水洗淨後，用無水硫酸鎂乾燥，濾除乾燥劑及將濾液 減壓蒸餾。將得到之粗生成物付諸於矽凝膠管柱層析（溶出 液，乙酸乙酯：己烷=3 : 1 )，將包含目的物之溶出份濃 縮，懸浮於乙酸乙酯，將其用己烷稀釋及濾取結晶，用己 烷洗淨後，藉由通風乾燥，得到為淡黃色結晶之標題化合 物（1.70g，4.87 mmol，49%)。 1H-NMR 光譜（CDCl3)(5(ppm): 4.00 (3H，s)，4·08 (3H，s)， 7·50 (1H，s)，7.54 (1H，s)，7·70 (1H，d，J=4.8 Hz)，8.37 (1H， s)，8.83 (1H，d，J=4.8 Hz)。 製造例235-2 2 - ( 6，7 - 乳基林-4-基硫）嚷吐-5-基胺 將6,7- —甲乳基-4- ( 5-硝基4吐-2-基硫）峻琳（699 mg， -355 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 裝 訂iH-NMR spectrum (DMSO-d6) 6 (PPni): 3·94 (3H, s), 3·96 (3H, s), 4·54 (2Η, d, J=5.6 Ηζ), 5·51 ( 1Η, t, J=5.6 Ηζ), 6.65 (1Η, d, J=4.0Hz), 6.74 (lH, d, J=4.8Hz), 7.02-7.07 (lH, m), 7.22-7·27 (1H ,m),7·28-7·34 (3H,m),7·39 (1H,s), 7.80-7.84 (1H, m), 8.46-8.50 (2H,m),10.89 (1H,br s ). The intermediate is synthesized as follows. Production example 232- 1 (5-(6,7-s. methoxy) 4 phenanthyl-4-yl thio) far phen-2-one) carbamic acid benzoate 5-(6,7-dimethoxyquine Phenyl-4-ylthio)quin-2-ylamine (696 mg, 352 - paper size applicable to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304061 A7 B7 V. Description of invention (347 2.00 mmol And pyridine (174 mg, 2.20 mmo) dissolved in tetrahydrofuran (1 〇ml)-dimercaptocaramine (5 ml) in a mixed solvent, and then added phenyl chloroformate (329 mg, 2.10 mmol). The mixture was stirred at room temperature for 1 hour, and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. Ethyl acetate was added to the obtained crude product, which was then added to hexanes, and the crystals which were crystallised, which was crystallized to give the title compound (720 mg, 1.64 mmol, 82%). Spectrum (CDCl3) 5 (ppm)·· 4·08 (3H, s), 4.09 (3H, s), 6.86-6.92 (2Η, m), 7.10-7.16 (2Η, m), 7·20-7· 26 (2Η,m), 7.34 (1H,s),7.36-7.41 (2H m), 7.80-7.85 (1H, m), 8.35 (1H, d, J = 5.6 Hz), 8.75 (1H, br s). Example 233 5-(6,7-dioxane group (4,7--) was obtained in the same manner as in Example 230 in the same manner as in Example 230 (5. (6,7-). Phenyl dimethoxyquinolin-4-ylthio)thiophen-2-yl)carbamate (43.9 mg, 0.100 mmol) and 3-aminobenzyl alcohol (24.6 mg, 0.200 mmol) The title compound (25.0 mg '0·054 mmol, 54%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 3·95 (3H, s), 3·97 (3H, s) 5 (46 (2H, d, J = 5.6 Hz), 5.19 (1H, t ,Hz),6·70 (1H,d, J=4.〇Hz), 6.75 (1H, d, J=4.8 Hz), 6.93-6.97 (1H, m)5 7.21-7·26 (1H,m ), 7.30-7.34 (3H, m), 7·40 (1H, s), 7.43-7.46 (1H, -353 - Former Zhang Scale General China National Standard (CNS) A4 Specification (210 x 297 mm) 1304061 A7 B7 V. Description of invention (348) m), 8·48 (1H, d, J = 4.8 Hz), 8.97 (1H, s). Example 234 N-(5(6,7-dioxin) 4-Phenyl-4-ylthiophen-2-yl)-indole'-(4-hydroxyiylphenyl)urea in the same manner as in Example 230, from (5-(6,7-dimethoxy) Phenyl-4-ylthio)porphin-2-yl)carbamic acid phenyl ester (43.9 mg, 〇·1 mmol) and 4-amino benzyl alcohol (224 mg, 1.82 mmol) afforded pale yellow crystal The title compound (27.0 mg, 0.058 mmol, 58%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 3·94 (3H, s), 3·97 (3H, s), 4·42 ( 2Η,d,J=5.6 Ηζ),5.07 (1Η,t,J=5.6 Ηζ), 6.69 (1Η,d, J=4.0 Hz), 6.75 (1H, d, J=5.0 Hz), 7.21-7.26 ( 2H, m), 7.30-7.34 (2H m), 7.38-7.43 (3H, m), 8.47 (1H, d, J = 5.0 Hz), 8.88 (1H, s), 10.13 (1H, s) 〇 Example 23 5 K2-(6,7-II A gas, 4, 4-pyrimidin-5-yl W-indolyl urea, 2-(6,7-dimethoxy-threo-4-ylthio)uyl ol-5-ylamine (64 · 0 mg, 0.200 mmol) and phenyl isocyanate (26.2 mg, 0.220 mmol) in dimethylformamide (1 ml), stirred at room temperature for 15 h. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated, and the filtrate was evaporated under reduced pressure. The crude product was applied to a gel column chromatography ( The eluate, ethyl acetate··methanol=30: 1), the concentrate containing the target substance was concentrated, suspended in ethyl acetate, diluted with hexane, and crystallized by filtration, washed with hexane, and then borrowed. The title compound (53.2 mg, 0.121 mmol, _____-354 - the paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A? _ _ B7 Description of the invention (349 ) 60%) 0 iH-NMR spectrum (DMSO-d6) 5 (ppm): 3 94 (3H, s), 3.95 (3H, s), 6.98-7.05 (2Η, m), 7.26-7.34 (2H, m), 7.39 (1H, s)3 7.43-7·47 (3H, m ), 7.64 (1H, s), 8.55 (1H, d, J = 4.8 Hz), 9_10 (1H, s), 10.29 (1H, br s) The following synthetic intermediates. Master 告 例 Example 23 5- 1 i.7-Dimethoxy·4-(5-nitrop-stazole-2-one thio)porphyrin 6,7-dimethoxy-1H-quinoline- 4-thione (2·21 g, 10.0 mmol) was suspended in dimethylformamide (30 ml), and 2-bromo-5-nitrothiazole (2·30 g, 11·〇mmol) was added at 0 °C. After that, it was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and 1N aqueous sodium hydroxide, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained crude product was subjected to a gel column chromatography (eluent, ethyl acetate:hexane = 3:1), and the fractions containing the desired product were concentrated, suspended in ethyl acetate, and used. The title compound (1.70 g, 4.87 mmol, 49%) was obtained. 1H-NMR spectrum (CDCl3) (5 (ppm): 4.00 (3H, s), 4·08 (3H, s), 7·50 (1H, s), 7.54 (1H, s), 7·70 (1H) , d, J = 4.8 Hz), 8.37 (1H, s), 8.83 (1H, d, J = 4.8 Hz). Production Example 235-2 2 - (6,7 - lactyl-4-ylthio)嚷吐-5-ylamine will 6,7--methyllacyl-4-( 5-nitro-4-t-2-yl thio) Jun Lin (699 mg, -355 - this paper size applies to Chinese National Standard (CNS) A4 size (210X297 mm) binding

線 1304061明 5月 Γ~^) Α7 Β7 2.00 mmol)，鐵（ 559 mg，10.0 mmol)及氯化銨（1.07 g， 20·0 mmol)懸浮在乙醇（20 ml)-水（5 ml)之混合溶媒中，於 80 °C加熱攪拌20分鐘。反應終了後，將反應混合物經矽藻 土過濾，用乙酸乙酯-四氫呋喃之混合溶媒洗出。將有機層 用水及飽和食鹽水洗淨，用硫酸鎂乾燥後，濾除乾燥劑及 將濾液減壓蒸餾。將得到之粗生成物付諸於矽凝膠管柱層 析（溶出液，乙酸乙酯：甲醇=30 : 1)，將包含目的物之溶 出份濃縮，得到為黃褐色結晶之標題化合物（丨9〇 mg， 0.595 mmol，30%) 〇 iH-NMR 光譜（CDCl3)5(ppm): 3.99 (2H，br s)，4·04 (3H，s)， 4·05 (3Η，s)，7·10 (1Η，d，J=5.2 Hz), 7.17 (1Η，s)，7·41 (1Η， s)，7·42 (1H，s)，8·54 (1H，d，J=5.2 Hz) 〇 實施例236 N-(2-(6,7-二甲氧基g套琳-4-基硫）4咬-5 -基）氣笨 基）脲 以與實施例235同樣之手法，從2-(6,7-二甲氧基喹啉-4-基硫）p塞也-5-基胺（64.0 mg，0.200 mmol)及異氰酸4-氣苯 酯（30.1 mg，0.220 mmol)，得到為無色結晶之標題化合物 (62·3 mg，0.136 mmol，68%) 〇 ipi-NMR 光譜（DMSO-d6)5(ppm): 3.94 (3H，s)，3·95 (3H，s)， 7.03 (1H，d，J=4.8 Hz)，7·10-7·18 (2H，m)，7.39 (1H，s)， 7.42-7.48 (3H，m)，7.64 (1H，s)，8·55 (1H，d，J=4.8 Hz)，9.14 (1H，s)，10·32 (1Ή，br s)。 實施例237 -356 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐）Line 1304061May May Γ~^) Α7 Β7 2.00 mmol), iron (559 mg, 10.0 mmol) and ammonium chloride (1.07 g, 20·0 mmol) suspended in ethanol (20 ml)-water (5 ml) The mixture was heated and stirred at 80 ° C for 20 minutes in a mixed solvent. After the end of the reaction, the reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The obtained crude product was subjected to hydrazine gel column chromatography (eluent, ethyl acetate:methanol = 30:1), and the fractions containing the desired compound were concentrated to give the title compound as a yellow brown crystal. 9〇mg, 0.595 mmol, 30%) 〇iH-NMR spectrum (CDCl3) 5 (ppm): 3.99 (2H, br s), 4·04 (3H, s), 4·05 (3Η, s), 7 ·10 (1Η,d,J=5.2 Hz), 7.17 (1Η,s),7·41 (1Η, s),7·42 (1H,s),8·54 (1H,d,J=5.2 Hz 〇 Example 236 N-(2-(6,7-dimethoxyg-teridin-4-ylsulfanyl)4 octa--5-yl) oxalyl)urea in the same manner as in Example 235, from 2-(6,7-dimethoxyquinolin-4-ylsulfanyl)p-s--5-ylamine (64.0 mg, 0.200 mmol) and 4-phenylphenyl isocyanate (30.1 mg, 0.220 mmol) The title compound (62·3 mg, 0.136 mmol, 68%) was obtained as colorless crystals. 〇ipi-NMR spectrum (DMSO-d6) 5 (ppm): 3.94 (3H, s), 3·95 (3H, s) , 7.03 (1H,d,J=4.8 Hz),7·10-7·18 (2H,m), 7.39 (1H,s), 7.42-7.48 (3H,m),7.64 (1H,s),8 · 55 (1H, d, J = 4.8 Hz), 9.14 (1H, s), 10.32 (1Ή, br s). Example 237 -356 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂Binding

線 1304061 A7 ' · B7 五、發明説明（351) Ν-(2-(6·7-二甲氣基4:啉·4-—基硫）噗唑-5-基）-N，“3 -氯茇 基）脲 以與實施例235同樣之手法，從2-(6,7-二甲氧基♦啉-4-基硫）p塞咬_5-基胺（95.8 mg，0·300 mmol)及異氰酸3-氟苯 酯（45.2 mg，0.330 mmol)，得到為無色結晶之標題化合物 (70.0 ing * 0.153 mmol , 51%) 〇 iH-NMR 光譜（DMS〇-d6)5(ppm): 3·94 (3H，s)，3·95 (3H，s)， 6.80-6.86 (1Η，m)，7.06 (1Η，d，J=4.8 Ηζ)，7·16·7·20 (1Η，m)， 7·28-7·35 (1H，m)，7.38-7.45 (3H，m)，7·66 (1H，s)，8·55 (1H， d，J=4.8 Hz)，9·33 (1H，s)，10.37 (1H，br s)。 實施例23 8 N-(3 -氰基笨基）-N*-(2-(6,7 -二甲氧基g奎淋-4-基硫）ΐ?塞峻一 5-基）脲 以與實施例235同樣之手法，從2-(6,7-二甲氧基喹啉-4-基硫）邊咬-5-基胺（95.8 mg，0.300 mmol)及異氰酸3-氰基 苯酯（47·6 mg，0··33 0 mmol)，得到為淡黃色結晶之標題化 合物（94·0 mg，0.203 mmol，68%)。 W-NMR 光譜（DMSO-d6)5(ppm): 3.94 (3H，s)，3.95 (3H，s)， 7.07 (1H, d5 J=4.8 Hz), 7.40 (1H, s), 7.43 (1H, s), 7.45-7.54 (2H，m)，7·67 (1H，s)，7·70-7·74 (1H，m)，7.91-7.94 (1H，m)， 8·56 (1H，d，J=4.8 Hz)，9·44 (1H，s)，10.49 (1H，br s)。 實施例239 N-(2,4-二氣笨基二甲氳基喹啉-4-养硫）違 唑-5-某）Μ 357 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐） 1304061 〜 -. A7 _ B7 五、發明説明（352 ) 以與實施例235同樣之手法，從2-(6,7-二甲氧基峻琳 基硫塞咬-5-基胺（95.8 mg，0.300 mmol)及異氰酸2,4_二 氟苯酯（5 1 ·2 mg，0.330 mmol)，得到為淡褐色結晶之標題 化合物（123 mg，0.259 mmol，86%)。 W-NMR光譜（DMSO-d6)(5(ppm): 3.94 (3H，s)，3.95 (3H，s)， 7.04 (1H, d, J=4.8 Hz), 7.05-7.09 (1H, m), 7.30-7.37 (1H, m), 7.39 (1H，s)，7·43 (1H，s)，7·65 (1H，s)，7.84-7.91 (1H，m)， 8.54 (1H，d，J=4.8 Hz)，8·84 (lH，s)，10.48 (1H，br s)。 實施例240 N-(2-氣笨基）-N*-(2-(6,7-二甲氣某g奎g林-4-基硫）p塞峻- 5· 基）脲 以與實施例235同樣之手法，從2-(6,7-二甲氧基喹啉-4-基硫唑-5-基胺（95.8 mg，0.300 mmol)及異氰酸2-氯苯 酯（50.6 mg，0.330 mmol)，得到為淡褐色結晶之標題化合 物（132 mg，0.279 mmo卜 93%) 〇 iH-NMR 光譜（DMS〇-d6)5(ppm): 3·94 (3H，s)，3·95 (3H，s)， 7.05 (1Η，d，J=5.0 Hz), 7.07-7·12 (1Η，m)，7·28-7·34 (1Η，m)， 7·39 (1H，s)，7.43 (1H，s)，7.47-7.50 (1H，m)，7·67 (1H，s)， 8.01-8.04 (1H，m)，8·55 (1H，d，J=5.0 Hz)，8·62 (1H，s)， 10.85 (1H，br s)。 實施例241 N-(3 -氣笨基）-Ν、（2·(6,7- 一甲幕口套g林-4-基硫）口篆峻- 5· 基）脲 以與實施例2 3 5同樣之手法’從2 - ( 6，7 -二甲氧基ρ奎琳-4 - -358 - 本纸張尺度適用中國國家標準(CMS) Α4規格（210 X 297公釐） 1304061 〜 A7 B7 五、發明説明（353 ) 基硫）喧咬-5-基胺（95.8 mg ’ 0.300 mmol)及異氰酸3-氯苯 酯（50.6 mg，0.330 mmol)，得到為淡褐色結晶之標題化合 物（124 mg，0.262 mmol，87%) 〇 W-NMR 光譜（DMS〇-d6)5(ppm): 3.94 (3H，s)，3·95 (3H，s)， 7.04-7.09 (2H，m)，7·30-7·34 (2H，m)，7·40 (1H，s)，7·43 (1H， s)，7.63-7.66 (2H，m)，8.55 (1H，d，J=4.8 Hz)，9·30 (1H，s)， 10.40 (1H，br s)。 實施例242 N-(4-氣笨基W-(2-(6,7-二甲氧基1?杳〃林-4-基硫）嗤嗅-5-基）脲 以與實施例235同樣之手法，從2-(6,7-二曱氧基喹啉-4-基硫）違也-5-基胺（95·8 mg，0.300 mmol)及異氰酸4-氯苯 酯（50.6 mg，0.33 0 mmol)，得到為無色結晶之標題化合物 (120 mg，0.253 mmol，85%)。 ifi-NMR 光譜（DMS〇-d6)3(Ppm): 3·94 (3H，s)，3.95 (3ίί，s)， 7.04 (1H，d，J=4.8 Hz)，7.31-7.36 (2H，m)，7.39 (1H，s)，7.43 (1H，s)，7.45-7.50 (2H，m)，7·65 (1H，s)，8·55 (1H，d，J=4.8 Hz)，9.24 (1H，s)，10.34 (1H，br s)。 實施例243 N二ί 2- (6,7-二甲氧基g林-4-基瑞）違唑-5-基）-N，-(遠唾- 2-基）脲 將2-(6,7-二甲氧基喹啉-4-基硫）噻唑-5-基胺（216 mg , 0.676 mmol)及说啶（58·8 mg , 0.743 mmol)溶於四氫呋喃（3 ml)中，於冰冷下加入氯曱酸4-硝基苯酯（15〇 mg，〇.743 -359 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 、 A7 _____B7 五、發明説明（354 ) mmol)，於室溫攪掉30分鐘後，加入2-胺基嘍唑（101 mg , 1·〇1 mmol)·及三乙胺（1 ml)後，於60°C加熱攪摔丨小時。將 反應液在乙酸乙自旨與水間分溶，將有機層用水及飽和食鹽 水洗淨，用無水硫酸鎂乾燥，濾除乾燥劑及將濾液減壓蒸 餾。將得到之粗生成物付諸於矽凝膠管柱層析（溶出液，乙 酸乙酯：甲醇=30 : 1)，將包含目的物之溶出份濃縮，懸 浮於乙酸乙酯，將其用己烷稀釋及濾取結晶，用己烷洗淨 後’藉由通風乾燥’得到為無色結晶之標題化合物（5 7 mg，0.128 mmol，19%)。 iH-NMR 光譜（DMSO-d6)c5(ppm): 3.94 (3H，s)，3.95 (3H，s)， 7.03-7.09 (2H，m)，7.34-7.38 (1H，m)，7·40 (1H，s)，7.43 (1H， s)，7·66 (1H，br s)，8·55 (1H，d，J=4.8 Hz)。 實施例244 T—里基-( 5- (3-奉基脉）p塞吩-2·基硫）4说· 卷酿胺 將4-(5 -胺基ρ塞吩-2-基硫）-7-甲氧基τ»奎啦_6_幾龜胺（49.0 mg，0.150 mmol)及異氰酸苯酯（19·6 mg , 〇 165 mm〇i)在二 甲基甲醯胺（lml)中，於室溫攪拌2小時。將反應液在乙酸 乙画旨與水間分溶’將有機層用水及飽和食鹽水洗淨，用無 水硫酸鎂乾燥，濾除乾燥劑及將濾液減壓蒸餾。將得到之 粗生成物懸浮於乙酸乙酯中，將其用己烷稀釋及濾取結 晶，用己烷洗淨後，藉由通風乾燥，得到為淡黃色結晶之 標題化合物（25·0 mg，0.056 mmol，37%)。 iH-NMR光譜（DMSO-d6)5(ppm): 4·02 (3H，s)，6.72 (1H，d， J=3.4 Hz), 6.77 (1H, d, J=4.8 Hz), 6.98-7.03 (1H, m), 7.27- -360 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜 A7 ____B7___ 五、發明説明（355 ) 7·34 (2H，m)，7.35 (1H，d，J=3.4 Hz)，7.43-7.49 (2H，m)， 7·53 (1H，s·)，7·80 (1H，br s)，7·89 (1H，br s)，8·52 (1H，s)， 8·65 (1H，d，J=4.8 Hz)，8·95 (1H，br s)，10.21 (1H，br s)。 如下述合成中間體。 製造例244-1 U氧_基-4-(5-硝某4吩-2-基硫啉-6-#醯胺 將4-氯-7-甲氧基喹啉-6-羧醯胺（1.18 g，5.00 mmol)及硫 化鈉（1.20 g，5.50 mmol)於二甲基甲醯胺（10 ml)中，於60 t加熱攪拌3小時。將反應液冷卻至室溫後，加入2-溴-5-稍基邊吩（1.25 g，6.00 mmol)，然後於60°C加熱攪捽1小 時。使反應液回到室溫後，注入冰水（50 ml)中，濾取析出 之結晶，用水及甲醇洗淨後，藉由通風乾燥，得到為黃褐 色結晶之標題化合物（700 mg，1.94 mmol，39%)。 ΐΐί·ΝΜΙΙ光譜（DMS〇-d6)5(ppm): 4.04 (3H，s)，7.17 (1H，d， J=4.6 Hz)，7.59 (1H，s)，7·66 (1H，d，J=4.0 Hz)，7·82 (1H，br s)，7.90 (1H，br s)，8.23 (1H，d，J=4.0 Hz)，8.53 (1H，s)，8.76 (1H，d，J=4.6 Hz)。 製造例244-2 L4- ( 5-胺基嗟吩-2-基硫）-7-甲氣某4却· 6-势g產胺 將7-甲氧基-4-(5-硝基噻吩-2-基硫）喹啉羧醯胺（32〇 mg，0.885 mmol),鐵（247 mg , 4·43 mm〇l)及氯化銨（481 mg，8·85 mmol)懸浮在乙醇（8 ml)-水（2 ml)-二甲基甲醯胺 (1 ml)之混合落媒中，並於80°C加熱攪拌15分鐘。反應終 了後’將反應混合物經麥藻土過;慮，用四氫吱喃-甲醇之混 -361 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（356 ) 合溶媒洗出。在有機層中加入乙酸乙酯，用水及飽和食鹽 水洗淨，用.無水硫酸鎂乾燥，濾除乾燥劑及將遽液減壓蒸 餾。將得、到之粗生成物付諸於矽凝膠管柱層析（溶出液’乙 酸乙酯：甲醇=20 ·· 1)，將包含目的物之溶出份濃縮，得 到為黃褐色結晶之標題化合物（164 mg，〇·495 mmol， 56%)- 光譜（DMS〇-d6)5(ppm): 4.02 (3H，s)，6.00 (1H，d， J=4.0 Hz)，6.34 (2H，s)，6·83 (1H，d，J=4.8 Hz)，7·08 (1H，d， J=4.0 Hz), 7.51 (1H，s)，7·77 (1H，br s)，7.86 (1H，br s)，8·47 (1H，s)，8·66 (1H，d，J=4.8 Hz)。 實施例245 4-(5-(3-(4-氣苯基）脈）g塞吩-2-基硫）-7-甲氣基口奎琳-6 ·琴 醯胺 以與實施例244同樣之方法，從4-(5-胺基嘍吩-2-基硫）-7-甲氧基口奎啉-6-羧醯胺（49.0 mg，0.150 mmol)及異氰酸4-氟苯酯（22.6 mg，0.165 mmol)得到為無色結晶之標題化合 物（50.0 mg，0.107 mmol，71%)。 W-NMR 光譜（DMS〇-d6)5(ppm): 4·03 (3H，s)，6·72 (1H，d， J=4.0 Hz), 6.76 (1H, d, J=4.8 Hz), 7.10-7.18 (2H, m), 7.35 (1H，d，J=4.0 Hz)，7.45-7.51 (2H，m)，7·53 (1H，s)，7.80 (1H， br s), 7.89 (1H, br s), 8.52 (1H, s)5 8.65 ( 1H, d, J=4.8 Hz), 8·99 (1H，br s)，10.24 (1H，br s)。 實施例246 . 7-甲氧基- 4- (5-(3 -違座-2 -基腺）p塞吩-2-幕硫）邊g林- 6- # g產Line 1304061 A7 ' · B7 V. Description of the invention (351) Ν-(2-(6·7-dimethylene 4: phenanthyl-4-ylthio)oxazol-5-yl)-N, "3 - Chloroguanidinium urea in the same manner as in Example 235, from 2-(6,7-dimethoxymorpholin-4-ylsulfanyl) p-bito-5-ylamine (95.8 mg, 0·300 mmol) And 3-fluorophenyl isocyanate (45.2 mg, 0.330 mmol) to give the title compound (70.0 ing * 0.153 mmol, 51%) as colorless crystals 〇iH-NMR spectrum (DMS 〇-d6) 5 (ppm) : 3·94 (3H, s), 3·95 (3H, s), 6.80-6.86 (1Η, m), 7.06 (1Η, d, J=4.8 Ηζ), 7·16·7·20 (1Η, m), 7·28-7·35 (1H,m), 7.38-7.45 (3H,m),7·66 (1H,s),8·55 (1H, d,J=4.8 Hz),9· 33 (1H, s), 10.37 (1H, br s). Example 23 8 N-(3-Cyanophenyl)-N*-(2-(6,7-dimethoxyg quinol-4 -ylthio)anthracene-5-yl)urea in the same manner as in Example 235, biting 5-aminoamine from 2-(6,7-dimethoxyquinolin-4-ylsulfide) (95.8 mg, 0.300 mmol) and 3-cyanophenyl isocyanate (47·6 mg, 0·········· 68%) W-NMR spectrum (DMSO-d6) 5 (ppm): 3.94 (3H, s), 3.95 (3H, s), 7.07 (1H, d5 J = 4.8 Hz), 7.40 (1H, s), 7.43 (1H, s), 7.45-7.54 (2H, m), 7.67 (1H, s), 7·70-7·74 (1H, m), 7.91-7.94 (1H, m), 8.56 (1H, d, J = 4.8 Hz), 9·44 (1H, s), 10.49 (1H, br s). Example 239 N-(2,4-dioxaphenyldimethyl quinolin-4 - sulphur) azole-5-m) 357 357 This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 1304061 ~ -. A7 _ B7 V. Invention Description (352) 235, the same method, from 2-(6,7-dimethoxy-junylthioserate-5-ylamine (95.8 mg, 0.300 mmol) and 2,4-difluorophenyl isocyanate (5 1 The title compound (123 mg, 0.259 mmol, 86%). W-NMR spectrum (DMSO-d6) (5 (ppm): 3.94 (3H, s), 3.95 (3H, s), 7.04 (1H, d, J = 4.8 Hz), 7.05-7.09 (1H, m), 7.30-7.37 (1H, m), 7.39 (1H, s), 7·43 (1H, s), 7·65 (1H, s), 7.84-7.91 (1H, m), 8.54 (1H, d, J = 4.8 Hz), 8.84 (lH, s), 10.48 (1H, br s). Example 240 N-(2-gas base)-N*-(2-(6,7-dimethyl gas) G-g-glin-4-ylthio)p-suppressor-5-urea urea in the same manner as in Example 235, from 2-(6,7-dimethoxyquinolin-4-ylthiazol-5 - ylamine (95.8 mg, 0.300 mmol) and 2-chlorophenyl isocyanate (50.6 mg, 0.330 mmol). (DMS〇-d6)5(ppm): 3·94 (3H,s),3·95 (3H,s), 7.05 (1Η,d,J=5.0 Hz), 7.07-7·12 (1Η,m ),7·28-7·34 (1Η,m), 7·39 (1H,s), 7.43 (1H,s), 7.47-7.50 (1H,m),7·67 (1H,s), 8.01 -8.04 (1H, m), 8.55 (1H, d, J = 5.0 Hz), 8.62 (1H, s), 10.85 (1H, br s). Example 241 N-(3 - gas-based )-Ν, (2·(6,7-一甲幕口套g林-4-基硫) 口篆峻 - 5· base Urea in the same way as in Example 2 3 5 'from 2 - ( 6,7 -dimethoxy ρ 奎 琳 -4 - -358 - This paper scale applies Chinese National Standard (CMS) Α 4 specifications (210 X 297 1304061 ~ A7 B7 V. Description of the invention (353) thiol) bite-5-ylamine (95.8 mg '0.300 mmol) and 3-chlorophenyl isocyanate (50.6 mg, 0.330 mmol), The title compound (124 mg, 0.262 mmol, 87%) of yellow crystals 〇W-NMR spectrum (DMS 〇-d6) 5 (ppm): 3.94 (3H, s), 3·95 (3H, s), 7.04- 7.09 (2H,m),7·30-7·34 (2H,m),7·40 (1H,s),7·43 (1H, s), 7.63-7.66 (2H,m),8.55 (1H , d, J = 4.8 Hz), 9·30 (1H, s), 10.40 (1H, br s). Example 242 N-(4-indolyl W-(2-(6,7-dimethoxy)-indolyl-4-ylthio)oxime-5-yl)urea was obtained in the same manner as in Example 235 The method is 2-(6,7-dimethoxyoxyquinolin-4-ylsulfanyl)--5-ylamine (95·8 mg, 0.300 mmol) and 4-chlorophenyl isocyanate (50.6 The title compound (120 mg, 0.253 mmol, 85%) was obtained as colorless crystals. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (3ίί,s), 7.04 (1H,d,J=4.8 Hz),7.31-7.36 (2H,m),7.39 (1H,s),7.43 (1H,s),7.45-7.50 (2H,m), 7·65 (1H, s), 8.55 (1H, d, J = 4.8 Hz), 9.24 (1H, s), 10.34 (1H, br s). Example 243 N 2ί 2- (6,7 -dimethoxyglycine-4-ylidene)-oxazol-5-yl)-N,-(far-salt-2-yl)urea 2-(6,7-dimethoxyquinoline-4- Thiothiazol-5-ylamine (216 mg, 0.676 mmol) and pyridine (58·8 mg, 0.743 mmol) were dissolved in tetrahydrofuran (3 ml), and 4-nitrophenyl chloroformate was added under ice cooling. (15〇mg, 〇.743 -359 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061, A7 _____B7 V. (354) mmol), after stirring at room temperature for 30 minutes, add 2-aminocarbazole (101 mg, 1·〇1 mmol)· and triethylamine (1 ml), then heat at 60 ° C Wrestle for hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained crude product was subjected to hydrazine gel column chromatography (eluent, ethyl acetate:methanol = 30:1), and the fractions containing the desired product were concentrated, suspended in ethyl acetate, and used for The title compound (5 7 mg, 0.128 mmol, 19%) was obtained. iH-NMR spectrum (DMSO-d6) c5 (ppm): 3.94 (3H, s), 3.95 (3H, s), 7.03-7.09 (2H, m), 7.34-7.38 (1H, m), 7·40 ( 1H, s), 7.43 (1H, s), 7.66 (1H, br s), 8·55 (1H, d, J = 4.8 Hz). Example 244 T-Ric-(5-(3-Benyl) p-Phenyl-2·ylthio) 4 says · The amine can be 4-(5-amino-p-phen-2-ylthio) -7-Methoxy τ»奎啦_6_Homochelamide (49.0 mg, 0.150 mmol) and phenyl isocyanate (19·6 mg, 〇165 mm〇i) in dimethylformamide (1 ml) In the mixture, it was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and water. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained crude product was suspended in ethyl acetate, EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 0.056 mmol, 37%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 4·02 (3H, s), 6.72 (1H, d, J = 3.4 Hz), 6.77 (1H, d, J = 4.8 Hz), 6.98-7.03 (1H, m), 7.27- -360 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ~ A7 ____B7___ V. Invention description (355) 7·34 (2H, m), 7.35 (1H,d,J=3.4 Hz), 7.43-7.49 (2H,m), 7·53 (1H,s·),7·80 (1H,br s),7·89 (1H,br s) , 8·52 (1H, s), 8·65 (1H, d, J = 4.8 Hz), 8.95 (1H, br s), 10.21 (1H, br s). The intermediate is synthesized as follows. Production Example 244-1 U-oxy-yl-4-(5-nitano-4phen-2-ylsulfanyl-6-#decylamine 4-chloro-7-methoxyquinolin-6-carboxamide 1.18 g, 5.00 mmol) and sodium sulphide (1.20 g, 5.50 mmol) in dimethylformamide (10 ml), stirred for 3 hours with stirring at 60 t. After cooling the reaction mixture to room temperature, 2-bromo -5- slightly flank (1.25 g, 6.00 mmol), and then stirred at 60 ° C for 1 hour while heating. The reaction solution was returned to room temperature, poured into ice water (50 ml), and the precipitated crystals were collected by filtration. The title compound (700 mg, 1.94 mmol, 39%) was obtained as a yellow-brown crystals eluted with EtOAc (EtOAc: EtOAc) s), 7.17 (1H, d, J = 4.6 Hz), 7.59 (1H, s), 7.66 (1H, d, J = 4.0 Hz), 7·82 (1H, br s), 7.90 (1H, Br s), 8.23 (1H, d, J = 4.0 Hz), 8.53 (1H, s), 8.76 (1H, d, J = 4.6 Hz). Production Example 244-2 L4-( 5-Amino porphin- 2-ylthio)-7-methyl gas 4 but 6-potential g to produce amine 7-methoxy-4-(5-nitrothiophen-2-ylthio)quinoline carboxamide (32 〇mg , 0.885 mmol), iron (247 mg, 4.43 mm〇l) and ammonium chloride (481 Mg, 8·85 mmol) was suspended in a mixed solvent of ethanol (8 ml)-water (2 ml)-dimethylformamide (1 ml) and stirred at 80 ° C for 15 minutes. 'The reaction mixture is passed through the diatomaceous earth; consider, mix with tetrahydrofuran-methanol-361 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (356) The solvent is washed out. Ethyl acetate is added to the organic layer, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated and evaporated. The product was subjected to hydrazine gel column chromatography (eluent of ethyl acetate:methanol = 20 ··1), and the fractions of the title compound were concentrated to give the title compound (164 mg, · 495 mmol, 56%) - Spectrum (DMS 〇-d6) 5 (ppm): 4.02 (3H, s), 6.00 (1H, d, J = 4.0 Hz), 6.34 (2H, s), 6·83 ( 1H,d,J=4.8 Hz),7·08 (1H,d, J=4.0 Hz), 7.51 (1H,s),7·77 (1H,br s),7.86 (1H,br s),8 · 47 (1H, s), 8.66 (1H, d, J = 4.8 Hz). Example 245 4-(5-(3-(4-Phenylphenyl) vein) g-cephen-2-ylthio)-7-methyl-hydroxyphenylin-6-prostamine was the same as in Example 244 a method from 4-(5-aminopurin-2-ylsulfanyl)-7-methoxy-hydroxyquinoline-6-carboxamide (49.0 mg, 0.150 mmol) and 4-fluorophenyl isocyanate (22.6 mg, 0.165 mmol). W-NMR spectrum (DMS 〇-d6) 5 (ppm): 4·03 (3H, s), 6.72 (1H, d, J = 4.0 Hz), 6.76 (1H, d, J = 4.8 Hz), 7.10-7.18 (2H, m), 7.35 (1H, d, J=4.0 Hz), 7.45-7.51 (2H, m), 7·53 (1H, s), 7.80 (1H, br s), 7.89 (1H , br s), 8.52 (1H, s)5 8.65 ( 1H, d, J=4.8 Hz), 8·99 (1H, br s), 10.24 (1H, br s). Example 246. 7-Methoxy-4-(5-(3-indol-2-yl)-p-thiophene-2- sulphur)-g-g- 6-# g

裝 訂Binding

線 -362 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公愛） 1304061 A7 B7 五、發明説明（357 ) 將4-(5 -胺基喧吩-2-基硫）-7-甲氧基峻琳-6-幾醯胺（66.0 mg，0.200 mmol)及嘍唑-2-基胺基甲酸苯酯（66.〇 mg , 0.3 00 mmol)在二甲基亞颯（1 mi)中，於85 °C攪拌2小時。將Line-362 - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 public) 1304061 A7 B7 V. Description of invention (357) 4-(5-Aminothiophen-2-ylthio)-7 -Methoxy Junlin-6-myramine (66.0 mg, 0.200 mmol) and phenyl oxazol-2-ylcarbamate (66. mg, 0.3 00 mmol) in dimethyl hydrazine (1 mi In the mixture, stir at 85 ° C for 2 hours. will

反應液在乙酸乙酯與水間分溶，將有機層用水及飽和食鹽 水洗淨’用無水硫酸鎂乾燥，遽除乾燥劑及將滤液減壓蒸 餾。將得到之粗生成物付諸於矽凝膠管柱層析（溶出液，乙 酸乙酯：甲醇=15 ·· 1)，將包含目的物之溶出份濃縮，懸 洋於乙敷乙S旨’將其用己燒稀釋及;慮取結晶，用己燒洗淨 後，藉由通風乾燥，得到為無色結晶之標題化合物（35,〇 mg，0.077mmol，38%)。 1H-NMR 光 if(DMSO-d6)5(ppm): 4.03 (3H，s)，ό·77 (1H d J=4.8 Hz)，6·77-6·83 (1H，m)，7·01-7·12 (1H，m)，7.34-7.39The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then evaporated and evaporated. The obtained crude product was subjected to hydrazine gel column chromatography (eluent, ethyl acetate:methanol = 15 ··1), and the dissolved fraction containing the target substance was concentrated, and the suspension was applied to the acetonitrile. The title compound (35, 〇mg, 0.077 mmol, 38%) was obtained as a colorless crystals. 1H-NMR light if (DMSO-d6) 5 (ppm): 4.03 (3H, s), ό·77 (1H d J=4.8 Hz), 6·77-6·83 (1H, m), 7·01 -7·12 (1H, m), 7.34-7.39

(2H, m), 7.51 (1H, s)5 7.80 (1H, br s), 7.89 (1H, br s), 8.52 (1H，s)，8·65 (1H，d，J=4.8 Hz)。 實施例247 5- ({ 7-『〇-( 一甲胺基）丙氣基1 - 6-甲氧基-4- 4成蓽y 疏丄-2-喳吩基1 - Ν’ - (4-氟茉某、月尿 將5-({7-[3-(二乙胺基）丙氧基卜6_甲氧基-4_喹啉基} 硫）-2-硫苯胺190 mg，異氰酸對-氟苯酯69 mg及四氫呋喃 3 0 ml於室溫攪拌30分鐘。將有機溶媒減壓餾去。殘餘物藉 由使用NH型矽凝膠之管柱層析精製（乙酸乙酯，繼而乙酸 乙醋：甲醇=10 : 1)。將溶媒減壓餾去，在殘餘物中加入乙 酸乙酯及使之固化，得到丨6 mg黃褐色固體。 -363 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公愛) 1304061 A7 B7 五、發明説明（358 ) 1H-NMR (DMSO^d6) (5 (ppm): 0.93 (6H, t, J=7.2 Hz), 1.87 (2H，tt，2 Hz，7.2 Hz)，2.40-2.57 (6H, m)，3.94 (3H，s)， 4.15 (2H, t5 J=7.2 Hz), 6.68 (1H, d, J=4.0 Hz), 6.71 (1H, d3 j二4.8 Hz)，7·11 (2H，dd，J=8,8 Hz，8.8 Hz)，7.28 (1H，s)， 7.30 (1H，d，J=4.0 Hz)，7·34 (1H，s)，7·45 (2H，dd，Ju Hz， 4.8 Hz)，8.44 (lH，d，J=4.8 Hz)，8.94 (1H，bs)，10.15 (1H， bs) 0 如下述得到中間體。 舉造例2 4 7 -1 7-ί字氧基）-6-甲氧基-1,4 -二氣-4-p争，林硫酮 將7-(爷氧基）-6-甲氧基-1，4-二氫- 4-p奎淋28·1 g，五硫化 二磷53.4 g，碳酸氫鈉53.7 g及二乙二醇二曱醚2〇〇 mls8〇 °C攪拌2小時。使反應液回到室溫後，展開在冰水中，授拌 40分鐘後濾取固體，並於60 °C風乾。得到29.1 g黃色粉末。 lH-NMR (DMSO-d6) δ (ppm): 3.85 (3H, s), 5.22 (2H, s)3 7.15 (1H，s)，7·17 (1H，d，J=6.4 Hz)，7.33-7.50 (5H，m)，7·71 (1H， d，J=6.4 Hz)，8·11 (1H，s)。 製造例247-2 2- {「7-(宇氧基）-6-甲氧基杳淋某1絲卜5_硝基遠吩 將7-(爷氧基）-6-甲氧基-1，4-二氫-4-峻淋硫酮14.3 g，2-溴-5-硝基4吩10 g ’破酸_ 9.9 g及二甲基甲酿胺MO mg， 並於室溫攪;拌6小時。加入水及;慮取析出之固體，將固體用 水及乙酸乙·§旨接續洗淨β得到1 5 ·7 g黃色粉末。 !H-NMR (DMSO-d6) δ (ppm): 3.92 (3H, s), 5.29 (2H, s), 7.23 -364 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）(2H, m), 7.51 (1H, s)5 7.80 (1H, br s), 7.89 (1H, br s), 8.52 (1H, s), 8·65 (1H, d, J = 4.8 Hz). Example 247 5-({ 7- 〇-(monomethylamino)propenyl 1 - 6-methoxy-4- 4 荜 y 丄 丄 喳 喳 喳 喳 喳 1 - Ν ' - (4 -Fluorol, moon urine will be 5-({7-[3-(diethylamino)propoxy b 6-methoxy-4_quinolinyl} thio)-2-thioaniline 190 mg, different The mixture was stirred for 30 minutes at room temperature, and the organic solvent was evaporated under reduced pressure. Then, ethyl acetate: methanol = 10: 1). The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue and solidified to give hexane 6 mg of a tan solid. -363 - The paper size is applicable to the country of China Standard (CNS) A4 specification (210 X 297 public) 1304061 A7 B7 V. Description of invention (358) 1H-NMR (DMSO^d6) (5 (ppm): 0.93 (6H, t, J=7.2 Hz), 1.87 (2H, tt, 2 Hz, 7.2 Hz), 2.40-2.57 (6H, m), 3.94 (3H, s), 4.15 (2H, t5 J=7.2 Hz), 6.68 (1H, d, J=4.0 Hz) , 6.71 (1H, d3 j two 4.8 Hz), 7·11 (2H, dd, J=8, 8 Hz, 8.8 Hz), 7.28 (1H, s), 7.30 (1H, d, J = 4.0 Hz), 7·34 (1H, s), 7·45 (2H, dd, Ju Hz, 4.8 Hz) , 8.44 (lH, d, J = 4.8 Hz), 8.94 (1H, bs), 10.15 (1H, bs) 0 The intermediate is obtained as follows. Example 2 4 7 -1 7-ί-oxy)-6 -Methoxy-1,4-dialdehyde-4-p, linthione 7-(yloxy)-6-methoxy-1,4-dihydro- 4-p-quinone 28·1 g, 53.4 g of phosphorus pentasulfide, 53.7 g of sodium hydrogencarbonate and 2 g of diethylene glycol dioxane at 2 ° mls 8 ° C. After the reaction solution was returned to room temperature, it was spread in ice water and mixed for 40 minutes. The solid was taken and air dried at 60 ° C to give 29.1 g of a yellow powder. lH-NMR (DMSO-d6) δ (ppm): 3.85 (3H, s), 5.22 (2H, s)3 7.15 (1H, s), 7·17 (1H, d, J=6.4 Hz), 7.33-7.50 (5H, m), 7·71 (1H, d, J=6.4 Hz), 8·11 (1H, s). Manufacturing Example 247- 2 2- {"7-(Yooxy)-6-methoxyindole leaching 1 silk 5_nitro far pheno- 7-(thyloxy)-6-methoxy-1,4-di Hydrogen-4-thiophenone ketone 14.3 g, 2-bromo-5-nitro-4 phenoline 10 g 'acid-breaking _ 9.9 g and dimethyl ketoamine MO mg, and stirred at room temperature; mix for 6 hours. Water was added; the precipitated solid was taken into consideration, and the solid was washed with water and acetic acid to obtain 1 5 · 7 g of a yellow powder. !H-NMR (DMSO-d6) δ (ppm): 3.92 (3H, s), 5.29 (2H, s), 7.23 -364 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) )

裝 訂Binding

線 1304061 A7Line 1304061 A7

(1H，dd，&gt;4.8 Hz，“ Hz)，7 32 ^•〇 Hz), .7.55 〇H, s), 7,7 〇H j ^ ^ ^ d&gt; 8.16 〇H, dd, ^.4H2,2.〇HZ)}8；8(；J= d4THZj ^ Hz) 〇 (1H, dd5 J=4.8 Hz, 1.6 製造例247-3 將7-(爷氧基）-6-甲氧基_4_[(5_確基_ 4广’.三氣乙酸〜及硫代苯甲…丨於6二)二= 時到室溫後’減㈣去㈣，在殘餘物中 = :之=:氫_容液直至發泡停止為止。二 出足固體，得到2.7 g黃色粉末。 叮 !H-NMR (DMSO-d6) 5 (ppm): 3.92 (3H, s), 7.16 (lH d 厂 HZ)，7.31(1H，s)，7.33(1H，s) 7 55 (iH，d，j=4 〇Hz)| 8.15 (1H, d, J=4.0 Hz), 8.52 (lHj d, J=4.8 Hz) 〇 製造例247-4(1H, dd, &gt; 4.8 Hz, "Hz", 7 32 ^•〇Hz), .7.55 〇H, s), 7,7 〇H j ^ ^ ^ d&gt; 8.16 〇H, dd, ^.4H2 , 2. 〇HZ)}8;8(;J= d4THZj ^ Hz) 〇(1H, dd5 J=4.8 Hz, 1.6 Production Example 247-3 7-(Oxyoxy)-6-methoxy_4_ [(5_OK基_4广'. Three gas acetic acid ~ and thiobenzoic acid... 丨6 6) two = time to room temperature after 'minus (four) to (four), in the residue = : = = hydrogen _ The liquid was allowed to stand until the foaming stopped. Two solids were obtained to obtain 2.7 g of a yellow powder. 叮! H-NMR (DMSO-d6) 5 (ppm): 3.92 (3H, s), 7.16 (lH d HZ), 7.31 ( 1H, s), 7.33 (1H, s) 7 55 (iH, d, j = 4 〇 Hz) | 8.15 (1H, d, J = 4.0 Hz), 8.52 (lHj d, J = 4.8 Hz) 〇 Manufacturing example 247-4

U 口林）氧）丙基1胺 將6-曱氧基-4- [ (5-硝基-2- ρ塞吩）硫]· 7- u套琳500 mg，3-二乙胺基丙醇290 mg，偶氮二羧酸二乙酯39〇 mg，三苯膦 590 mg，四氫吱喃30 ml，1-甲基-2-吨哈咬嗣2 〇1及二甲基 亞颯10 ml於0°C攪拌5小時，繼而於室溫攪拌1〇小時。加入 水及用乙酸乙酯萃取。將萃取液用2N鹽酸水溶液逆萃取， 在鹽酸水溶·液萃·取液中加入5N氫氧化鈉水溶液並用乙酸乙 酯萃取，將萃取液用水及食鹽水接續洗淨以及用無水硫酸 -365 -本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜 ' - A7 __ B7 五、發明説明（36〇) ^ 鎂乾燥。使乙酸乙酯層通過塗佈NH型矽凝膠之破璃濾器， 然後減壓餘去溶媒，得到500 mg赤褐色油狀物。 ^-NMR (DMSO-d6) 5 (ppm): 0.92 (6H, t, J=7.2 Hz), 1.87 (2H，tt，J=7,2 Hz，7·2 Hz), 2.40-2.58 (6H，m)，3·93 (3H，s)， 4.20 (2H，t，J=7.2 Hz)，7.21 (1H，d，J=4.8 Hz)，7·37 (1H，s)， 7·42 (1H，s)，7.58 (1H，d，J=4.0 Hz)，8·18 (1H，d，J=4.0 Hz)， 8.60 (1H，d，J=4.8 Hz)。 製造例247-5 g-({ 7-Π-(二乙胺某）丙氣基卜6-甲氫某-4-4啉基丨硫）-2-噻吩胺 將N，N-二乙基-N-[3-({6-曱氧基-4-[(5-硝基-2-嘍吩基） 硫]-7-喹啉}氧）丙基]胺525 mg，鐵粉33 0 mg，氯化銨660 mg，乙醇20 ml及水5 ml於80°C攪拌80分鐘。經矽藻土過 濾。在濾液中加入NH型矽凝膠及減壓餾去溶媒，以使反應 生成物附著於矽凝膠。該矽凝膠饋入充填有NH型矽凝膠之 乾燥管柱中，然後進行管柱精製（乙酸乙酯，繼而乙酸乙 酯：甲醇=3 : 1)。得到190 mg褐色油狀物。 1H-NMR (DMSO-d6) 5 (ppm): 0.91 (6H, t, J=7.2 Hz), 1.88 (2H, tt, J=7.2 Hz, 7.2 Hz), 2.47-2.57 (6H, m), 3.92 (3H, s), 4.16 (2H, t5 J=7.2 Hz), 5.96 (1H, d, J=4.0 Hz), 6.76 (1H, d5 J=4.8 Hz), 6.25-6.30 (2H, m), 7.04 (1H, d, J=4.0 Hz), 7.22 (1H, s)，7·33 (1H，s)，8·45 (1H，d，J=4.8 Hz)。 實施例248 * N- f 2-(丨7- f 3-〔二乙胺基）丙氣某1 - 6-甲氫基-4-4啉基}硫）二 -366 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1304061 A7 B7 五、發明説明（361 ) 11—嗓-5-基1 - Ν' M-氯苽某）胧 將N，N-二乙基-N-[3-({6-甲氧基-4-[(5-硝基-1，3-噻唑_ 2-基）硫]-7-喹啉}氧）丙基]胺770 mg，鐵粉480 mg，乙醇 17 ml及乙酸3.4 ml於8〇°C攪拌10分鐘。在反應液中加入水 100 ml，乙酸乙酯60 ml及碳酸鉀10 g，繼而經矽藻土過 濾。將濾液分層，使乙酸乙酯層通過塗佈NH型矽凝膠之玻 璃濾器。在如此得到之乙酸乙酯溶液中加入異氰酸對氟苯 酯0.58 ml，並於室溫攪拌17小時。在濾液中加入nh型♦凝 膠及減壓餾去溶媒，以使反應生成物附著於矽凝膠。該碎 凝膠饋入充填有NH型夕凝膠之乾燥管柱中，然後進行管柱 精製（乙酸乙酯：甲醇=1〇〇 ·· 1，繼而50 : 1，繼而10 : ^。 得到30 mg為淡黃色固體之目的物。 lH-NMR (DMSO-d6) 5 (ppm): 0.93 (6H, t, J=7.2 Hz), 1.88 (2H, tt, J=6.4 Hz, 6.4 Hz), 2.46 (4H, q5 J=7.2 Hz), 2.55 (2H, t, J=6.4 Hz), 3.92 (3H, s), 4.17 (2H, t, J=6.4 Hz), 7.00 (1H, d3 J=5.2 Hz)，7.10 (2H, dd，J=8.8 Hz，8·8 Hz), 7·36 (1H，s)， 7.38 (1H，s)，7·43 (2H，dd，J=8.8 Hz, 4.8 Hz)，7,60 (1H，s)， 8·51 (1H，d，J=5.2 Hz), 9.10 (1H，bs)。 如下述得到中間體。 _ i告例 248- 1 2-(『7-(尤乳基）-6-甲氧基- 4-4 g林基1繞卜5 -麟某- -口塞峻 將7-(卞氧基）-6-甲氧基-1，4 -二風-4-峻啦硫銅14.8 g，2-溴-5-硝基-·1，3“，塞唆丨〇·4 g，碳酸奸10.3 g及二甲基甲酿胺 150 ml於室溫攪拌50分鐘。在反應液中加入水8〇〇 m卜濾取 -367 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 A7 B7 五、發明説明（362 析出之固體，用乙酸乙酯洗淨以及得到為淡土黃色粉末之 目的物13.4. g。 lH-NMR (DMSO-d6) 6 (pprxi)： 3.87 (3H, s)5 5.32 (2H, s), 7·32-7·53 (6H，m)，7·64 (1H，s)，7.86 (1H，d，J=4.8 Hz)，8.70 (1H，s)，8.80 (1H，d，J=4.8 Hz)。 製造例248-2 6-氧基_4·「（5·硝基_ 某）硫奎啉醇 將2-{[7-(芊氧基）-6-甲氧基-4-喹啉基]硫卜5-硝基-1，3-嘍唑2.0 g，三氟乙酸20 ml及硫代苯甲醚2 ml於65 °C攪拌90 分鐘。回到室溫傻’減壓餘去溶媒，在殘餘物中加入甲醇 40 ml，繼而加入碳酸氫鈉水溶液直至發泡停止為止。濾取 析出之固體，得到1 ·4 g黃色粉末。 iH-NMR (DMSO-d6)5(ppm): 3.87 (3H，s)，7.40 (1H，s)5 7.43 (1H，s)，7·78 (1H，d，J=4.8 Hz)，8.71 (1H，d，J=2.4 Ηζ)，8·74 (1H，dd，J=4.8 Hz，2·4 Hz)，1〇·52 (1H，s)。 製造例248-3 二乙基-N-「3-({6-甲菊^^心「（5•硝基唑-2-某） 硫卜7-喹啉丨氣）丙基1胺 使用6-甲氧基- 4- [(5-硝基- ΐ，3-ρ塞吐-2-基）硫]-7-口奎淋， 以與製造例247-2同樣之方式得到目的物。 lH-NMR (DMSO-d6) 5 (ppm): Ο.95 (6H, t, J=6.8 Hz), 1.91 (2H, tt, J=6.4 Hz, 6.4 Hz), 2.45^2.65 (6H, m)5 3.86 (3H, s), 4.20 (2H，t，J=6.4 Hz)，7·42 (1H，s)，7·49 (1H，s)，7·83 (1H， d，J=4.4 Hz)，8·69 (1H，s)，8.79 (1H，d，J=4.4 Hz)。 -368 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公爱）U mouth forest) oxy) propyl 1 amine 6-decyloxy-4- [(5-nitro-2- ρ phenophene) sulphide] 7- u set of 500 mg, 3-diethylaminopropyl Alcohol 290 mg, diethyl azodicarboxylate 39 〇 mg, triphenylphosphine 590 mg, tetrahydrofuran 30 ml, 1-methyl-2-tonhabit 2 〇1 and dimethyl azine 10 The ml was stirred at 0 ° C for 5 hours and then at room temperature for 1 hour. Water was added and extracted with ethyl acetate. The extract was back-extracted with 2N aqueous hydrochloric acid solution, and 5N aqueous sodium hydroxide solution was added to the aqueous solution of hydrochloric acid and liquid extraction, and extracted with ethyl acetate. The extract was washed successively with water and brine, and anhydrous sulphuric acid-365- The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ~ ' - A7 __ B7 V. Description of invention (36〇) ^ Magnesium drying. The ethyl acetate layer was passed through a glass filter of a NH-type ruthenium gel, and then the solvent was removed under reduced pressure to give 500 mg of a brown oil. ^-NMR (DMSO-d6) 5 (ppm): 0.92 (6H, t, J = 7.2 Hz), 1.87 (2H, tt, J=7, 2 Hz, 7·2 Hz), 2.40-2.58 (6H, m),3·93 (3H,s), 4.20 (2H,t,J=7.2 Hz), 7.21 (1H,d,J=4.8 Hz),7·37 (1H,s), 7·42 (1H , s), 7.58 (1H, d, J = 4.0 Hz), 8.18 (1H, d, J = 4.0 Hz), 8.60 (1H, d, J = 4.8 Hz). Production Example 247-5 g-({ 7-Π-(diethylamine)propenyl sulfonyl 6-methylhydrogen-4--4- phenylphosphonium thiol)-2-thiopheneamine N,N-diethyl -N-[3-({6-decyloxy-4-[(5-nitro-2-nonyl)thio]-7-quinolin}oxy)propyl]amine 525 mg, iron powder 33 0 Mg, ammonium chloride 660 mg, ethanol 20 ml and water 5 ml were stirred at 80 ° C for 80 minutes. Filtered through diatomaceous earth. An NH type hydrazine gel was added to the filtrate, and the solvent was distilled off under reduced pressure to adhere the reaction product to the hydrazine gel. The hydrazine gel was fed into a drying column packed with an NH type hydrazine gel, and then subjected to column purification (ethyl acetate, followed by ethyl acetate: methanol = 3:1). Yield 190 mg of a brown oil. 1H-NMR (DMSO-d6) 5 (ppm): 0.91 (6H, t, J = 7.2 Hz), 1.88 (2H, tt, J = 7.2 Hz, 7.2 Hz), 2.47-2.57 (6H, m), 3.92 (3H, s), 4.16 (2H, t5 J=7.2 Hz), 5.96 (1H, d, J=4.0 Hz), 6.76 (1H, d5 J=4.8 Hz), 6.25-6.30 (2H, m), 7.04 (1H, d, J=4.0 Hz), 7.22 (1H, s), 7·33 (1H, s), 8.45 (1H, d, J = 4.8 Hz). Example 248 * N-f 2-(丨7- f 3-[diethylamino)propene gas 1 - 6-methylhydro-4-ylolinyl} sulfur) di-366 - This paper size is applicable to China National Standard (CNS) A4 Specification (210X297 mm) 1304061 A7 B7 V. Description of Invention (361 ) 11—嗓-5-Base 1 - Ν' M-Chloro 苽) 胧N,N-Diethyl-N -[3-({6-methoxy-4-[(5-nitro-1,3-thiazol-2-yl)thio]-7-quinoline}oxy)propyl]amine 770 mg, iron powder 480 mg, 17 ml of ethanol and 3.4 ml of acetic acid were stirred at 8 ° C for 10 minutes. 100 ml of water, 60 ml of ethyl acetate and 10 g of potassium carbonate were added to the reaction mixture, followed by filtration through diatomaceous earth. The filtrate was layered, and the ethyl acetate layer was passed through a glass filter coated with a NH-type ruthenium gel. To the ethyl acetate solution thus obtained, 0.58 ml of p-fluorophenyl isocyanate was added, and stirred at room temperature for 17 hours. An nh type ♦ gel was added to the filtrate, and the solvent was distilled off under reduced pressure to cause the reaction product to adhere to the ruthenium gel. The crushed gel was fed into a drying column packed with NH-type night gel, and then subjected to column purification (ethyl acetate:methanol=1〇〇··1, then 50:1, then 10:^). Mg is the object of a pale yellow solid. lH-NMR (DMSO-d6) 5 (ppm): 0.93 (6H, t, J = 7.2 Hz), 1.88 (2H, tt, J = 6.4 Hz, 6.4 Hz), 2.46 (4H, q5 J=7.2 Hz), 2.55 (2H, t, J=6.4 Hz), 3.92 (3H, s), 4.17 (2H, t, J=6.4 Hz), 7.00 (1H, d3 J=5.2 Hz) ), 7.10 (2H, dd, J=8.8 Hz, 8·8 Hz), 7·36 (1H, s), 7.38 (1H, s), 7·43 (2H, dd, J=8.8 Hz, 4.8 Hz) ), 7,60 (1H, s), 8·51 (1H, d, J = 5.2 Hz), 9.10 (1H, bs). Intermediates are obtained as follows. _ i 例248- 1 2-(『7 -(尤乳基)-6-methoxy-4-4 g林基1的卜五 -麟某- - 口塞峻7-(decyloxy)-6-methoxy-1,4 - 2 wind - -4- sulphur copper 14.8 g, 2-bromo-5-nitro-·1,3", sputum · 4 g, carbonated 10.3 g and dimethyl ketoamine 150 ml in the room Stir for 50 minutes. Add 8 μm of water to the reaction solution -367 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 130406 1 A7 B7 V. Inventive Description (362. The precipitated solid, which was washed with ethyl acetate and obtained as a pale yellow powder, 13.1 g. lH-NMR (DMSO-d6) 6 (pprxi): 3.87 (3H, s)5 5.32 (2H, s), 7·32-7·53 (6H,m),7·64 (1H,s), 7.86 (1H,d,J=4.8 Hz), 8.70 (1H, s) , 8.80 (1H, d, J = 4.8 Hz). Production Example 248-2 6-oxy_4·"(5·nitro-) sulfur quinolinol 2-{[7-(decyloxy) -6-Methoxy-4-quinolinyl]thiophene 5-nitro-1,3-oxazole 2.0 g, 20 ml of trifluoroacetic acid and 2 ml of thioanisole were stirred at 65 ° C for 90 minutes. After returning to room temperature, the solvent was removed under reduced pressure, and 40 ml of methanol was added to the residue, and then aqueous sodium hydrogencarbonate was added until the foaming was stopped. The precipitated solid was collected by filtration to give a white powder. iH-NMR (DMSO-d6) 5 (ppm): 3.87 (3H, s), 7.40 (1H, s) 5 7.43 (1H, s), 7·78 (1H, d, J = 4.8 Hz), 8.71 ( 1H, d, J = 2.4 Ηζ), 8.74 (1H, dd, J = 4.8 Hz, 2·4 Hz), 1〇·52 (1H, s). Production Example 248-3 Diethyl-N-"3-({6-甲菊^^心"(5•Nitrozole-2-) Thio 7-quinolinium oxime) Propylamine 1 -Methoxy-4-[(5-nitro-indole, 3-ρsec-2-yl)sulfonyl]-7-hydroxyquinone, the object obtained was obtained in the same manner as in Production Example 247-2. -NMR (DMSO-d6) 5 (ppm): Ο.95 (6H, t, J = 6.8 Hz), 1.91 (2H, tt, J = 6.4 Hz, 6.4 Hz), 2.45^2.65 (6H, m)5 3.86 (3H, s), 4.20 (2H, t, J = 6.4 Hz), 7·42 (1H, s), 7·49 (1H, s), 7·83 (1H, d, J = 4.4 Hz) ,8·69 (1H,s),8.79 (1H,d,J=4.4 Hz). -368 - This paper size applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 public)

裝 訂Binding

線 1304061 A7 B7 五、發明説明（363 ) 實施例249 甲氧乙基）-4-( 3-氯-4-( ΓΓ環丙胺某）羰基1胺某}茇 A基）-7-(2-甲氣基乙氣某）-6-4说藉醯胺 4-(3-氯-4-{[(環丙胺基）羰基]胺基}苯氧基）_7-(2-甲氧 基乙氧基）-6-喹啉羧酸200 mg，2-甲氧乙胺38 mg，苯并三 咬-1-基氧-參（一甲胺基）鱗六氟鱗酸鹽（B〇p試劑）23〇 mg， 二乙胺0.12 ml及二甲基甲酿胺5 ml於室溫攪摔14小時。在 反應〉谷蜂中加入水及乙故乙g旨並萃取，在萃取液中加入ΝΗ 型矽凝膠及減壓餾去溶媒，以使反應生成物吸著於矽凝膠 上。將該矽凝膠饋入充填有NH型矽凝膠之乾燥管柱中，然 後進行管柱精製（乙酸乙酯）。減壓餾去溶媒，得到為固體 之目的物120 mg。 lH-NMR (DMSO-d6) 5 (ppm): 0.38-0.45 (2H3 m)5 0.62-0.68 (2H, m), 2.48-2.60 (1H, m), 3.30 (3H, s), 3.37 (3H, s), 3.45-3.55 (4H, m), 3.79 (2H, t5 J=4.4 Hz), 4.40 (2H, t, J-4.4 Hz) 6.52 (1H, d5 J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=9.2 Hz, 2.8 Hz), 7.49 (1H5 d5 J=2.8 Hz), 7.55 (lH, s), 7.97 (1H，s)，8·26 (1H，d，J=9.2 Hz)，8·42·8·47 (1H，m)，8·66 (1H， d，J=5.2 Hz)，8.74 (1H，s)。 如下述仔到中間體。 鏨造例249」1 4-氯-7-(h甲氧乙氧基）-6-♦啉#酸曱酯 將7-(2-甲氧乙氧基）-4-_基-1，4-二氫-6-唆琳幾酸75 g，亞硫醯氯60 ml及二甲基曱醯胺1 ml於80 °C授掉3小時。 -369 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 ' * A7 ____ B7 五、發明説明（撕） 將反應落液減壓蒸餾，在殘餘物中加入甲苯並減壓蒸餾， 如此進仃2.次。在殘餘物中加入甲醇，繼而加入三乙胺1〇 ml。將如此所得之溶液減壓蒸餾，在殘餘物中加入5n氫氧 化鈉水落液調成pH 4以及用乙酸乙酯萃取。使乙酸乙酯層 通過塗佈NH型矽凝膠之玻璃濾器，然後減壓餾去溶媒。在 殘餘物中加入乙醚及濾取固體，得到36§為淡褐色固體之 目的物。將濾液藉使用NH型矽凝膠之管柱層析（己烷··乙 酸乙醋=3 ·· 1)精製，得到為淡黃色固體之目的物13 g。 H-NMR (DMSO-d6) 5 (ppm): 3.33 (3H, s), 3.71-3.75 (2H, m), 3.86 (3H, s), 4.32-4.35 (2H, m), 7.62 (1H, s)5 7.66 (1H, d, J=4.8 Hz)3 8.42 (1H, s), 8.83 (1H, d, J=4.8 Hz) 〇 製造例249-7 崦啉藉醢甲 將4-氯-7-(2-甲氧乙氧基）_ 6-喹啉羧酸甲酯4·9 g，肛胺 基-3-氯酚2.0g，氫化鈉55〇 mg&amp;二甲基甲醯胺2〇⑹於丨⑽ °C授拌2小時。回到室溫，加入水及用乙酸乙醋萃取。在萃 取溶液中加入矽凝膠以及減壓餾去溶媒。將該矽凝膠饋入 无填有矽凝膠之乾燥管柱中，然後藉管柱層析精製（己烷： 乙酸乙酯=1 : 1 ,繼而乙酸乙酯）。得到為紫色固體之目的 物3.2 g 〇 ^-NMR (DMSO^d6)5(ppm): 3.34 (3H, s), 3.72 (2H, t, J=4.4 Hz), 3.83 (3H, s), 4.29 (2H, t, J=4.4 Hz), 5.44 (2H, s), 6.44 OH, d, 1=5.6 Hz), 6.88 (1H, d, J^.8 Hz), 7.00 (lH, dd, -370 -Line 1304061 A7 B7 V. Description of the Invention (363) Example 249 methoxyethyl)-4-(3-chloro-4-(anthracycline)carbonyl 1 amine 茇A group)-7-(2- A gas-based ethylene gas, a certain -6-4, is described by the amine 4-(3-chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)_7-(2-methoxyethoxy Benzene-6-quinolinecarboxylic acid 200 mg, 2-methoxyethylamine 38 mg, benzotrizetone-1-yloxy-paraxyl (monomethylamino) hexafluorofluorate (B〇p reagent) 23 〇 mg, 0.12 ml of diethylamine and 5 ml of dimethyl ketoamine were stirred at room temperature for 14 hours. In the reaction, the bee was added with water and the mixture was extracted, and a ruthenium-type gel was added to the extract, and the solvent was distilled off under reduced pressure to cause the reaction product to be adsorbed on the ruthenium gel. The ruthenium gel was fed into a dry column packed with an NH type ruthenium gel, and then subjected to column purification (ethyl acetate). The solvent was distilled off under reduced pressure to give the title compound 120m. lH-NMR (DMSO-d6) 5 (ppm): 0.38-0.45 (2H3 m)5 0.62-0.68 (2H, m), 2.48-2.60 (1H, m), 3.30 (3H, s), 3.37 (3H, s), 3.45-3.55 (4H, m), 3.79 (2H, t5 J=4.4 Hz), 4.40 (2H, t, J-4.4 Hz) 6.52 (1H, d5 J=5.2 Hz), 7.18 (1H, d , J=2.8 Hz), 7.23 (1H, dd, J=9.2 Hz, 2.8 Hz), 7.49 (1H5 d5 J=2.8 Hz), 7.55 (lH, s), 7.97 (1H, s), 8·26 ( 1H, d, J = 9.2 Hz), 8·42·8·47 (1H, m), 8.66 (1H, d, J = 5.2 Hz), 8.74 (1H, s). Take the following to the intermediate.錾例例249"1 4-Chloro-7-(hmethoxyethoxy)-6-♦ porphyrin# acid decyl ester 7-(2-methoxyethoxy)-4-yl-1,4 - 75 g of dihydro-6-indolyl acid, 60 ml of sulfinium chloride and 1 ml of dimethyl decylamine were allowed to stand at 80 ° C for 3 hours. -369 - This paper size applies to Chinese National Standard (CNS) A4 size (210X297 mm) 1304061 ' * A7 ____ B7 V. Description of invention (tear) The reaction liquid is distilled under reduced pressure, toluene is added to the residue and decompressed. Distillation, so go in 2. times. Methanol was added to the residue, followed by the addition of triethylamine 1 〇 ml. The solution thus obtained was distilled under reduced pressure, and a 5n aqueous sodium hydroxide solution was added to the residue to adjust to pH 4 and extracted with ethyl acetate. The ethyl acetate layer was passed through a glass filter coated with an NH type hydrazine gel, and then the solvent was distilled off under reduced pressure. Ethyl ether was added to the residue and the solid was filtered to give the title compound of 36 s as pale brown solid. The filtrate was purified by column chromatography (hexane················ H-NMR (DMSO-d6) 5 (ppm): 3.33 (3H, s), 3.71-3.75 (2H, m), 3.86 (3H, s), 4.32-4.35 (2H, m), 7.62 (1H, s ) 5 7.66 (1H, d, J = 4.8 Hz) 3 8.42 (1H, s), 8.83 (1H, d, J = 4.8 Hz) 〇Manufacturing Example 249-7 Porphyrin by 4-arm-7- Methyl (2-methoxyethoxy)-6-quinolinecarboxylate 4·9 g, anionic amino-3-chlorophenol 2.0 g, sodium hydride 55 〇 mg &amp; dimethylformamide 2 〇 (6) Mix at 丨(10) °C for 2 hours. Return to room temperature, add water and extract with ethyl acetate. A hydrazine gel was added to the extraction solution and the solvent was distilled off under reduced pressure. The hydrazine gel was fed into a dry column without a hydrazine gel, and then purified by column chromatography (hexane: ethyl acetate = 1 : 1 , then ethyl acetate). Obtained as a purple solid, 3.2 g 〇^-NMR (DMSO^d6) 5 (ppm): 3.34 (3H, s), 3.72 (2H, t, J = 4.4 Hz), 3.83 (3H, s), 4.29 (2H, t, J=4.4 Hz), 5.44 (2H, s), 6.44 OH, d, 1=5.6 Hz), 6.88 (1H, d, J^.8 Hz), 7.00 (lH, dd, -370) -

1304061 A7 B7 五、發明説明（365 J=8.8 Hz, 2.4 Hz), 7.23 (1H, d5 J=2.4 Hz), 7.49 (1H, s), 8.53 (1H，s)，8.63 (1H，d，J=5.6 Hz)。 製造例249j 4:,.{3-氯笨氣羰基）胺某i苽氳基卜7·(2·甲氣乙氧 6-。奎琳藉酸甲酯1304061 A7 B7 V. INSTRUCTIONS (365 J=8.8 Hz, 2.4 Hz), 7.23 (1H, d5 J=2.4 Hz), 7.49 (1H, s), 8.53 (1H, s), 8.63 (1H, d, J =5.6 Hz). Production Example 249j 4:,.{3-Chloro carbonyl carbonyl) Amine 苽氲 卜 7 · · · · · · · · · · · · · · · · · · · ·

將4:(4-胺基-3-氯苯氧基）-7-(2-曱氧乙氧基）·6-喳啉羧 酸甲醋3.2 g，吡啶〇·71 ml及四氫呋喃5〇 mi攪捽，及滴入氯 甲酸苯g旨1.1 40分鐘後，加入吡啶〇.8 ml及氯甲酸苯酯 1.1 ml並再授掉1〇分鐘。加入水及用乙酸乙酯萃取，使萃取 液通過塗佈矽凝膠之玻璃濾器，將矽凝膠用乙酸乙酯沖洗 及減壓餾去溶媒。在殘餘物中加入己烷及乙酸乙酯及濾取 固體，得到3.2 g微紅色固體。 lH-NMR (CDC13) ά (ppm): 3.50 (3H, s)3 3.80 (2H, t, J=4.44:(4-Amino-3-chlorophenoxy)-7-(2-decyloxyethoxy)·6-porphyrincarboxylic acid methyl vinegar 3.2 g, pyridinium·71 ml and tetrahydrofuran 5〇mi After stirring, and dropping benzene g of chloroformate for 1.1 40 minutes, add 8 ml of pyridinium and 1.1 ml of phenyl chloroformate and transfer for another 1 minute. Water was added and extracted with ethyl acetate, and the extract was passed through a glass filter coated with a gel, and the ruthenium gel was washed with ethyl acetate and the solvent was evaporated under reduced pressure. Hexane and ethyl acetate were added to the residue, and the solid was filtered to affordd, m. lH-NMR (CDC13) ά (ppm): 3.50 (3H, s)3 3.80 (2H, t, J=4.4

Hz)，3·98 (3H，s)，4.37 (2H，t，J=4.4 Hz)，6·49 (1H，d，J=5.6 Hz)，7.17-7.30 (6H，m)，7.40-7.52 (3H，m)，8.30-8.37 (1H， m)，8·66 (1H，d，J=5.6 Hz)，8·80 (1H，s)。 製造例249-4 {f(環丙胺幕）羰基1胺某}茇羞甚 氧基）-6- g林麴酸甲酷 將4-{3-氯-4-[(苯氧羰基）胺基]苯氧基}-7_(2_甲氧乙氧 基）-6-喹啉羧酸甲酯3.2 g，環丙胺ι·3 mi及二甲基甲酿胺⑼ ml於60 °C攪拌10分鐘。回到室溫後，加入水並用乙 乙酉旨 萃取。在萃·取液中加入矽凝膠及減壓餾去溶媒。將梦碎^ 膠饋入充填有矽凝膠之乾燥管柱中，然後藉管柱層析j乙= -371 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（366 ) 乙酯，繼而乙酸乙酯：甲醇=50 : 1，繼而20 : 1)精製。得 到為白色粉末之目的物2.26 g。 lH-NMR (DMSO-d6) (5 (ppm): 0.38-0.45 (2H, m), 0.61-0.69 (2H，m)，2.50-2.58 (1H，m)，3·36 (3H，s)，3·73 (2H，t，J=4.4 Hz)，3.84 (3H，s)，4.31 (2H，t，J=4.4 Hz)，6·51 (1H，d，J=5.2Hz),3·98 (3H,s), 4.37 (2H,t,J=4.4 Hz),6·49 (1H,d,J=5.6 Hz), 7.17-7.30 (6H,m), 7.40-7.52 (3H, m), 8.30-8.37 (1H, m), 8.66 (1H, d, J = 5.6 Hz), 8·80 (1H, s). Production Example 249-4 {f(cyclopropylamine)carbonyl 1 amine 茇 茇 甚 甚 甚 ) 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 Methyl phenoxy}-7-(2-methoxyethoxy)-6-quinolinecarboxylate 3.2 g, cyclopropylamine ι·3 mi and dimethylamine (9) ml were stirred at 60 ° C for 10 minutes. . After returning to room temperature, water was added and extracted with ethyl acetate. A hydrazine gel was added to the extract and the solvent was distilled off under reduced pressure. Feed the dream gel into the drying column filled with enamel gel, and then use the column chromatography j B = -371 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of the Invention (366) Ethyl ester, followed by ethyl acetate: methanol = 50: 1, then 20: 1) refined. 2.26 g of the object was obtained as a white powder. lH-NMR (DMSO-d6) (5 (ppm): 0.38-0.45 (2H, m), 0.61-0.69 (2H, m), 2.50-2.58 (1H, m), 3·36 (3H, s), 3·73 (2H, t, J=4.4 Hz), 3.84 (3H, s), 4.31 (2H, t, J=4.4 Hz), 6·51 (1H, d, J=5.2

Hz), 7M8 (1H, s), 7.24 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.49 (1H, d，J=2.4 Hz)，7·52 (1H，s)，7.96 (1H，s)，8.26 (1H，d，J=8.8Hz), 7M8 (1H, s), 7.24 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.49 (1H, d, J=2.4 Hz), 7·52 (1H, s), 7.96 (1H, s), 8.26 (1H, d, J = 8.8

Hz)，8·55 (1H，s)，8·67 (1H，d，J=5.2 Hz)。 製造例249-5 4-Π-氪-4-(「（瓖丙胺基）蕤某1胺基}笨氳基7-(2-甲氣乙 氧基）· ό· 〃奎g林複酸 將4-(3-氯-4-{[(環丙胺基）羰基]胺基}苯氧基）-7-(2-甲 氧乙氧基）-6-喹啉羧酸甲酯2.26 g，2N氫氧化鈉20 m卜甲 醇20 ml及四氫呋喃20 ml，並於室溫攪捽1小時。加入5N鹽 酸水液，減壓餾去10 ml有機溶媒以及濾取析出之固體。用 甲醇與水之混合溶媒洗淨固體，得到為微紅色粉末之目的 物 2 · 0 g 〇 lH-NMR (DMSO-d6) 5 (ppm): 0.38-0.45 (2H, m), 0.60-0.68 (2H, m), 2.50-2.59 (1H, m), 3.34 (3H, s), 3.73 (2H? t, J=4.4 Hz), 4.30 (2H, t, J=4.4 Hz), 6.51 (1H, d5 J=5.2 Hz), 7.23 (1H? dd, J=9.2 Hz, 2.8 Hz), 7.25 (1H, s), 7.49 (1H5 d, J=2.8 Hz), 7.50 (1H, s), 8.00 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.50 (1H, s), 8·66 (1H.，d, J=5.2 Hz)。 實施例250 372 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（367Hz), 8·55 (1H, s), 8.67 (1H, d, J = 5.2 Hz). Production Example 249-5 4-Π-氪-4-("(瓖propylamino)蕤一一胺基} 氲基基7-(2-methoxy ethoxy)·ό·〃奎g林酸酸4-(3-Chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxylic acid methyl ester 2.26 g, 2N 20 ml of methanol, 20 ml of methanol and 20 ml of tetrahydrofuran, and stirred at room temperature for 1 hour. Add 5 N hydrochloric acid aqueous solution, distill off 10 ml of organic solvent under reduced pressure, and filter out the precipitated solid. Mix with methanol and water. The solvent was washed to obtain a target material as a reddish powder. 2·0 g 〇lH-NMR (DMSO-d6) 5 (ppm): 0.38-0.45 (2H, m), 0.60-0.68 (2H, m), 2.50 -2.59 (1H, m), 3.34 (3H, s), 3.73 (2H? t, J=4.4 Hz), 4.30 (2H, t, J=4.4 Hz), 6.51 (1H, d5 J=5.2 Hz), 7.23 (1H? dd, J=9.2 Hz, 2.8 Hz), 7.25 (1H, s), 7.49 (1H5 d, J=2.8 Hz), 7.50 (1H, s), 8.00 (1H, s), 8.25 (1H , d, J = 9.2 Hz), 8.50 (1H, s), 8·66 (1H., d, J = 5.2 Hz). Example 250 372 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (367

Mr(2-f.厂革彳-4-Π-氣-4“[·(環丙胺某）羰基1胺基丨苯氣 基）-7“2-甲氫某乙氣基）-6-4啉#醯胺 使用2-氟乙胺鹽酸鹽，以與實施例249同樣之方法，得到 目的物。Mr(2-f.厂革彳-4-Π-气-4"[·(cyclopropylamine)carbonyl 1amine hydrazine benzene)-7"2-methylhydrogen ethane group)-6-4 The title compound was obtained in the same manner as in Example 249, using 2-fluoroethylamine hydrochloride.

!H-NMR (DMSO-d6) 5 (ppm): 0.38^0.45 (2H, m)5 0.60-0.68 (2H, m)5 2.48-2.58 (1H, m)3 3.3 5 (3H, s), 3.61 (1H, td, J=4.8 Hz，4·8 Hz)，3.68 (1H，td，J=4.8 Hz，4.8 Hz)，3.78 (2H，t， J=4.8 Hz)，4·41 (2H，t，J=4.8 Hz)，4.50 (1H，t，J=4.8 Hz)， 4.62 (1H, t, J=4.8 Hz), 6.53 (1H, d, J=5.2 Hz), 7.20 (1H, s), 7.24 (1H5 dd3 J=9.2 Hz, 2.4 Hz), 7.49 (1H, d, J=2.4 Hz), 7.56 (1H, s)3 7.98 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.59 (1H5 t, X8 Hz)，8·67 (1H，d，J=5.2 Hz)，8.70 (1H，s)。 實施例2 5 1!H-NMR (DMSO-d6) 5 (ppm): 0.38^0.45 (2H, m)5 0.60-0.68 (2H, m)5 2.48-2.58 (1H, m)3 3.3 5 (3H, s), 3.61 (1H, td, J=4.8 Hz, 4·8 Hz), 3.68 (1H, td, J=4.8 Hz, 4.8 Hz), 3.78 (2H, t, J=4.8 Hz), 4·41 (2H, t , J=4.8 Hz), 4.50 (1H, t, J=4.8 Hz), 4.62 (1H, t, J=4.8 Hz), 6.53 (1H, d, J=5.2 Hz), 7.20 (1H, s), 7.24 (1H, d, J = 9.2 Hz), 7.49 (1H, d, J = 2.4 Hz), 7.56 (1H, s)3 7.98 (1H, s), 8.26 (1H, d, J=9.2 Hz) , 8.59 (1H5 t, X8 Hz), 8.67 (1H, d, J = 5.2 Hz), 8.70 (1H, s). Example 2 5 1

氯-4二（K環丙胺某）蕤某lfe某}茇氧甚U 7-(2-甲氧基乙氣墓）-6-4淋羧酿胺 使用〇-甲基羥胺鹽酸鹽，以與實施例249同樣之方式得到 目的物。 ^-NMR (DMSO-d6) (5 (ppm): 0.38-0.44 (2H, m)3 0.62-0.98 (2H，m)，2.50-2.60 (1H，m)，3·35 (3H，s)，3·73 (3H，s)，3·77 (2H，t，J=4.4 Hz)，4.35 (2H，t，J=4.4 Hz)，6·52 (1H，d，J=5.2Chloro-4 bis (K cyclopropylamine) 蕤 a lfe a} 茇 甚 U U 7-(2-methoxy ethane tomb) -6-4 carboxy aryl amine using 〇-methyl hydroxylamine hydrochloride, The object was obtained in the same manner as in Example 249. ^-NMR (DMSO-d6) (5 (ppm): 0.38-0.44 (2H, m)3 0.62-0.98 (2H, m), 2.50-2.60 (1H, m), 3·35 (3H, s), 3·73 (3H, s), 3.77 (2H, t, J = 4.4 Hz), 4.35 (2H, t, J = 4.4 Hz), 6.52 (1H, d, J = 5.2

Hz), 7.18 (1H, s), 7.22 (1H, dd5 J=9.2 Hz, 2.4 Hz), 7.47 (1H, d，J=2.4 Hz)，7.52 (1H，s)，7·96 (1H，s)，8.26 (1H，d，J=9.2 Hz)，8·41 (1Ή，s)，8·66 (1H，d，J=5.2 Hz)，11.30 (1H，s)。 實施例252 373 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 B7 五、發明説明（368 ) 氨某-7-(2-甲乳某A氣某）-+琳-4-摹硫卜g塞吩-2-基} - 3 - (嗤-2 -基） 以與實施例246同樣之方法，從4-(5-胺基-嘍吩-2-基硫）-7-(2-甲氧基乙氧基）-喹淋-6-甲腈（118 mg)及嘍唑-2-基胺 基甲酸苯酯（77 mg)，得到為固體之標題化合物（45 mg)。 W-NMR光譜（DMSO-d6) 5 (ρριη): 3.3 6 (3H，s)，3.75-3.78 (2H， m)，4.40-4.42 (2H，m)，6.76-6.79 (1H，m)，6.80 (1H，d，J=5.2 Hz)，7.02-7.08 (1H，m)，7·32·7·38 (1H，m)，7·35 (1H，d， J=4.0 Hz), 7.63 (1H, s), 8.62 (1H, s), 8.70 (1H, d3 J=5.2 Hz)〇 製造例252-1 7_(2_甲氣基乙氳基卜4-硫酮-1ί4_二新4呲甲時 以與製造例226- 1同樣之方法，從6-氰基-7-甲氧基乙氧 基-1Η-喹啉-4-酮（10 g)，得到為固體之標題化合物（9 g)。 h-NMR光譜（DMSO-d6) 5 (ppm): 3·35 (3H，s)，3.74-3.77 (2H， πι), 4.31-4.34 (2Η, m), 7.16-7.19 (2H, m)5 7.82 (1H, d, J=6.8 Hz)，8·86 (1H，s)，12.84 (1H，br s)。 製造例252-2 K 2 -甲氣基乙氧基）-4 - ( 5 -硝某4吩-2 -某硫）4 g汰-6 -甲月奢 以與製造例226-2同樣之方法，從7-(2-甲氧基乙氧基）·‘ 硫酮-1，4-二氫峻琳-6-甲腈（7.1 g)及2-溪-5-硝基p塞吩（6.3 g)，得到為固體之標題化合物（2.2 g)。 H-NMR 光譜（DMSOO (5 (ppm): 3·35 (3H，s)，3.75-3.78 (2H， m)，4.41-4.44 (2Η，m)，7·18 (1Η，d，J=4.4 Ηζ)，7·68 (1Η，d， -374 - 本紙張尺度適用中國國家搮準(CNS) A4規格(210 x 297公釐） 裝 力Hz), 7.18 (1H, s), 7.22 (1H, dd5 J=9.2 Hz, 2.4 Hz), 7.47 (1H, d, J=2.4 Hz), 7.52 (1H, s), 7·96 (1H, s ), 8.26 (1H, d, J = 9.2 Hz), 8.41 (1Ή, s), 8.66 (1H, d, J = 5.2 Hz), 11.30 (1H, s). Example 252 373 - This paper scale is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Invention description (368) Ammonia -7-(2-甲乳一A气) -+琳-4-摹thiob g-cephen-2-yl} - 3 - (嗤-2-yl) In the same manner as in Example 246, from 4-(5-amino-purin-2- Base thio)-7-(2-methoxyethoxy)-quinolin-6-carbonitrile (118 mg) and phenyl oxazol-2-ylcarbamate (77 mg) gave the title Compound (45 mg). W-NMR spectrum (DMSO-d6) 5 (ρριη): 3.3 6 (3H, s), 3.75-3.78 (2H, m), 4.40-4.42 (2H, m), 6.76-6.79 (1H, m), 6.80 (1H,d,J=5.2 Hz), 7.02-7.08 (1H,m), 7·32·7·38 (1H,m),7·35 (1H,d, J=4.0 Hz), 7.63 (1H , s), 8.62 (1H, s), 8.70 (1H, d3 J=5.2 Hz) 〇Production Example 252-1 7_(2_甲气乙氲基卜4-thione-1ί4_二新4呲甲The title compound (9 g) was obtained as a solid (yield from EtOAc (EtOAc) h-NMR spectrum (DMSO-d6) 5 (ppm): 3·35 (3H, s), 3.74-3.77 (2H, πι), 4.31-4.34 (2Η, m), 7.16-7.19 (2H, m) 5 7.82 (1H, d, J=6.8 Hz), 8·86 (1H, s), 12.84 (1H, br s). Production example 252-2 K 2 -methyl ethoxy)-4 - ( 5 -Nitrate 4 pheno-2 - sulphur) 4 g -6 - A month of luxury, in the same manner as in Production Example 226-2, from 7-(2-methoxyethoxy)·'thione-1 4-Dihydro-Junlin-6-carbonitrile (7.1 g) and 2-r--5-nitro-p-phene (6.3 g) gave the title compound (2.2 g). H-NMR spectrum (DMSOO (5 (ppm): 3·35 (3H, s), 3.75-3.78 (2H, m), 4.41-4.44 (2Η, m), 7·18 (1Η, d, J=4.4 Ηζ),7·68 (1Η,d, -374 - This paper size applies to China National Standard (CNS) A4 size (210 x 297 mm).

綉 l3〇4〇6l A7 B7 i、發明説明（Embroidery l3〇4〇6l A7 B7 i, invention description (

J-4.8 Hz), 7.69 (1H, s), 8.23 (1H, d, J=4.4 Hz), 8.70 (lH, s) 8.79 (1H，d，J=4.8 Hz)。 ’ 製造例252-3 胺基-g塞吩-2-基硫）-7-(2-甲氣某乙氧甚^奋说甲月奇 依照製造例226-3，從7-(2-甲氧基乙氧基）·‘（％硝基喧 吩-2-基硫）喹啉-6-甲腈（2.2 g)，得到為固體之標題化合物 (〇·93 g)。 h-NMR 光譜（DMSO-d6)5(PPm): 3·35 (3H，s)，3·74-3·78 (2H， m)，4.38-4.41 (2Η，m)，5·98 (1Η，d，J=3.6 Ηζ)，6·37 (2Η，t， br s)，6.86 (1H，d，J=4.8 Hz)，7.07 (1H，d，J=3.6 Hz)，7.61 (1H，s)，8·54 (1H，s)，8·71 (1H，d，J=4.8 Hz)。 f施例253 5 -「6-氰基- 7-(2-甲氧基乙氧基）-g套被-4-基硫i違吩·2-基卜3“4-氯苽某 以與實施例252同樣之方法，從4-(5-胺基-嘧吩-2-基硫）-Ό-甲氧基乙氧基）-喹啉-6-甲腈（30 mg)及異氰酸4-氟苯 酯，得到為固體之標題化合物（24 mg)。 h-NMR 光譜（DMSO-d6)5(ppm): 3.36 (3H，s)，3·75·3·78 (2H， m), 4.39-4.43 (2H，m)，6·71 (1H，d，J=3.6 Hz)，6.80 (1H，d， J=4.8 Hz), 7.12 (2H, t, J=9.2 Hz), 7.34 (1H, d? J=4.0 Hz)5 7.43-7.47 (2H，m)，7·63 (1H，s)，8.62 (1H，s)，8.70 (1H，d， J=4.8 Hz)，8.97 (1H，br s)，10.23 (1H，bi* s)。 實施例254 ·- 氰基- 7-(2-曱氲某乙氫基）4啉-4-基硫塞吩-2- -375 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)J-4.8 Hz), 7.69 (1H, s), 8.23 (1H, d, J=4.4 Hz), 8.70 (lH, s) 8.79 (1H, d, J = 4.8 Hz). 'Manufacturing Example 252-3 Amino-g-cephen-2-ylthio)-7-(2-A gas, an ethoxy group, and a sulphur, said Azuki according to Production Example 226-3, from 7-(2-A Ethoxyethoxy)·'(% nitroguanidin-2-ylsulfuryl)quinolin-6-carbonitrile (2.2 g) gave the title compound (·········· DMSO-d6)5(PPm): 3·35 (3H, s), 3·74-3·78 (2H, m), 4.38-4.41 (2Η, m), 5·98 (1Η, d, J= 3.6 Ηζ),6·37 (2Η,t, br s), 6.86 (1H,d,J=4.8 Hz),7.07 (1H,d,J=3.6 Hz), 7.61 (1H,s),8·54 (1H, s), 8.71 (1H, d, J = 4.8 Hz) f Example 253 5 - "6-Cyano- 7-(2-methoxyethoxy)-g quilt-4 - thiol i thiophene-2-pyrene 3 "4-chloroindole in the same manner as in Example 252, from 4-(5-amino-pyrimen-2-ylthio)-oxime-methoxy Ethoxy)-quinoline-6-carbonitrile (30 mg) and 4-fluorophenylisocyanate afforded the title compound (24 mg). H-NMR spectrum (DMSO-d6) 5 (ppm): 3.36 (3H, s), 3·75·3·78 (2H, m), 4.39-4.43 (2H, m), 6·71 (1H, d , J=3.6 Hz), 6.80 (1H, d, J=4.8 Hz), 7.12 (2H, t, J=9.2 Hz), 7.34 (1H, d? J=4.0 Hz)5 7.43-7.47 (2H,m ), 7·63 (1H, s), 8.62 (1H, s), 8.70 (1H, d, J = 4.8 Hz), 8.97 (1H, br s), 10.23 (1H, bi* s). Example 254 ·-Cyano- 7-(2-indole-2-hydroxy-4-yl-4-ylthiothiophene-2-375 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X) 297 mm)

iiIi

1304061 A7 B7 五、發明説明（370 ) 羞J - 3- (3 -氣笨基）服 以與實施.例252同樣之方法，從4-(5-胺基·噻吩-2-基硫）_ 7-(2-甲氧基乙氧基）-喹啉-6-甲腈（30 mg)及異氰酸3 -氟苯 酯，得到為固體之標題化合物（20 mg)。 ^-NMR 光譜（DMSO-d6) 5 (ppm): 3·36 (3H，s)，3.75-3.78 (2H， m)，4.39-4.43 (2H，m)，6.73 (1H，d，J=4.0 Ηζ)，6·81 (1H，d， J-4.8 Hz), 6.78-6.85 (1H, m), 7.15-7.19 (1H, m), 7.27-7.32 (1H，m), 7.35 (1H，d，J=4.0 Hz), 7.40-7.45 (1H，m)，7·63 (1H， s)，8·62 (1H，s)，8.70 (1H，d，J=4.8 Hz)，9·18 (1H，br s)， 10.30 (1H，br s)。 复施例255 1^{ 5-「6-氨基-7-(2-甲氫基乙氣某U备啉-4-基硫吩 基卜3 -環丙脲 以與實施例252同樣之方法，從4-(5-胺基-4吩-2-基硫）_ 7-(2-甲氧基乙氧基）-喹啉-6-甲腈（35 mg)及環丙胺，得到 為固體之標題化合物（15 mg)。 A-NMR 光譜（DMSO-d6) 5 (ppm): 0.41-0.46 (2H，m)，〇,6κ 〇·68 (2Η，m)，2.48-2.55 (1Η，m)，3·36 (3Η，s)，3.75-3.79 (2Η， m)，4·39-4·43 (2H，m)，6.63 (1H，d，J=4.0 Hz)，6.77 (1H，d， J=4.8 Hz)，6.79-7.84 (1H，m)，7·28 (1H，d，J=4.0 Hz)，7.62 (1H，s)，8·60 (1H，s)，8·69 (1H，d，J=4.8 Hz)，9.93 (1H，br s) 0 實施例256 . · 1- { 5-Γ6-氨某- 7-(2-甲氫基乙氣基）4啉-4-基硫1噻吩 376 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐）1304061 A7 B7 V. INSTRUCTIONS (370) Shame J - 3- (3 - gas base) is subjected to the same method as in Example 252, from 4-(5-aminothiophen-2-ylthio)_ 7-(2-Methoxyethoxy)-quinoline-6-carbonitrile (30 mg), m.p. ^-NMR spectrum (DMSO-d6) 5 (ppm): 3·36 (3H, s), 3.75-3.78 (2H, m), 4.39-4.43 (2H, m), 6.73 (1H, d, J=4.0 Ηζ),6·81 (1H,d, J-4.8 Hz), 6.78-6.85 (1H, m), 7.15-7.19 (1H, m), 7.27-7.32 (1H,m), 7.35 (1H,d, J=4.0 Hz), 7.40-7.45 (1H,m),7·63 (1H, s),8·62 (1H,s), 8.70 (1H,d,J=4.8 Hz),9·18 (1H , br s), 10.30 (1H, br s). Example 255 1^{ 5-"6-Amino-7-(2-methylhydroethane-U-Buolin-4-ylthiophene-3-cyclopropanil in the same manner as in Example 252, From 4-(5-Amino-4 phen-2-ylthio)-7-(2-methoxyethoxy)-quinoline-6-carbonitrile (35 mg) and cyclopropylamine as a solid Title compound (15 mg) A-NMR spectrum (DMSO-d6) 5 (ppm): 0.41-0.46 (2H, m), 〇, 6 κ 〇 · 68 (2 Η, m), 2.48-2.55 (1 Η, m) , 3·36 (3Η, s), 3.75-3.79 (2Η, m), 4·39-4·43 (2H, m), 6.63 (1H, d, J=4.0 Hz), 6.77 (1H, d, J=4.8 Hz), 6.79-7.84 (1H, m), 7·28 (1H, d, J=4.0 Hz), 7.62 (1H, s), 8·60 (1H, s), 8.69 (1H , d, J = 4.8 Hz), 9.93 (1H, br s) 0 Example 256. · 1- { 5-Γ6-Ammonia- 7-(2-Methylhydroethane)-4-phenyl-4-yl Sulfur 1 thiophene 376 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂 、線 1304061 、 A7Binding, line 1304061, A7

發明説明 以與實施例252同樣之方法，從4-(5-胺基嘍吩基硫）· 7-(2-甲氧基乙氧基）喹啉-6_甲腈（38 mg)及異氰酸氟苯 酯，得到為固體之標題化合物（15 mg)。 H-NMR光 if(DMSO-d6)5(ppm): 3.36 (3H，s)，3·75-3·78 (2H， m)，4/39-4.43 (2Η，m)，6·72 (1Η，d，J=4.0 Ηζ)，6·80 (1Η，d，DESCRIPTION OF THE INVENTION In the same manner as in Example 252, from 4-(5-aminononylthio)-7-(2-methoxyethoxy)quinolin-6-carbonitrile (38 mg) and The title compound (15 mg) was obtained as a solid. H-NMR light if (DMSO-d6) 5 (ppm): 3.36 (3H, s), 3·75-3·78 (2H, m), 4/39-4.43 (2Η, m), 6.72 ( 1Η,d,J=4.0 Ηζ),6·80 (1Η,d,

J-4.8 Hz), 7.02-7.08 (1H, m), 7.12-7.16 (1H, m), 7.21-7.27 (1H，m)，7.36 (1H，d，J=4.0 Hz)，7.63 (1H，s)，7·99-8·04 (1H， m)，8·62 (1H，s)，8.70 (1H，d，J=4.8 Hz)，8·74-8·78 (1H，m)， 10.45 (1H，bi* s) 〇 f施例257 ϋ5· f 6-氰基-7- (2-甲氧基乙氳基）4淋-4-某硫1違吩_ 基笨基骑J-4.8 Hz), 7.02-7.08 (1H, m), 7.12-7.16 (1H, m), 7.21-7.27 (1H, m), 7.36 (1H, d, J=4.0 Hz), 7.63 (1H, s ),7·99-8·04 (1H, m),8·62 (1H,s), 8.70 (1H,d,J=4.8 Hz),8·74-8·78 (1H,m), 10.45 (1H, bi* s) 〇f Example 257 ϋ5· f 6-Cyano-7-(2-methoxyethenyl) 4 leaved -4- sulphur 1 violent _ base stupid ride

以與實施例252同樣之方法，從4-(5-胺基噻吩-2-基硫）-7_ (2-甲氧基乙氧基）喹啉-6-甲腈（38 mg)及異氰酸苯酯，得 到為固體之標題化合物（12 mg)。 (H-NMR 光譜（DMSO-d6)(J (ppm): 3·36 (3H，s)，3.75-3.78 (2H， m)，4.39-4.43 (2H，m)，6·71 (1H，d，J=4.0 Hz)，6.81 (1H，d， J=4.8 Hz)，6.97-7.01 (1H，m)，7·28 (2H，t，J=7.6 Hz)，7.34 (1H，d，J=4.0 Hz)，7·44 (2H，d，J=7.6 Hz)，7·63 (1H，s)，8.62 (1H，s)，8.70 (1H，d，J=4.8 Hz), 8·94 (1H，br s)，10.21 (1H， br s) o 實施例258 . · {5-「6-氰基-7-(2-甲氣某乙氣基）4啉-4-基硫吩-2- -377 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 _____B7 五、發明説明（372 ) 基:二氟苽某）Μ 以與實施.例252同樣之方法，從4-(5-胺基嘍吩-2-基硫）· 7-(2-甲氧基乙氧基）喹啉甲腈（30 mg)及異氰酸2,‘二氟 苯酉旨’ 4于到為固體之標題化合物（18 mg)。 a-NMR 光譜（DMSO-d6) 5 (ppm): 3·35 (3H，s)，3.74-3.78 (2H， m), 4.39-4.43 (2H, m), 6.71 (1H, d, J=4.0 Hz), 6.80 (1H, d, J==4.8 Hz), 7.01-7.08 (1H, m), 7.29-7.34 (1H, m), 7.35 (1H, d, J=4.0 Hz)，7·63 (1H，s)，7.89-7.97 (1H，m)，8·62 (1H，s)， 8.70 (1H，d，J=4.8 Hz)，8·73 (1H，bi: s)，10.44 (1H，bi: s)。 f施例259 1 - dJ 6-讯基-7- (2-甲氣基乙氣某）4淋-4-某硫吩_ 2-基} -_3-(對甲笨某）脲 以與實施例252同樣之方法，從4-(5-胺基嘍吩-2-基硫）-7-(2-甲氧基乙氧基）喹啉-6-甲腈（3〇 mg)及異氰酸對甲苯 酯，得到為固體之標題化合物（28 mg) » iH-NMR光譜（DMSO-d6)5(ppm): 2.23 (3H，s)，3.36 (3H，s), 3.75-3.78 (2H, m), 4.39-4.43 (2H, m), 6.69 (1H, d, J=4.0 Hz), 6.80 (1H，d，J=4.8 Hz), 7.08 (2H，d，J=8.0 Hz)，7·32 (2H，d， J=8.0 Hz)，7·33 (1H，d，J=4.0 Hz)，7·63 (1H，s)，8.61 (1H，s)， 8.70 (1H，d，J=4.8 Hz)，8.81 (1H，br s)，10.15 (1H，br s)。 實施例260 U 5- f 6-氣基 7-(足:土氧基6氧某）α♦啦-4·幕結1 4吟-2-基}-3-(3-著美茇某）胧 以與實施例252同樣之方法’從4-(5-胺基噻吩-2-基硫）- -378- 本紙張尺度適用中國國家標準(CMS) A4規格(210 X 297公釐） 裝 訂 線 1304061 A7 B7 五、發明説明（373 ) 7-(2-甲氧基乙氧基奎，林_ 6-甲腈（30 mg)及異氰酸弘氰基苯 酉曰’传·到為固體之標題化合物（3 3 m g)。 iH-NMR 光譜（DMSO-d6)(5 (ppm): 3.36 (3H，S)，3·75-3.78 (2H， m), 4.39-4.43 (2H, m), 6.75 (1H, d, J=4.0 Hz), 6.80 (1H, d, J=4.8 Hz), 7.36 (1H, d, J=4.0 Hz), 7.43-7.52 (2H, m)5 7.63 (1H, s), 7.70-7.73 (1H, m), 7.91-7.94 (1H, m), 8.62 (1H, s),8.70 (1H，d，J=4.8 Hz), 9.30 (1H，br s), 10.44 (1H, br s)。 實施例261 5 - f…讯基-7- (2-甲氧基乙氧基）g奎淋-4-篆硫1破吩-2-基}-3“心氰某苽某）胧 以與實施例252同樣之方法，從4-(5-胺基噻吩-2-基硫）-7-(2-甲氧基乙氧基）喹啉-6-甲腈（30 mg)及異氰酸4-氰基苯 酉旨’仔到為固體之標題化合物（2 8 mg)。 h-NMR 光譜（DMSO-d6)5(ppm): 3·35 (3H，s)，3·74-3·78 (2H， m), 4.39-4.43 (2H, m), 6.76 (1H, d, J=4.0 Hz), 6.80 (1H, d, J=4.8 Hz), 7.36 (1H, d, J=4.0 Hz), 7.61-7.66 (3H, m), 7.71-7.75 (2H, m), 8.62 (1H, s), 8.70 (1H, d, J=4.8 Hz), 9.48 (1H, br s)，10·44 (1H，br s)。 實施例262 N-「4-(7-(2-曱氣基乙氣基）-6-1某-4-4啉某）氣笨基卜Ν' (4-環丙某 以與實施例249-4同樣之方法，從7-(2-甲氧基乙氧基）-6-氰基-4-( 4-胺基-3-氯苯氧基）喹啉（380 mg)，得到為固體之 標題化合物（220 mg)。 -379 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 袈 Μ 線 1304061 A7 B7 五、發明説明（374 H-NMR 光譜（〇1^3〇46)(5(??111):0.38-0.44(211，111)，0.63-0.69 (2H，m)，2·53-2·60 (1H，m), 3·36 (3H，s)，3·76·3 79 (2H， m), 4.40-4.43 (2H, m), 6.58 (1H, d, J=5.2 Hz), 7.19 (1H, d3 J=2.8 Hz), 7.25 (1H, dd, J=2.8, 1=8.8 Hz), 7.50 (iH, d3 J=2.8 Hz), 7.63 (1H, s), 7.98 (1H, s), 8.28 (1H, d, J=8.8 Hz), 8.73 (1H，d·，J=5.2 Hz), 8·74 (1H，s)。 盤造例262-14-(5-Aminothiophen-2-ylsulfanyl)-7-(2-methoxyethoxy)quinolin-6-carbonitrile (38 mg) and isocyanide in the same manner as in Example 252 The title compound (12 mg) was obtained as a solid. (H-NMR spectrum (DMSO-d6) (J (ppm): 3·36 (3H, s), 3.75-3.78 (2H, m), 4.39-4.43 (2H, m), 6.71 (1H, d , J=4.0 Hz), 6.81 (1H, d, J=4.8 Hz), 6.97-7.01 (1H, m), 7·28 (2H, t, J=7.6 Hz), 7.34 (1H, d, J= 4.0 Hz), 7.44 (2H, d, J = 7.6 Hz), 7·63 (1H, s), 8.62 (1H, s), 8.70 (1H, d, J = 4.8 Hz), 8·94 ( 1H, br s), 10.21 (1H, br s) o Example 258 . · {5-"6-Cyano-7-(2-methyl-ethane) 4- phenyl-4-ylthiophene-2 - -377 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 _____B7 V. Description of invention (372) Base: Difluoromethane) Μ In the same way as in Practice 252 From 4-(5-Aminophenanthr-2-ylsulfanyl)-7-(2-methoxyethoxy)quinolinecarbonitrile (30 mg) and isocyanic acid 2, 'difluorobenzoquinone The title compound (18 mg) is obtained as a solid. a-NMR spectrum (DMSO-d6) 5 (ppm): 3·35 (3H, s), 3.74-3.78 (2H, m), 4.39-4.43 ( 2H, m), 6.71 (1H, d, J=4.0 Hz), 6.80 (1H, d, J==4.8 Hz), 7.01-7.08 (1H, m), 7.29-7.34 (1H, m), 7.35 ( 1H, d, J=4.0 Hz), 7·63 (1H, s) , 7.89-7.97 (1H, m), 8.62 (1H, s), 8.70 (1H, d, J = 4.8 Hz), 8.73 (1H, bi: s), 10.44 (1H, bi: s) f Example 259 1 - dJ 6- 信基-7- (2-methyl-based ethyl ethane) 4 leaved -4- thiophene _ 2- yl} - _ 3- (for a benzene) urea with Example 252, in the same manner, from 4-(5-aminopurin-2-ylsulfanyl)-7-(2-methoxyethoxy)quinolin-6-carbonitrile (3 mg) The title compound (28 mg) was obtained as a solid (yield: DMSO-d6) 5 (ppm): 2.23 (3H, s), 3.36 (3H, s), 3.75-3.78 (2H , m), 4.39-4.43 (2H, m), 6.69 (1H, d, J=4.0 Hz), 6.80 (1H,d,J=4.8 Hz), 7.08 (2H,d,J=8.0 Hz),7 · 32 (2H, d, J = 8.0 Hz), 7·33 (1H, d, J = 4.0 Hz), 7·63 (1H, s), 8.61 (1H, s), 8.70 (1H, d, J =4.8 Hz), 8.81 (1H, br s), 10.15 (1H, br s). Example 260 U 5-f 6-gas group 7-(foot: earth oxygen 6 oxygen) α♦啦-4·curtain knot 1 4吟-2-yl}-3-(3-美美茇)适用 In the same manner as in Example 252 'from 4-(5-Aminothiophen-2-ylthio)- -378- This paper scale applies Chinese National Standard (CMS) A4 size (210 X 297 mm) gutter 1304061 A7 B7 V. INSTRUCTIONS (373) 7-(2-methoxyethoxy quinone, linyl-6-carbonitrile (30 mg) and isocyanic acid cyanobenzoquinone The title compound (3 3 mg). iH-NMR spectrum (DMSO-d6) (5 (ppm): 3.36 (3H, S), 3.75-3.78 (2H, m), 4.39-4.43 (2H, m), 6.75 (1H, d, J=4.0 Hz), 6.80 (1H, d, J=4.8 Hz), 7.36 (1H, d, J=4.0 Hz), 7.43-7.52 (2H, m)5 7.63 (1H, s ), 7.70-7.73 (1H, m), 7.91-7.94 (1H, m), 8.62 (1H, s), 8.70 (1H, d, J = 4.8 Hz), 9.30 (1H, br s), 10.44 (1H , br s). Example 261 5 - f... keki-7-(2-methoxyethoxy)g quinol-4-indole thiol 1 broken phen-2-yl}-3 "heart cyanide a) in the same manner as in Example 252, from 4-(5-aminothiophen-2-ylsulfanyl)-7-(2-methoxyethoxy)quinolin-6-carbonitrile (30 mg And isocyanide 4-cyanobenzoquinone as the title compound (28 mg) as a solid. h-NMR spectrum (DMSO-d6) 5 (ppm): 3·35 (3H, s), 3·74-3· 78 (2H, m), 4.39-4.43 (2H, m), 6.76 (1H, d, J=4.0 Hz), 6.80 (1H, d, J=4.8 Hz), 7.36 (1H, d, J=4.0 Hz ), 7.61-7.66 (3H, m), 7.71-7.75 (2H, m), 8.62 (1H, s), 8.70 (1H, d, J=4.8 Hz), 9.48 (1H, br s), 10.44 (1H, br s). Example 262 N-"4-(7-(2-indoleylethane group)-6-1 -4-4 porphyrin) a gas stupid base Ν' (4-ring The same procedure as in Example 249-4 was carried out from 7-(2-methoxyethoxy)-6-cyano-4-(4-amino-3-chlorophenoxy)quinoline ( The title compound (220 mg) was obtained as a solid. -379 - This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 袈Μ Line 1304061 A7 B7 V. Description of invention (374 H-NMR spectrum (〇1^3〇46) (5(? ?111): 0.38-0.44 (211, 111), 0.63-0.69 (2H, m), 2·53-2·60 (1H, m), 3·36 (3H, s), 3·76·3 79 (2H, m), 4.40-4.43 (2H, m), 6.58 (1H, d, J=5.2 Hz), 7.19 (1H, d3 J=2.8 Hz), 7.25 (1H, dd, J=2.8, 1= 8.8 Hz), 7.50 (iH, d3 J=2.8 Hz), 7.63 (1H, s), 7.98 (1H, s), 8.28 (1H, d, J=8.8 Hz), 8.73 (1H,d·,J= 5.2 Hz), 8·74 (1H, s).

以與製造例395- 1同樣之方法，從用公知方法得到之* )口杳 氯-7-甲氧基乙氧基-6-氰基喹淋（800 mg)，得到為固體之 標題化合物（380 mg)。In the same manner as in Production Example 395-1, the title compound was obtained as a solid (yield: mp. 380 mg).

iH-NMR 光譜（DMSO-d6) 5 (ppm)·· 3.36 (3H，s)，3.75.3 78 (2H m)，4·39,4·41 (2H，m)，5.46 (2H，br s)5 6·51 (1H，d，J==5 2’ Hz), 6·89 (1H，d5 J=8.8 Hz)，7.01 (1H，dd，J=2.8, J二8,8 Hz 7·24 (1H, d，J=2.8 Hz)，7.60 (1H，s)，8·70 (1H, d，J=5.2 Hz)’ 8.71 (1H，s)。 ’ f施例263 以與實施例10同樣之方法，從[4-(4-胺基苯氧基）-7-甲氧 基喹啉-6-基]胺基曱酸芊酯（330 mg)及異氰酸4-氟笨g旨， 仔到為固體之標題化合物（3 80 mg)。 1H-NMR 光譜（DMSO-d6)6(Ppm): 3·97 (3H，S)，5.19 (2H，S)， 6.42 (1H, d, J-5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.19 (2h, d ______ - 380 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) A7 B7iH-NMR spectrum (DMSO-d6) 5 (ppm)·· 3.36 (3H, s), 3.75.3 78 (2H m), 4·39, 4·41 (2H, m), 5.46 (2H, br s ) 5 6·51 (1H,d,J==5 2' Hz), 6·89 (1H, d5 J=8.8 Hz), 7.01 (1H, dd, J=2.8, J 2,8 Hz 7· 24 (1H, d, J = 2.8 Hz), 7.60 (1H, s), 8.70 (1H, d, J = 5.2 Hz) ' 8.71 (1H, s). ' f Example 263 and Example 10 In the same manner, from [4-(4-aminophenoxy)-7-methoxyquinolin-6-yl]amino decanoate (330 mg) and isocyanate 4-fluoro , the title compound (3 80 mg) as a solid. 1H-NMR spectrum (DMSO-d6) 6 (Ppm): 3·97 (3H,S), 5.19 (2H,S), 6.42 (1H, d, J-5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.19 (2h, d ______ - 380 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7

1304061 五、發明説明（375 ) J=8.8 Hz), 7.29-7.49 (8H, m), 7.57 (2H, d, J=8.8 Hz), 8 49 (1H，d，J-5,2 Hz)，8.67 (1H，s)，8.80 (1H，br s)，8·87 (1H br s)，8·98 (1H，s)。 ’ 如下述合成中間體。 邈造例263- 11304061 V. INSTRUCTIONS (375) J=8.8 Hz), 7.29-7.49 (8H, m), 7.57 (2H, d, J=8.8 Hz), 8 49 (1H, d, J-5, 2 Hz), 8.67 (1H, s), 8.80 (1H, br s), 8.87 (1H br s), 8.98 (1H, s). ' As a synthetic intermediate as described below. 263例263- 1

(7-甲乳基·4 -嗣某-1，4 -二氫〃奎淋-6-某）胺甚甲酸午~西旨 將7-甲氧基-4-酮基-1，4-二氫β奎淋-6-幾酸（2.58 g)溶於 N，N-二甲基甲醯胺（50 ml)，然後加入苄醇（3 29如），二苯 基鱗酿胺（2.51 ml)及三乙胺（1.63 ml)，並於95«c加熱攪摔5 小時。將反應液注入飽和食鹽水中，用乙酸乙醋萃取，有 機層用無水硫酸鎂乾燥後濃縮。將得到之殘餘物付諸於NH 型碎凝膠管柱層析（乙酸乙醋-甲醇,得到為固體之標 題化合物（2·03 g)。 1H-NMR 光譜（DMSO-d6)(5(ppm): 3·85 (3H，s)，5·14 (2H s) 5.93 (1H，d，J=7.2 Ηζ)，7.07 (1H，s)，7 39·7 43 (5Η，’^’ 7.74-7.81 (1H，m)，8·30 (1H，br s)，8.75 (1H，s)，1197 (况 br s) 〇 製造例263-2 甲氧基4嗾-6-基）胺基甲酸 將（7-曱氧基-4-酮基-1,4-二氫喳啉基）胺基甲酸苄酯 (2 g)加至亞硫酿氣（20 ml)及N，N-二甲基甲醯胺（〇·5加）之 混合溶液中並加熱回流2小時。反應终了後，餾去亞疏酿 氣’然後反覆進行加入甲苯及濃縮之作業3次，得到為固體 之標題化合物（2.4 g)。 -381 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐)(7-Methyl-based 4-anthracene-1,4-dihydroquinone-6-) amine-acidic acid-nine 7-methoxy-4-keto-1,4-di Hydrogen β quino-6-acid (2.58 g) was dissolved in N,N-dimethylformamide (50 ml), then benzyl alcohol (3 29), diphenylaramine (2.51 ml) And triethylamine (1.63 ml), and stirred at 95 «c for 5 hours. The reaction solution was poured into a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The residue obtained was subjected to EtOAc (EtOAc-EtOAc) eluted eluted elut elut ): 3·85 (3H, s), 5·14 (2H s) 5.93 (1H, d, J=7.2 Ηζ), 7.07 (1H, s), 7 39·7 43 (5Η, '^' 7.74- 7.81 (1H,m),8·30 (1H,br s),8.75 (1H,s),1197 (condition br s) 〇Production Example 263-2 methoxy 4嗾-6-yl)carbamic acid Benzyl (7-decyloxy-4-keto-1,4-dihydroporphyrinyl)carbamate (2 g) added to sulphuric gas (20 ml) and N,N-dimethyl The mixed solution of decylamine (5 liters) was heated and refluxed for 2 hours. After the end of the reaction, the argon was distilled off, and then the work of adding toluene and concentration was repeated three times to obtain the title compound (2.4 g) as a solid. -381 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

訂 線 1304061 A7 B7 376 五、發明説明（ iH-NMR光譜（DMSO-d6)5(ppm)·· 3·98 (3H，s), 5·22 (2H，s)， 7.26-7.49 (6H, m), 7.55 (1H, d, J=5.2 Hz), 8.63 (1H, d, J=5.2 Hz)，8·65 (1H，s)，9.12 (1H，br s)。 製造例263-3 「4-(4-胺基苯氧基）-7-甲氣4啉-6-某1胺基甲酸芊 以與製造例7同樣之方式，從（4-氯-7-甲氧喹啉-6-基）胺 基曱酸苄酯（2.4 g)及4-硝基酚（2·07 g)，得到4-苯氧基喹啉 體（465 mgp將該4-苯氧基p奎淋體（450 mg)以與製造例8同 樣之方式這原’得到為固體之標題化合物（330 mg)。 iH-NMR 光譜（DMSO-d6)5(ppm): 3·96 (3H，s)，5.15 (2H，br s), 5.18 (2H, s), 6.34 (1H, d, J=5.2 Hz), 6.65 (2H, d, J=8.4 Hz), 6.90 (2H, d, J=8.4 Hz), 7.29-7.46 (6H, m), 8.45 (1H, d, J=5.2 Hz)，8.65 (1H，s)，8·95 (1H, s)。 實施例264 胺基-7-甲氧基4啉-4-基氣）茉某氟芡基） 脲 將（4-{4-[3-(4-氟苯基）脲]苯氧基}-7-曱氧喹啉-6-基）胺 基甲酸芊酯（100 mg)溶於四氫呋喃（1〇 ml) -甲醇（10 ml)之 混合溶液，加入10%鈀/碳（10 mg)，在1氣壓氫氣蒙氣及室 溫下授拌7小時。將反應液經碎藻土過遽，將遽液濃縮，得 到為固體之標題化合物（60 mg)。 1H-NMR 光譜（DMSO-d6)5(ppm): 3.94 (3H，s)，5.44 (2H，s)， 6·34 (1H，d，J=5:2 Hz)，7.07-7.15 (4H，m)，7.23 (1H，s)，7·23 (1H, s), 7.43-7.48 (2H, m), 7.53 (2H, d, J=8.8 Hz), 8.25 (1H, -382 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 裝 訂 線 1304061 A7 B7 五、發明説明（377 ) d，J=5.2 Hz)，8.83 (1H，br s)，8·87 (1H，br s)。 實施例265 N-(4· { 4_：丄3· (4_氟苯基）脲1笨氧幕} ·7·甲氧其十说·6_苯、 乙醯胺 將1-[4-(6-胺基-7-甲氧基喹啉-4-基氧）苯氧基(‘氟 苯基）脲（50 mg)溶於吡啶（5 ml)，加入無水乙酸（〇5㈤^及 放置於室溫12小時。將反應液注入飽和食鹽水中以及用乙 酸乙酯萃取，將有機層用硫酸鎂乾燥及濃縮，得到為固體 之標題化合物（50 mg)。 h-NMR 光譜（DMSO-d6)5(ppm): 2,17 (3H，s)，4.01 (3H s) 6·41 (1H，d，J-5·6 Ηζ)，7·11 (2H，t，J=8.8 Ηζ)，7·18 (2H d J=8.8 Hz), 7.42-7.49 (3H, m), 7.57 (2H, d, J=8.8 Hz), 8.49 (1H, d? J=5.6 Hz), 8.78 (1H, br s), 8.85 (1H, br s), 8.98 (1H, s)，9·45 (1H，s) 〇 實施例266 N_:(4- { 4-[3-(4- l苯基）踩1笨氳基卜7-甲氫美口争琳j某） 甲磺醯胺 將1-[4-(6 -胺基-7-甲氧基p奎琳-4-基氧）苯氧基]-3-(4-氟 苯基）脲（50 mg)溶於四氫呋喃（3 ml)，加入三乙胺（〇.3 mi) 及甲續醯氯（14# 1)並於室溫揽拌1小時。將反應液注入飽 和氯化銨水溶液中及用乙酸乙酯萃取，將有機層用飽和食 鹽水沖洗及用硫酸鎂乾燥。將有機層濃縮，將得到之殘餘 物付諸於矽·凝膠·層析，用溶媒（乙酸乙酯-甲醇= 5-1)溶出， 得到為固體之標題化合物（13 mg)。 -383 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 裝 訂Setting line 1304061 A7 B7 376 V. Description of the invention (iH-NMR spectrum (DMSO-d6) 5 (ppm)································ m), 7.55 (1H, d, J=5.2 Hz), 8.63 (1H, d, J=5.2 Hz), 8·65 (1H, s), 9.12 (1H, br s). Manufacturing Example 263-3 4-(4-Aminophenoxy)-7-methyl-4-bromo-6-yl-1 guanidinecarboxylate in the same manner as in Production Example 7, from (4-chloro-7-methoxyquinolin-6 - benzyl benzyl decanoate (2.4 g) and 4-nitrophenol (2.07 g) to give 4-phenoxyquinoline (465 mgp of 4-phenoxy p-quinone ( 450 mg) The title compound (330 mg) was obtained as a solid in the same manner as in the preparation of the compound. </ RTI> NMR spectrum (DMSO-d6) 5 (ppm): 3·96 (3H, s), 5.15 ( 2H, br s), 5.18 (2H, s), 6.34 (1H, d, J=5.2 Hz), 6.65 (2H, d, J=8.4 Hz), 6.90 (2H, d, J=8.4 Hz), 7.29 -7.46 (6H, m), 8.45 (1H, d, J = 5.2 Hz), 8.65 (1H, s), 8.95 (1H, s). Example 264 Amino-7-methoxy-4-phenyl- 4-(4-[4-[4-(4-fluorophenyl)urea]phenoxy}-7-fluorenylquinolin-6-yl)carbamic acid Ester ester (100 mg) is dissolved in tetrahydrofuran 1 〇 ml) - a mixed solution of methanol (10 ml), 10% palladium on carbon (10 mg), and mixed at 1 atmosphere of hydrogen gas at room temperature for 7 hours. The reaction solution was passed through the algae. The sputum was concentrated to give the title compound (60 mg): Compound: Compound: Compound d, J=5:2 Hz), 7.07-7.15 (4H, m), 7.23 (1H, s), 7·23 (1H, s), 7.43-7.48 (2H, m), 7.53 (2H, d, J=8.8 Hz), 8.25 (1H, -382 - This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) Gutter 1304061 A7 B7 V. Invention description (377) d, J=5.2 Hz ), 8.83 (1H, br s), 8.87 (1H, br s). Example 265 N-(4·{4_:丄3·(4-fluorophenyl)urea 1 stupid screen} ·7·methoxy-decade·6-benzene, acetamidine 1-[4-( 6-Amino-7-methoxyquinolin-4-yloxy)phenoxy ('fluorophenyl)urea (50 mg) dissolved in pyridine (5 ml), added with anhydrous acetic acid (〇5 (5)^ and placed in The reaction mixture was poured into EtOAc EtOAc (EtOAc). (ppm): 2,17 (3H, s), 4.01 (3H s) 6.41 (1H, d, J-5·6 Ηζ), 7·11 (2H, t, J=8.8 Ηζ), 7· 18 (2H d J=8.8 Hz), 7.42-7.49 (3H, m), 7.57 (2H, d, J=8.8 Hz), 8.49 (1H, d? J=5.6 Hz), 8.78 (1H, br s) , 8.85 (1H, br s), 8.98 (1H, s), 9·45 (1H, s) 〇 Example 266 N_: (4- { 4-[3-(4- lphenyl) step 1 clumsy Keb 7-methylhydrogen sulphide j) sulphonamide will be 1-[4-(6-amino-7-methoxyp-quinolin-4-yloxy)phenoxy]-3- (4-Fluorophenyl)urea (50 mg) was dissolved in tetrahydrofuran (3 ml), triethylamine (〇.3 mi) and chlorohydrin (14# 1) were added and stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. Chromatography, elution with a solvent (ethyl acetate-methanol = 5-1) to give the title compound (13 mg) as a solid. -383 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding

線 1304061 A7 B7 五、發明説明（378 ) W-NMR 光譜（DMS〇-d6)(Hppm): 3·05 (3H，s)，3.98 (3H，s), 6.43 (1H, d., J=5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.19 (2H, d, J=8.8 Hz), 7.43-7.48 (3H, m), 7.57 (2H, d, J=8.8 Hz), 8.12 (1H, s), 8.53 (1H, d, J=5.2 Hz), 8.76 (1H, br s), 8.84 (1H, br s)，9.31 (1H，br)。 實施例267 (4-(3-氟-4-f 3-(4-氣笨基）脲1笨氣某卜7-甲氣〃奎啉-6-某） 胺基甲酸芊酯 以與實施例1〇同樣之方式，從[4-(4-胺基-3-氟-苯氧基）-7-甲氧喹啉·6·基]胺基甲酸苄酯（166 mg)及異氰酸4-氟苯 酯得到為固體之標題化合物（1 80 mg)。 iH-NMR 光譜（DMSO-d6)(5(ppm): 3·97 (3H, s)，5·18 (2H，s)， 6.51 (1Η, d, J=5.2 Hz), 7.05-7.09 (1H, m)3 7.12 (2H, t, J=8.8 Hz), 7.29-7.41 (4H, m), 7.42-7.49 (5H, m), 8.20 (1H, t, J=8.8 Hz)，8·52 (1Ή，d，J=5.2 Hz)，8·62-8·64 (1H，m)，8·65 (1H，s)， 8.99 (1H，s)，9·12 (1H，br s)。 如下述合成中間體。 製造例267- 1 [4-(3 -氟-4-硝基笨氣基）-7-甲氧基ττ奎〃株-6-基1胺某甲齡爷 li. 將（4-氯-7-甲氧基喹啉-6-基）胺基甲酸苄酯（158 g)加至 1-甲基-2-吡咯啶酮（5 ml)中，加入3 -氟-心硝基酚（〇.87 g) 及N，N-二異丙基乙胺（1.2 ml)並於130°C加熱搅掉6小時。將 反應液注入飽和碳酸氫鈉水溶液，用乙酸乙g旨萃取，將有 -384 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)Line 1304061 A7 B7 V. Illustrative (378) W-NMR spectrum (DMS〇-d6) (Hppm): 3·05 (3H, s), 3.98 (3H, s), 6.43 (1H, d., J= 5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.19 (2H, d, J=8.8 Hz), 7.43-7.48 (3H, m), 7.57 (2H, d, J=8.8 Hz), 8.12 (1H, s), 8.53 (1H, d, J=5.2 Hz), 8.76 (1H, br s), 8.84 (1H, br s), 9.31 (1H, br). Example 267 (4-(3-Fluoro-4-f 3-(4-indolyl)urea 1 stupid 7-methylpyridinium quinone-6-) guanidinium carbamate and examples 1〇 In the same manner, from [4-(4-Amino-3-fluoro-phenoxy)-7-methoxyquinolin-6-yl]carbamate (166 mg) and isocyanic acid 4 -Fluorophenyl ester gave the title compound (1 80 mg) as a solid. iH-NMR spectrum (DMSO-d6) (5 (ppm): 3·97 (3H, s), 5·18 (2H, s), 6.51 (1Η, d, J=5.2 Hz), 7.05-7.09 (1H, m)3 7.12 (2H, t, J=8.8 Hz), 7.29-7.41 (4H, m), 7.42-7.49 (5H, m), 8.20 (1H, t, J=8.8 Hz), 8.52 (1Ή, d, J=5.2 Hz), 8·62-8·64 (1H, m), 8·65 (1H, s), 8.99 ( 1H, s), 9·12 (1H, br s). The intermediate was synthesized as follows. Production Example 267- 1 [4-(3 -Fluoro-4-nitrophenyl)-7-methoxy ττ 〃-6-yl 1 amine, a sylvestre li. Add benzyl (4-chloro-7-methoxyquinolin-6-yl)carbamate (158 g) to 1-methyl-2- To the pyrrolidone (5 ml), 3-fluoro-cardonitrophenol (〇.87 g) and N,N-diisopropylethylamine (1.2 ml) were added and stirred at 130 ° C for 6 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate. With the extraction of acetic acid, there will be -384 - the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂Binding

線 l3〇4〇6i A7Line l3〇4〇6i A7

機層用飽和食鹽水洗淨後用硫酸鎂乾燥。將有機層濃縮， 將得到之殘餘物付諸於NH矽凝膠管柱層析，用溶媒（乙酸 乙醋）溶出，得到為固體之標題化合物（188 mg)。 h-NMR光譜（DMSO-d6)5(ppm): 3 98 (3H，s)，5 16 (2H，s)， 6·96 (1H，d，J=5.2 Ηζ)，7·16-7·21 (1H，m)，7.28-7.43 (5H，m)， 7*50 OH, s), 7.53-7.58 (1H, m), 8.26 (1H, t, J=8.8 Hz), 8.51 (旧，s)，8.66 (1H，d，J=5.2 Hz)，9.04 (1H，br s)。 复造例2670 氟苯氧基）-7-甲氣基碴啉-6-某甲酸- 11 以與製造例10同樣之方法，將[4-(3-氟硝基苯氧基）· 7_甲氧基喹啉-6_基]胺基甲酸芊酯（188 mg)在乙醇與水之 混合液中，用鐵及氯化銨還原，得到為固體之標題化合物 (170 mg) 〇 1H-NMR 光譜（DMSO-d6)5(ppm): 3.96 (3H，s)，5·18 (4H，br s)，6·40 (1H，d，J=5.2 Hz)，6.79-6.86 (2H，m)，7.04 (1H，dd， J=2.4 Hz, J=12 Hz), 7.29-7.46 (6H, m)5 8.47 (1H5 d5 J=5.2 Hz)，8.63 (1H，s)，8·95 (1H，br s)。 實施例268 胺基-7-甲氣基4啉-4-某氣）-2-氣笨基1-3-M-氪 苯基）脲 以與實施例264同樣地，從（4-{3-氟-4-[3-(4-氟苯基）脲] 苯氧基}-7-·甲氧喹啉-6-基）胺基甲酸芊酯（180 mg)，得到 為固體之標題化合物（125 mg)。The machine layer was washed with saturated brine and dried over magnesium sulfate. The organic layer was concentrated, EtOAcjjjjjjjjj H-NMR spectrum (DMSO-d6) 5 (ppm): 3 98 (3H, s), 5 16 (2H, s), 6·96 (1H, d, J = 5.2 Ηζ), 7·16-7· 21 (1H,m), 7.28-7.43 (5H,m), 7*50 OH, s), 7.53-7.58 (1H, m), 8.26 (1H, t, J=8.8 Hz), 8.51 (old, s ), 8.66 (1H, d, J = 5.2 Hz), 9.04 (1H, br s). Reproducible Example 2670 Fluorophenoxy)-7-methylphenol porphyrin-6-formic acid- 11 In the same manner as in Production Example 10, [4-(3-fluoronitrophenoxy)·7_ Ethyl methoxyquinolin-6-yl]carbazate (188 mg) was purified from EtOAc (EtOAc:MeOHMeOHMeOHMeOH Spectrum (DMSO-d6) 5 (ppm): 3.96 (3H, s), 5·18 (4H, br s), 6·40 (1H, d, J = 5.2 Hz), 6.79-6.86 (2H, m) , 7.04 (1H, dd, J=2.4 Hz, J=12 Hz), 7.29-7.46 (6H, m)5 8.47 (1H5 d5 J=5.2 Hz), 8.63 (1H, s), 8.95 (1H, Br s). Example 268 Amino-7-carbamoyl-4-oxo-4-one gas-2-oxophenyl 1-1-3-M-nonylphenyl)urea was obtained from (4-{3) in the same manner as in Example 264. -Fluoro-4-[3-(4-fluorophenyl)urea]phenoxy}-7-methoxysulfonyl-6-yl)carbazate (180 mg) afforded the title compound (125 mg).

訂Order

線line

-385 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) ^--- 1304061 ' A7 ' * B7 五、發明説明（380 ) W-NMR 光譜（DMSO-d6)5(ppm): 3.94 (3H，s)，5·45 (2H，br s)，6·45 (1H，d，J=5.2 Hz)，6.96-7.01 (1H，m)，7.12 (2H，t， J=&amp;、8 Hz)，7.17-7.26 (3H，m)，7.42-7.48 (2H，m)，8.13 (1H，t， J=9.2 Hz)，8.29 (1H，d，J=5.2 Hz)，8·58 (1H，br s)，9.10 (1H， br s) o 實施例269 乙醯胺 以與實施例265同樣之方法，從l-[4-(6-胺基-7-酽氧基峻 淋-4-基氧）-2-氟苯基]-3-(4-氟苯基）躲（60 mg)，得到為固 體之標題化合物（50 mg)。 h-NMR 光譜（DMSO-d6)5(ppm): 2·16 (3H，s)，4·01 (3H，s) 6.50 (1Η, d, J=5.2 Hz), 7.05-7.09 (1H, m)3 7.12 (2H, t3 J-8.8-385 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ^--- 1304061 ' A7 ' * B7 V. Description of invention (380 ) W-NMR spectrum (DMSO-d6) 5 ( Ppm): 3.94 (3H, s), 5·45 (2H, br s), 6.45 (1H, d, J = 5.2 Hz), 6.96-7.01 (1H, m), 7.12 (2H, t, J =&amp;, 8 Hz), 7.17-7.26 (3H, m), 7.42-7.48 (2H, m), 8.13 (1H, t, J = 9.2 Hz), 8.29 (1H, d, J = 5.2 Hz), 8·58 (1H, br s), 9.10 (1H, br s) o Example 269 acetamide in the same manner as in Example 265, from 1-[4-(6-amino-7-decyloxy) The title compound (50 mg) was obtained as a solid. H-NMR spectrum (DMSO-d6) 5 (ppm): 2·16 (3H, s), 4·01 (3H, s) 6.50 (1Η, d, J=5.2 Hz), 7.05-7.09 (1H, m )3 7.12 (2H, t3 J-8.8

Hz)，7.33 (1H, dd，J=2.8 Hz，J=12 Hz)，7.43-7.49 (3H，m)， 8.16-8.23 (1H, m), 8.52 (1H, d, J=5.2 Hz), 8.62 (1H5 br s), 8·96 (1H，br s)，9.12 (1H，br s)，9·45 (1H，br s)。 實施例270 { 4- Γ3 -氟-4·(3-(噻唑-2-基）脉）苯氧基1-7-甲氡喹成-心专丄 胺某甲酸芊酯 以與實施例224同樣地，將[4-(4-胺基氟苯氧基）_7•甲 氧基p奎淋-6-基]胺基甲酸爷酯（100 mg)及;X塞吐_ 2-基胺基甲 酸苯酯（79 mg)在二甲基亞颯（1 ml)中於8〇t加熱，得到為 固體之標題‘化合物（3 8 mg)。 h-NMR 光譜（DMSO-d6)5(ppm): 3.97 (3H，s)，5·19 (2H s) -386 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 B7 381 五、發明説明（ 6.53 (1H, d, J=5.2 Hz), 7.09-7.13 (1H, m), 7.14 (1H, d, J=3.6 Hz), 7.29-7,41 (5H, m), 7.42-7.46 (3H, m), 8.20 (1H, t, J=9.2 Hz), 8.53 (1H, d5 J=5.2 Hz), 8.65 (1H, s), 9.00 (1H, br s), 9.04 (1H, br)，10.83 (1H，br s)。 實施例271 2-基）Μ 將{4-[3-氟-4-(3-〇塞唑-2-基）脉）苯氧基]-7-甲氧基喹 6-基}胺基甲酸芊酯（1〇〇 mg)加至三氟乙酸（3及硫 代苯甲醚（0.1 ml)之混合溶液中，並於6〇。(：加熱攪拌2小 時。餾去溶媒，將殘餘物付諸於NH矽凝膠管柱層析，用溶 媒（乙酸乙酯·甲醇= 10-1)溶出，得到為固體之標題化合物 (23 mg)。 W-NMR 光譜（DMS〇-d6)5(ppm): 3.94 (3H，s)，5·47 (2H，br s)，6.48 (1H，d，J=5.2 Ηζ)，6·99-7·03 (1H，m)，7.13 (1H，d， J=3.6 Hz), 7.17 (1H，s)，7·23-7·31 (2H，m)，7·38 (1H，d， J-3.6 Hz), 8.13 (1H, t, J=8.8 Hz), 8.29 (1H, d, J=5.2 Hz), 8·97 (1H，br)，10.80 (1H，br)。 實施例272 ϋ-{4-『3-氣-4-(3-(噻唑-2-基）脲）茉氣某1-7-甲—氧林.6· 基}乙酿脖 以與實施例265同樣地，從1-[4-(6-胺基-7-甲氧基，奎淋_ 4-基氧）-2-·氟苯·基]-3-0塞峻-2-基）脲（15 mg)，得到為固體 之標題化合物（4 mg)。 -387 - 木紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)Hz), 7.33 (1H, dd, J=2.8 Hz, J=12 Hz), 7.43-7.49 (3H, m), 8.16-8.23 (1H, m), 8.52 (1H, d, J=5.2 Hz), 8.62 (1H5 br s), 8·96 (1H, br s), 9.12 (1H, br s), 9·45 (1H, br s). Example 270 { 4- Γ3 -Fluoro-4(3-(thiazol-2-yl) phenoxy)phenoxy 1-7-methylhydrazine quinone-chiral decylamine oxime formate is the same as in Example 224 , [4-(4-Aminofluorophenoxy)-7(methoxy) p-quinolate-6-yl]urethane (100 mg) and X-Septo-2-ylaminocarboxylic acid The phenyl ester (79 mg) was heated in dimethyl hydrazine (1 ml) at 8 EtOAc to afford the title compound <RTIgt; H-NMR spectrum (DMSO-d6) 5 (ppm): 3.97 (3H, s), 5·19 (2H s) -386 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 B7 381 V. INSTRUCTIONS ( 6.53 (1H, d, J=5.2 Hz), 7.09-7.13 (1H, m), 7.14 (1H, d, J=3.6 Hz), 7.29-7,41 (5H, m) , 7.42-7.46 (3H, m), 8.20 (1H, t, J=9.2 Hz), 8.53 (1H, d5 J=5.2 Hz), 8.65 (1H, s), 9.00 (1H, br s), 9.04 ( 1H, br), 10.83 (1H, br s). Example 271 2-yl) Μ {4-[3-Fluoro-4-(3-indazol-2-yl) phenoxy]- Ethyl 7-methoxyquino-6-yl}carbazate (1 mg) was added to a mixed solution of trifluoroacetic acid (3 and thioanisole (0.1 ml) at 6 〇. The mixture was heated and stirred for 2 hours. The solvent was evaporated, and the residue was evaporated to mjjjjjjjjjj W-NMR spectrum (DMS〇-d6) 5 (ppm): 3.94 (3H, s), 5·47 (2H, br s), 6.48 (1H, d, J = 5.2 Ηζ), 6·99-7· 03 (1H,m), 7.13 (1H,d, J=3.6 Hz), 7.17 (1H,s),7·23-7·31 (2H,m),7·38 (1H,d, J-3.6 Hz), 8.13 (1H, t, J=8.8 Hz), 8.29 (1H, d, J=5.2 Hz), 8·97 (1H, br), 10.80 (1H, br). Example 272 ϋ -{4-"3-Actyl-4-(3-(thiazol-2-yl)urea), a 1-7-methyl-oxo-lin.6-base of the jasmine gas, in the same manner as in Example 265, From 1-[4-(6-Amino-7-methoxy, quinolate-4-yloxy)-2-fluorobenzyl]-3-0-Shen-2-yl)urea (15 mg ), the title compound (4 mg) was obtained as a solid. -387 - Wood paper scale applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

訂Order

1304061 A7 B7 3821304061 A7 B7 382

五、發明説明（ W-NMR (DMSO-d6)5(ppm): 2·15 (3H，s)，4·02 (3H，s) 6 53 (1H，d，J=5.2 Hz)，7.07-7.12 (1H，m)，7·12 (1H，d，J二3 6 7.34-7.41 (2H, m), 7.45 (1H, s), 8.19 (1H, t5 J=9.2 Hz), ^53 (1H，d，J=5.2 Hz)，8.95-8.98 (1H，m)，9.07 (1H，br)5 9 45 br s) 〇 實施例2735. Description of the invention (W-NMR (DMSO-d6) 5 (ppm): 2·15 (3H, s), 4·02 (3H, s) 6 53 (1H, d, J = 5.2 Hz), 7.07- 7.12 (1H,m),7·12 (1H,d,J 2 3 6.34-7.41 (2H, m), 7.45 (1H, s), 8.19 (1H, t5 J=9.2 Hz), ^53 (1H , d, J = 5.2 Hz), 8.95-8.98 (1H, m), 9.07 (1H, br) 5 9 45 br s) 〇 Example 273

以與實施例266同樣地，從l-[ 4-( &amp;胺基甲氧基嗅林 4-基氧）-2-氟苯基]-3-(噻唑-2-基）脲（50 mg)，得到為固t 之標題化合物（5 mgp 一 裝 1H-NMR 光譜（DMSO-d6)5(ppm): 3.06 (3H，s)，4.00 (3H，s) 6.55 (1H, d, J=5.2 Hz), 7.09-7.16 (2H, m)3 7.25-7.35 (iH m) 7·39 (1H，d，J=3.2 Hz)，7·49 (1H，s)，8.10 (1H，s)，8.21 (ihIn the same manner as in Example 266, from 1-[4-( &amp;aminomethoxy olamine 4-yloxy)-2-fluorophenyl]-3-(thiazol-2-yl)urea (50 mg The title compound was obtained as solid t (5 mgp 1H-NMR spectrum (DMSO-d6) 5 (ppm): 3.06 (3H, s), 4.00 (3H, s) 6.55 (1H, d, J=5.2 Hz), 7.09-7.16 (2H, m)3 7.25-7.35 (iH m) 7·39 (1H,d,J=3.2 Hz),7·49 (1H,s),8.10 (1H,s),8.21 (ih

t，J=9.2 Hz)，8·57 (1H，d，J=5.2 Hz)，9.02 (1H，br s)，9.32 (1H，br s)，10.78 (1H，br s) 〇 實施例274 丄·「4-(¾丙踩）-3 -氟苯氧基1-7-甲氣基邊淋-6-某]·脸某甲 酸芊酯 以與實施例224同樣地，將[4-(4-胺基-3-氟苯氧基）-7-甲 氧基喹啉-6-基]胺基甲酸苄酯（1〇〇 mg)及環丙基胺基甲酸 苯酯（64 mg)在二甲基亞减（0.7 ml)中，於85°C加熱攪拌5小 時40分鐘，·得到為固體之標題化合物（11 mg)。 ^H-NMR 光譜（DMSO-d6) 5 (ppm): 0.37-0·41 (2H，m), 0.60- -388 - 本紙張尺度適用中國國家標準(CNS) A4規格（21〇x 297公釐） 1304061 A7 B7 383 五、發明説明（ 0.65 (2H，m)，2.50-2.56 (1H，m)，3.95 (3H，s)，5·16 (2H，s)， 6.46 (1H，d，J=5.2 Ηζ)，6·77-6·80 (1H，m)，6·99-7·03 (1H，m)， 7.23-7.45 (7H, m), 8.16 (1H, t, J=9.2 Hz), 8.19 (1H, s), 8.49 (1H，d，J=5.2 Hz)，8·63 (1H，s)，8·97 (1H，s)。 實施例275t, J = 9.2 Hz), 8.57 (1H, d, J = 5.2 Hz), 9.02 (1H, br s), 9.32 (1H, br s), 10.78 (1H, br s) 〇 Example 274 丄- "4-(3⁄4C)"-Fluorophenoxy 1-7-Methane-based lysine-6-m-] face-form carboxylic acid oxime ester [4-(4) in the same manner as in Example 224 -Amino-3-fluorophenoxy)-7-methoxyquinolin-6-yl]carbamic acid benzyl ester (1 mg) and phenyl cyclopropyl carbamate (64 mg) in two The mixture was heated and stirred at 85 ° C for 5 hours and 40 minutes to give the title compound (11 mg) as a solid. <H-NMR spectrum (DMSO-d6) 5 (ppm): 0.37- 0·41 (2H,m), 0.60- -388 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1304061 A7 B7 383 V. Description of invention (0.65 (2H, m), 2.50-2.56 (1H,m), 3.95 (3H,s),5·16 (2H,s), 6.46 (1H,d,J=5.2 Ηζ),6·77-6·80 (1H,m), 6·99-7·03 (1H,m), 7.23-7.45 (7H, m), 8.16 (1H, t, J=9.2 Hz), 8.19 (1H, s), 8.49 (1H,d,J=5.2 Hz), 8·63 (1H, s), 8.97 (1H, s). Example 275

Mr M-f 4二（環丙脲某）-3-氣茉氣基1 - 7-甲氣基咹啉-6_甚} Λ 醯胺 以與實施例264同樣地，將{4-[4-(環丙脲）-3-氟苯氧基]· 7-甲氧基喹啉-6-基}胺基甲酸苄酯（11 mg)在三氟乙酸（3 ml)及硫代苯曱醚（〇,5 ml)之混合溶液中，於60°C加熱攪拌 及脫去苄基。將得到之胺基體以與實施例265同樣之方法乙 醯化，得到為固體之標題化合物（2 mg)。 W-NMR 光譜（DMS〇-d6)5(PPm): 〇·36-0·40 (2H，m)，0.58· 0·63 (2H，m)，2·14 (3H，s)，2.46-2.55 (1H，m)，3·99 (3H，s)， 6.44 (1H5 d, J=5.2 Hz)3 6.77 (1H, d, J=2.8 Hz), 6.97-7.01 (1H，m)，7.23 (1H，dd，J=2.8 Hz，.J=11.6 Hz)，7.41 (1H，s)， 8·15 (1H，t，J=8.8 Hz)，8·17 (1H，br s)，8·48 (1H，d，J=5.2 Hz)，8.93 (1H，s)，9.42 (1H，s” 實施例276 4-f4-(環丙脲）-2-甲某芡氫某1-7-甲氣基4啉-6-羧醯胺 以與實施例11同樣地，從[4- (6-胺甲醯基-7-甲氧基喹啉-4-基氧）-3-甲基苯基]胺基甲酸苯酯（1〇〇 mg)及環丙胺’得 到為固體之標題化合物（61 mg)。 W-NMR 光譜（DMSO-d6) 5 (ppm): 〇·37-0·41 (2H，m)，0.59- -389 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 袭 訂 線 1304061 A7 B7 五、發明説明（384 ) 〇·65 (2H，m)，2·〇4 (3H，s)，2.49-2.55 (1H，m)，4·〇1 (3H，s)， 6.26 (1H，d，J=5.2 Ηζ)，6·41-6·47 (1H，m)，7.05 (1H，d，J=8.8Mr Mf 4 bis (cyclopropylurea)-3-gas rylate 1 - 7-methyl carbazine -6 _ } Λ 醯 以 以 同样 同样 同样 同样 同样 同样 同样 同样 同样 同样 同样 同样 同样 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- Benzylurea)-3-fluorophenoxy]·7-methoxyquinolin-6-yl}carbamic acid benzyl ester (11 mg) in trifluoroacetic acid (3 ml) and thiophenyl ether (〇 In a mixed solution of 5 ml), the mixture was heated and stirred at 60 ° C to remove the benzyl group. The obtained amine substrate was acetylated to give the title compound (2 mg). W-NMR spectrum (DMS〇-d6) 5 (PPm): 〇·36-0·40 (2H, m), 0.58· 0·63 (2H, m), 2·14 (3H, s), 2.46- 2.55 (1H,m),3·99 (3H,s), 6.44 (1H5 d, J=5.2 Hz)3 6.77 (1H, d, J=2.8 Hz), 6.97-7.01 (1H,m), 7.23 ( 1H, dd, J = 2.8 Hz, .J = 11.6 Hz), 7.41 (1H, s), 8·15 (1H, t, J = 8.8 Hz), 8·17 (1H, br s), 8.48 (1H, d, J = 5.2 Hz), 8.93 (1H, s), 9.42 (1H, s) Example 276 4-f4-(cyclopropylurea)-2-methyl hydrazine hydrogen 1-7-methyl In the same manner as in Example 11, a 4-phenyl-6-carboxycarboxamide was obtained from [4-(6-aminocarbamimid-7-methoxyquinolin-4-yloxy)-3-methylphenyl] Phenyl carbamate (1 mg) and cyclopropylamine gave the title compound (61 mg) as a solid. W-NMR spectrum (DMSO-d6) 5 (ppm): 〇·37-0·41 (2H, m),0.59- -389 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). Landing line 1304061 A7 B7 V. Invention description (384) 〇·65 (2H, m), 2 ·〇4 (3H,s), 2.49-2.55 (1H,m),4·〇1 (3H,s), 6.26 (1H,d,J=5.2 Ηζ),6·41-6·47 (1H, m),7.05 (1H,d,J=8.8

Hz), 7.35 (1Ή, dd, J=2.4 Hz, 1=8.8 Hz), 7.42 (1H, d, J=2.4 Hz), 7.48 (1H, s)3 7.71 (1H, br s), 7.84 (1H, br s), 8.27-8.42 UH/m)，8·59 (1H，d, J=5.2 Hz)，8·69 (1H，s)。 如下述合成中間體。 复造例276- 1 基笨氣基）-7-甲氫某4啉-6-# 以與製造例458- 1同樣之方法，從4-氯-7-曱氧喹啉_6-羧 酿胺（1 g)及4-胺基-2-甲基酚得到為固體之標題化合物（43〇 mg) 〇 1H-NMR光譜（DMSO-d6)5(ppm): 1·93 (3H, s)，4·01 (3H，s)， 5.06-5.09 (2H, m), 6.27 (1H, d, J=5.2 Hz), 6.49 (1H, dd, J=2.8 Hz, J=8.4 Hz), 6.54 (1H, d, J=2.8 Hz), 6.84 (1H, d! J=8.4 Hz), 7.47 (1H, s), 7.71 (1H5 br s), 7,83 (1H, br s), 8.59 (1H，d，J=5.2 Hz)，8·69 (1H，s)。 製造例276-2 酿基二7-甲氧基4淋曱某宏某1脖甚 甲酸苽S旨 以與製造例17同樣地，從4-(4-胺基-I甲基苯氧基卜7-甲 氧基喹啉-6-羧醯胺（330 mg)及氯碳酸苯酯，得到為固體之 標題化合物（112 mg)。 iH-NMR 光譜（DMSO-d6)5(ppm): 2.08 (3H，s)，4·〇2 (3H，s)， 6.30 (1Η, d, J=5.2 Hz), 7.19-7.55 (9H，m)，7 73 (m，br s)， -390 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公*) 1304061 A7 B7 五、發明説明（385 7·85 (1H，br s)，8.62 (1H，d，J=5.2 Hz)，8.71 (1H，s)，10.33 (1H, br s) 〇. ’ ’ 實施例277 乱冬基）·3-「4-(6-( 口比咬-2-基）-7H- p此哈并口密一 啶-4-基M.)笨基1脲Hz), 7.35 (1Ή, dd, J=2.4 Hz, 1=8.8 Hz), 7.42 (1H, d, J=2.4 Hz), 7.48 (1H, s)3 7.71 (1H, br s), 7.84 (1H , br s), 8.27-8.42 UH/m), 8.59 (1H, d, J = 5.2 Hz), 8.69 (1H, s). The intermediate is synthesized as follows. Reproduction Example 276-1 (stupidyl)-7-methylhydrogen 4 -6-# In the same manner as in Production Example 458-1, from 4-chloro-7-nonoxyquinoline-6-carboxylate Amine (1 g) and 4-amino-2-methylphenol gave the title compound as a solid (43 mg) 〇1H-NMR spectrum (DMSO-d6) 5 (ppm): 1.93 (3H, s) ,4·01 (3H,s), 5.06-5.09 (2H, m), 6.27 (1H, d, J=5.2 Hz), 6.49 (1H, dd, J=2.8 Hz, J=8.4 Hz), 6.54 ( 1H, d, J=2.8 Hz), 6.84 (1H, d! J=8.4 Hz), 7.47 (1H, s), 7.71 (1H5 br s), 7,83 (1H, br s), 8.59 (1H, d, J = 5.2 Hz), 8.69 (1H, s). Production Example 276-2 Styrene 2-7-methoxy 4 dripping a certain 1 neck, very formic acid hydrazine S is the same as in Production Example 17, from 4-(4-amino-Imethylphenoxyb) 7-Methoxyquinoline-6-carboxamide (330 mg) and phenyl chlorocarbonate afforded the title compound (112 mg) as a solid. iH-NMR spectrum (DMSO-d6) 5 (ppm): 2.08 ( 3H, s), 4·〇2 (3H, s), 6.30 (1Η, d, J=5.2 Hz), 7.19-7.55 (9H, m), 7 73 (m, br s), -390 - Paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 gong*) 1304061 A7 B7 V. Description of invention (385 7·85 (1H, br s), 8.62 (1H, d, J=5.2 Hz), 8.71 ( 1H, s), 10.33 (1H, br s) 〇. ' ' Example 277 乱冬基)·3-"4-(6-( 口比 bit-2-yl)-7H-p Pyridin-4-yl M.) Stupid 1 Urea

以與實施例10同樣之方法，從4-(6-(吡啶-2-基）-7H-毗咯 并[2,3-d]嘧啶-4-基氧）苯胺（90 mg)及異氰酸3_氟苯酯，得 到為固體之標題化合物（11 8 mg)。 W-NMR 光譜（〇^^〇-(16)5(??111):6.74-6.80 (111，111)，7.1卜 7.15 (1H，m)，7·20 (2H，d，J=8.8 Hz)，7.23 (1H，s)，7·29 (1H， t，J=7,6 Hz)，7.34-7.38 (1H，m)，7·46-7·51 (1H，d，m)，7.52 (2H，d，J=8.8 Hz)，7.87-7.92 (1H，m)，8.08 (1H，d，J=8.0 Hz)， 8.31 (1H，s)，8.63-8.66 (1H，m)，8·82 (1H，br s)，8.93 (1H，bf s)，12.78 (1H，br s)。 如下述合成中間體。In the same manner as in Example 10, 4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)aniline (90 mg) and isocyanide The title compound (11 8 mg) was obtained as a solid. W-NMR spectrum (〇^^〇-(16)5(??111):6.74-6.80 (111,111),7.1 7.15 (1H,m),7·20 (2H,d,J=8.8 Hz ), 7.23 (1H, s), 7·29 (1H, t, J=7, 6 Hz), 7.34-7.38 (1H, m), 7·46-7·51 (1H, d, m), 7.52 (2H,d,J=8.8 Hz), 7.87-7.92 (1H,m), 8.08 (1H,d,J=8.0 Hz), 8.31 (1H,s), 8.63-8.66 (1H,m),8· 82 (1H, br s), 8.93 (1H, bf s), 12.78 (1H, br s).

製造例277-1 4-(4 -硝基笨氣基比症-2-基比吟并密咬 以與製造例7同樣之方法，從4-氯-6-(吡啶-2-基）-7H-吡 咯并[2,3-d]嘧啶（0.8 g)及硝基酚（1.45 g)，得到為固體之 標題化合物（1.0 g)。 !H-NMR 光譜（DMSO-d6)5(PPm): 7.33 (1H，s)，7.37 (1H，dd， J=4.8 Hz, J=7.2 Hz), 7.59 (2H, d, J=9.2 Hz), 7.88-7.94 (1H, m), 8.12 (1H, d, J=7.2 Hz), 8.33 (2H, d, J=9.2 Hz), 8.38 (1H, s)，8·66 (1H，d，J=4.8 Hz)，12.92 (1H，br s)。 -391 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公董） 1304061Production Example 277-1 4-(4-Nitrostyrene-based thiophene-2-pyrimidinyl-pyrimidin and intimately, in the same manner as in Production Example 7, from 4-chloro-6-(pyridin-2-yl)- 7H-Pyro[2,3-d]pyrimidine (0.8 g) and nitrophenol (1.45 g) gave the title compound (1.0 g) as a solid. H-NMR spectrum (DMSO-d6) 5 (PPm) : 7.33 (1H, s), 7.37 (1H, dd, J = 4.8 Hz, J = 7.2 Hz), 7.59 (2H, d, J = 9.2 Hz), 7.88-7.94 (1H, m), 8.12 (1H, d, J=7.2 Hz), 8.33 (2H, d, J=9.2 Hz), 8.38 (1H, s), 8.66 (1H, d, J=4.8 Hz), 12.92 (1H, br s). 391 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 dongdong) 1304061

#造例277-1 吡咚并「273』嘧啶-4-基氣）茨ι 以與製造例8同樣地，從M4_硝基苯氧基）_M吡唉+ 基）-7H-吡咯并[2,3-d]嘧啶（1 〇 g),得到為固體之標 合物（0·4 H-NMRilolf (DMSO-d6) 5(ppm): 5.06 (2H, br s)5 6.60 (2H d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 7.07 (1H, s), 7.32^7.36#造例277-1 Pyridoxium "273"pyrimidin-4-yl gas) ι In the same manner as in Production Example 8, from M4_nitrophenoxy)_Mpyridinium+yl-7H-pyrrolo[ 2,3-d]pyrimidine (1 〇g), which gave a solid as a solid (0·4 H-NMRilolf (DMSO-d6) 5 (ppm): 5.06 (2H, br s) 5 6.60 (2H d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 7.07 (1H, s), 7.32^7.36

(1H，m)，7.86-7.91 (1H，m)，8.03 (1H，d，卜8·〇 Hz)，8·29 (1H s)，8·64 (1H，d，J=4 Hz)，12.71 (1H，br s)。 實施例278(1H,m), 7.86-7.91 (1H,m),8.03 (1H,d,Bu 8·〇Hz),8·29 (1H s),8·64 (1H,d,J=4 Hz), 12.71 (1H, br s). Example 278

以與實施例l〇同樣之方法，從扣（6_(吡啶基）·7η_吡咯 并[2,3-d]嘧啶-4-基氧）苯胺（100 mg)及異氰酸4•氟苯酯， 得到為固體之標題化合物（12〇 mg)。 ㈢ H-NMR 光爾（DMSO-d6) (5 (ppm): 7.11 (2H，t，8 Hz) 7·19 (2H，d，J=8.8 Hz)，7·22 (1H，s)，7·35 (1H，dd，J=7 2 Hz’ J=7.6 Hz)，7.43-7·48 (2H，m)，7·51 (2H，d，J=8 8 Hz)，7 87: 7.92 (1H，m)，8.08 (1H，d，】=8·〇 Hz)，8·32 (lH，s)，8 6心8 66 (1H，m)，8·73 (1H，br s)，8·75 (1H，br s)，12.78 (1H，br s)。 實施例279 比啶-2-基）-7H-毗咯并『2,3-dl 口^^^_ m t 基卜3-(4唑-2-·基）脲 以與實施例224同樣之方法，從4-(6-(吡啶基卜7Η-ίτ比 ___ - 392 - 本紙張尺度適用中國國家標準(CNS) A4規格（210X297公釐）In the same manner as in Example 10, from (6-(pyridyl)·7η_pyrrolo[2,3-d]pyrimidin-4-yloxy)aniline (100 mg) and isocyanate 4·fluorobenzene The title compound (12 mg) was obtained as a solid. (3) H-NMR light (DMSO-d6) (5 (ppm): 7.11 (2H, t, 8 Hz) 7.19 (2H, d, J = 8.8 Hz), 7·22 (1H, s), 7 · 35 (1H, dd, J=7 2 Hz' J=7.6 Hz), 7.43-7·48 (2H, m), 7·51 (2H, d, J=8 8 Hz), 7 87: 7.92 ( 1H,m),8.08 (1H,d,]=8·〇Hz),8·32 (lH,s),8 6 heart 8 66 (1H,m),8·73 (1H,br s),8 · 75 (1H, br s), 12.78 (1H, br s). Example 279 Bisdin-2-yl)-7H-pyrrolo and 2,3-dl mouth^^^_ mt kib 3-( 4-oxazol-2-yl)urea was prepared in the same manner as in Example 224 from 4-(6-(pyridyl) 7Η-ίτ to ___ - 392 - this paper scale was applied to the Chinese National Standard (CNS) A4 specification ( 210X297 mm)

訂Order

線 1304061 〜 ' ' A7 ___B7 五、發明説明（387 ) 咯并[2,3-d]喊淀-4-基氧）苯胺（1〇〇 mg)及（嘍唑-2-基）胺基 甲酸苯酯（116 mg)在二甲基亞砜（2 5 mi)中，於8〇。〇加熱攪 摔1小時’得到為固體之標題化合物（丨丨〇 mg)。 W-NMR 光譜（DMS〇-d6)5(ppm): 7·10 (1H，d，J=3.6 Hz)， 7.23 (2H，d，J=8.8 Hz)，7.24 (1H，s)，7.34-7.40 (2H，m)，7.55 (2H, d, J=8.8 Hz), 7.87^7.93 (1H, m), 8.09 (1H, d, J=8.0 Hz), 8.32 (1H，s)，8,63-8.67 (1H，m)，9·06 (1H，br s)，12.79 (1H， br s) o 音施例280 丄-(4:i.苯基U-『2-氟土（ 6_ (吡哇-2-某）-7H-毗咯# f 2,3- dl 嘧啶基氧笨某1-月辱 以與實施例ίο同樣之方法，從2_氟-4-(6-(吡啶基卜 7H-吡咯并[2,3-d]嘧啶-4-基氧）苯胺（100 mg)及異氰酸4·氟 苯酯，得到為固體之標題化合物（11〇 mg)。 H-NMR 光譜（DMSO-d6) 5 (ppm): 7.07-7.16 (3H，m)，7.28 (1H，s)，7.33-7.38 (2H，m)，7·42-7·48 (2H，m)，7.87-7.93 (1H， m), 8.08-8.14 (2H, m)5 8.33 ( 1H3 s), 8.53-8.56 (1H, m), 8.64- 8·66 (1H，m)，9.08 (1H，br s)，12.83 (1H，br s)。 如下述合成中間體。 製造例280-1Line 1304061 ~ ' ' A7 ___B7 V. INSTRUCTION DESCRIPTION (387 ) 咯[2,3-d] 淀 -4--4-yloxy)aniline (1 〇〇 mg) and (oxazol-2-yl) carbamic acid Phenyl ester (116 mg) in dimethyl sulfoxide (25 mi) at 8 Torr. The title compound (丨丨〇 mg) was obtained as a solid. W-NMR spectrum (DMS 〇-d6) 5 (ppm): 7·10 (1H, d, J = 3.6 Hz), 7.23 (2H, d, J = 8.8 Hz), 7.24 (1H, s), 7.34 7.40 (2H,m), 7.55 (2H, d, J=8.8 Hz), 7.87^7.93 (1H, m), 8.09 (1H, d, J=8.0 Hz), 8.32 (1H, s), 8,63 -8.67 (1H,m),9·06 (1H,br s),12.79 (1H, br s) o Example 280 丄-(4:i.phenyl U-"2-fluorine (6_ (pyridyl) Wow -2-)-7H-pyrrole #f 2,3- dl pyrimidinyloxy oxo 1-month humiliation in the same manner as in the example ί, from 2-fluoro-4-(6-(pyridyl) 7H-Pyrolo[2,3-d]pyrimidin-4-yloxy)aniline (100 mg) and 4·fluorophenyl isocyanate afforded the title compound (11 mg) as a solid. DMSO-d6) 5 (ppm): 7.07-7.16 (3H,m), 7.28 (1H,s),7.33-7.38 (2H,m),7·42-7·48 (2H,m),7.87-7.93 (1H, m), 8.08-8.14 (2H, m)5 8.33 ( 1H3 s), 8.53-8.56 (1H, m), 8.64- 8·66 (1H, m), 9.08 (1H, br s), 12.83 (1H, br s). The synthesis intermediate is as follows. Production Example 280-1

4-ϋ二氣硝幕茗氧基）-6-(吡啶某V7H-咄咯#「2,3-dl 以與製造例7同樣之方法，從w〇 9702266，PCT/EP 96/02728記載之4-氯-6-(吡啶-2-基）-7H-吡咯并[2,3_d]嘧 _— _- 393 - 本紙張尺度適用中國國家標準(CNS) A4規格（21〇x 297公爱） 1304061 A7 B7 五、發明説明（388 ) 啶（〇·7 g)及氟硝基酚（〇·95 g)，得到為固體之標題化合物 (0.75 g)。. iH-NMR 光譜（DMSO-d6)(5(ppm): 7·34-7·45 (3H，m)，7.74 (1H，dd，J=2.4 Hz, J=12.4 Ηζ)，7·89-7·94 (1H，m)，8·12 (1H， d, J=8.0 Hz), 8.28 (1H, t, J=8.8 Hz), 8.41 (1H, s), 8.65-8.68 (1H，m)，12.96 (1H，br s)。 製造例280-2 2-氟-4- ( 6-(吡啶-2-基）-7Η·吡咬并f 2,3-dl嘧l_4·某氣）笨 以與製造例8同樣地，從4-(3-氟-4-硝基苯氧基）-6_(吡 淀-2 -基）-7H- p比哈并[2,3- d]喃咬（750 mg)，得到為固體之 標題化合物（450 mg)。 !H-NMR 光譜（DMSO-d6) 5 (ppm): 5.10 (2H，br s)，6·79-6·83 (2H，m)，7.01-7.05 (1H，m)，7·16 (1H，s)，7.32-7.38 (1H，m)， 7.86-7.92 (1H, m), 8.06 (1H, d5 J=7.6 Hz), 8.31 (iH, s), 8.64 (1H，d，J=4.4 Hz)，12.75 (1H，br s)。 實施例281 j - (1:· +基）-3-「2-氣-4-(6-(?比咬-2-基）-7!1-朴卜.哈并「2,3-(1] 嘧啶-4-基氡某1月尿 以與實施例10同樣之方法，從2_氟-4_(6-(吡啶-2_基）_ 7Η-吡咯并[2,3-d]嘧啶-4-基氧）苯胺（1〇〇 mg)及異氰酸弘氟 苯醋，得到為固體之標題化合物（30 mg：)。 iH-NMR 光譜（DMSO-d6) (5 (ppm): 6.76-6.83 (1H，m)，7.11 (2H，d，J=8.8 Ηζ)，7·27·7·39 (4H，m)，7.48-7.53 (1H，m)， -394 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐）4-ϋ二气气幕茗oxy)-6-(pyridine some V7H-咄咯# "2,3-dl In the same manner as in Production Example 7, as described in WO 〇9702266, PCT/EP 96/02728 4-Chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3_d]pyrimidine-- _- 393 - This paper size applies to Chinese National Standard (CNS) A4 specification (21〇x 297 public) 1304061 A7 B7 V. Illustrative (388) pyridine (〇·7 g) and fluoronitrophenol (〇·95 g) gave the title compound (0.75 g) as a solid. iH-NMR spectrum (DMSO-d6) (5 (ppm): 7·34-7·45 (3H, m), 7.74 (1H, dd, J = 2.4 Hz, J = 12.4 Ηζ), 7·89-7·94 (1H, m), 8 ·12 (1H, d, J=8.0 Hz), 8.28 (1H, t, J=8.8 Hz), 8.41 (1H, s), 8.65-8.68 (1H, m), 12.96 (1H, br s). Example 280-2 2-Fluoro-4-(6-(pyridin-2-yl)-7Η·pyridin and f 2,3-dl azyl-4-4·a gas) was similar to Production Example 8 from 4- (3-Fluoro-4-nitrophenoxy)-6-(pyridin-2-yl)-7H-p-bi-[2,3-d]-bite (750 mg) afforded the title compound (450 mg).H-NMR spectrum (DMSO-d6) 5 (ppm): 5.10 (2H, br s), 6·79-6·83 (2H, m), 7.01-7.05 (1H, m), 7·16 ( 1H, s), 7.32-7.38 (1H, m), 7.86-7.92 (1H, m), 8.06 (1H, d5 J=7.6 Hz), 8.31 (iH, s), 8.64 (1H,d,J=4.4 Hz), 12.75 (1H, br s). Example 281 j - (1:· + base)-3-"2-gas-4-(6-(? ratio bit-2-yl)-7!1-朴卜.Ha and "2,3-(1) pyrimidin-4-yl hydrazine January urine in the same manner as in Example 10, from 2_fluoro-4_(6-(pyridine-2-yl)-7 Η -pyrolo[2,3-d]pyrimidin-4-yloxy)aniline (1 mg) and the title compound (30 mg:) as a solid. iH-NMR spectrum ( DMSO-d6) (5 (ppm): 6.76-6.83 (1H, m), 7.11 (2H, d, J = 8.8 Ηζ), 7·27·7·39 (4H, m), 7.48-7.53 (1H, m), -394 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)

裝 訂Binding

線 1304061 A7 B7 五、發明説明（389 7.87-7.94 (1H, m), 8.11 (2H, d, J=8.8 Hz), 8.34 (1H, s)3 8.61-8.65 (1H，m)，8·66 (1H，br d，5=4·〇 Hz)，9.27 (1H，br s)， 12.83 (1H，br s)。 f施例282 1: f 2.: U- (6-(吡哫·:·.2···-一基吡咯并「2,3- dl 嘧啶·4-某氫） 蓋基卜崦基）脲 以與實施例224同樣之方法，從2_氟·4_(6•(吡啶基）一 7Η-吡哈并[2,3-d] u密咬-4-基氧）苯胺（1〇〇叫）及（喧峻_2-基） 胺基甲酸苯酯（109 mg)，得到為固體之標題化合物（1〇〇 mg) 0 ^-NMR 光譜（DMSO-d6) 5 (ppm): 7.07-7.17 (2H，m)，7.29 (1H, s), 7.35-7.44 (3H, m), 7.87-7.95 (1H, m)3 8.08-8.15 (2H, m)，8.34 (1H，s)，8.66 (1H，br d，J=4.0 Hz)，8·99 (1H，br), 1〇·81 (1H，br s)，12.83 (1H, br s)。 f施例283 1-環丙基，3-f2-氣- 4-(6-(p比症-2-基）-7H-外h哈并Γ 2,3- dl喊 卓-4-基氣）笨基1脲 以與實施例224同樣地，從2-氟-4-(6-(吡啶-2-基）-7H-吡 咯并[2,3-d]嘧啶-4-基氧）苯胺（75 mg)及環丙基胺基甲酸苯 酯（66 mg)，得到為固體之標題化合物（15 mg)。 iH-NMR 光譜（01^130-〇16)5(??爪）：〇.37-0.42 (211，111)，0.60-0.66 (2H, m), 2.49-2.57 (1H, m), 6.76 (1H, d, J=2.4 Hz), 7·01-7·05 (1H，m)，7.24-7.29 (2H，m), 7·33-7·37 (1H，m)， 7.86-7.92 (1H, m), 8.05-8.12 (2H, m), 8.13-8.16 (1H, m), -395 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂 線 1304061 〜 ' * A7 ________ B7 五、發明説明（390 ) 8·32 (1H，s)，8·62-8·66 (1H，m)，12·79 (1H，br s)。 實施例284 , 7- ((2R) - 2- #呈基-3 - (口比啥咬-1 -基）丙象▲某）-4- ( 4 某氫V奎啉-6-甲月奢 以與實施例454同樣地，從4·(1Η-吲哚-5-基氧卜（2R)-7_ 環氧乙烷甲氧喹啉-6-甲腈（0·73 g)，得到為固體之標題化 合物（0.5 6 gp ^-NMR 光譜（DMSO-d6)5(ppm): 2.6^2·72(4Η，πι)，2.44-2.58 (6Η，m)，2.68-2.73 (1Η，m)，3.99-4.06 (1Η，m)，4.20 (1H，dd，J=6.0 Hz，J=10.4 Hz)，4.29 (1H，dd，J=3.6 Hz， J=10.4 Hz), 5.02 (1H, br s), 6.42 (1H, d, J=5.2 Hz), 6.44-6.48 (1H, m), 6.99 (1H, dd, J=1.6 Hz, J=8.4 Hz), 7.43-7.47 (2H，m)，7.51 (1H，d，J=8.4 Hz)，7.59 (1H，s)，8.65 (1H, d， J=5.2 Hz)，8·77 (1H，s) 〇 如下述合成中間體。 眚施例284-1 4-ΠΗ-Θ1嗓-5-基氣W2RV7-環氣乙技甲氳林-6-曱腈 使用4-甲基-1-苯磺酸[(2R)-環氧乙烷-2-基甲基]酯，藉 由與實施例7同樣之手法，從4-(1H-啕哚-5-基氧）-7-羥基 喹啉-6-甲腈（1 g)，得到為固體之標題化合物（0.73 g)。 W-NMR 光譜（DMSO-d6)5(ppm): 2.82 (1H，dd，J=2.4 Hz， J=4.8 Hz), 2.91 (1H, t5 J=4.8 Hz), 3.44-3.49 (1H, m), 4.17 (1H, dd, J=6.4 Hz, J=11.6 Hz), 4.71 (lH, dd, J=2.4 Hz, J=11.6 Hz), 6.44 (1H, d, J=5.2 Hz), 6.46-6-48 (1H, m), 6.99 _ - 396 - ；_ 本紙張尺度適用中國國家標準(CNS) A4規格（21〇x 297公釐） 1304061 ' ' A7Line 1304061 A7 B7 V. Description of the invention (389 7.87-7.94 (1H, m), 8.11 (2H, d, J=8.8 Hz), 8.34 (1H, s)3 8.61-8.65 (1H, m), 8.66 (1H, br d, 5=4·〇 Hz), 9.27 (1H, br s), 12.83 (1H, br s) f Example 282 1: f 2.: U- (6-(pyridinium: ·····---Pyrylpyrrolo- 2,3- dl-pyrimidine- 4-hydrogen)-dithiopyridyl)urea in the same manner as in Example 224, from 2-fluoro·4_(6•(pyridyl) a 7-pyridyl-pyrhino[2,3-d]u-tweet-4-yloxy)aniline (1 〇〇) and (喧 _2_2-yl) phenyl carbamate (109 mg), The title compound (1 〇〇mg) as a solid. 0^-NMR spectrum (DMSO-d6) 5 (ppm): 7.07-7.17 (2H, m), 7.29 (1H, s), 7.35-7.44 (3H, m) , 7.87-7.95 (1H, m)3 8.08-8.15 (2H, m), 8.34 (1H, s), 8.66 (1H, br d, J=4.0 Hz), 8·99 (1H, br), 1〇 · 81 (1H, br s), 12.83 (1H, br s) f Example 283 1-cyclopropyl, 3-f2-gas- 4-(6-(p ratio-2-yl)-7H- The same as in Example 224, from 2-fluoro-4-(6-(pyridin-2-yl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yloxy)aniline (75 </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 0.42 (211,111), 0.60-0.66 (2H, m), 2.49-2.57 (1H, m), 6.76 (1H, d, J=2.4 Hz), 7·01-7·05 (1H,m), 7.24-7.29 (2H,m), 7·33-7·37 (1H,m), 7.86-7.92 (1H, m), 8.05-8.12 (2H, m), 8.13-8.16 (1H, m), - 395 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Gutter 1304061 ~ ' * A7 ________ B7 V. Invention description (390 ) 8·32 (1H, s), 8.62- 8.66 (1H, m), 12.79 (1H, br s). Example 284, 7-((2R) - 2-#-formyl-3 - (mouth ratio bite-1 -yl) C-like ▲)-4- (4 a hydrogen V quinolin-6-a month luxury In the same manner as in Example 454, 4·(1Η-吲哚-5-yloxybu(2R)-7-oxirane methoxyquinoline-6-carbonitrile (0·73 g) was obtained as a solid. The title compound (0.5 6 gp ^-NMR spectrum (DMSO-d6) 5 (ppm): 2.6^2·72 (4 Η, πι), 2.44-2.58 (6 Η, m), 2.68-2.73 (1 Η, m), 3.99-4.06 (1Η, m), 4.20 (1H, dd, J=6.0 Hz, J=10.4 Hz), 4.29 (1H, dd, J=3.6 Hz, J=10.4 Hz), 5.02 (1H, br s) , 6.42 (1H, d, J=5.2 Hz), 6.44-6.48 (1H, m), 6.99 (1H, dd, J=1.6 Hz, J=8.4 Hz), 7.43-7.47 (2H,m),7.51 ( 1H,d,J=8.4 Hz), 7.59 (1H, s), 8.65 (1H, d, J=5.2 Hz), 8.77 (1H, s), such as the following synthetic intermediates. 眚Example 284-1 4-ΠΗ-Θ1嗓-5-based gas W2RV7-epoxy gas ethyl methacrylate -6-indoleonitrile using 4-methyl-1-benzenesulfonic acid [(2R)-oxirane-2-yl group The title compound was obtained as a solid from 4-(1H-indol-5-yloxy)-7-hydroxyquinolin-6-carbonitrile (1 g). (0.73 g). W-NMR Spectrum (DMSO-d6) 5 (ppm): 2.82 (1H, dd, J = 2.4 Hz, J = 4.8 Hz), 2.91 (1H, t5 J = 4.8 Hz), 3.44-3.49 (1H, m), 4.17 ( 1H, dd, J=6.4 Hz, J=11.6 Hz), 4.71 (lH, dd, J=2.4 Hz, J=11.6 Hz), 6.44 (1H, d, J=5.2 Hz), 6.46-6-48 ( 1H, m), 6.99 _ - 396 - ;_ This paper size applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1304061 ' ' A7

(1H，dd，J=2.4 Hz, J=8.8 Hz)，7.44-7.46 (2H，m)，7·52 (1Η· d J=8.8 Hz), 7.62 (1H, s), 8.67 (1H, d, J=5.2 Hz), 8.82 (iH s), 11.31 (1H，br s)。 ’ 5 ’ f施例285 羥某-3-(吡咯啶-1-甚、 氳〗g?丨哚-1 -淼醴環丙醯胺 將7-((2R)_2-羥基-3-(吡咯啶-1-基）丙氧基）_4·(1Η-4 嗓-5-基氧）喹啉-6-甲腈（0.56 g)用三乙矽烷基氯及咪唑予 以矽烷醚化，得到〇·48 g目的物。藉由與實施例31〇同樣之 方法從三乙矽烷醚（〇·2 g)得到醯胺化物，在乙酸，四氫吱 喃及水之混合溶液中於50°C脫保護，得到為固體之標題化 合物（3 5 mg)。 h-NMR 光譜（〇乂30-(16)5(??111):0.58-0.63 (211，111)，0.71-0.76 (2H, m), 1.84-1.94 (2H, m), 1.98-2.06 (2H, m), 2.73-2.79 (1H, m)5 3.07-3.16 (2H, m), 3.33-3.38 (2H, m), 3.57-3.64 (2H, m), 4.28-4.36 (3H, m), 6.55 (1H, d, J=5.6 Hz), 6.70 (1H, d, J=3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.53 (1H, d, J=2.4 Hz), 7.66 (1H, s), 7.88 (1H, d, J=3.6 Hz), 8.32 (1H, d, J=2.8 Hz), 8.35 (1H, d, J=8.8 Hz), 8.74 (1H, d, J=5.6 Hz)，8·87 (1H，s)。 實施例286 5-「6-氨基-7-n-Ub咯啶-1-某）雨氣基啉-4-基氧〗4哚-1 - #酸環丙醯胺 以與實施例310同樣之方法，從4-(1Η-θ丨哚-5-基氧）-7--397 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 1304061 A7 B7 五、發明説明（392 ) (3-(吡咯啶-1-基）丙氧基）喹啉-6-甲腈（150 mg)，得到為固 體之標題化合物（35 mg)。 iH-NMR 光譜（0^^0-心）5(??111):0.59-0.64 (211，111)，0.71-0.76 (2H5 m), 1.64-1.72 (4H? m), 1.95-2.03 (2H, m), 2.38-2·48 (4H，m)，2·59 (2H，d，J=6.8 Hz)，2·74-2·81 (1H，m)， 4.33 (2H，d，J=6.4 Hz)，6.47 (1H，d，J=5.2 Hz)，6.68 (1H，d， J=3.6 Hz)，7.19 (1H，dd，J=2.4 Hz，8.8 Hz)，7.52 (1H，d， J=2.4 Hz)，7.58 (1H，s)，7.90 (1H，d，J=3.6 Hz)，8·23 (1H，d， J=2.8 Hz)，8.35 (1H，d，J=8.8 Hz)，8·68 (1H，d，J=5.2 Hz)， 8·79 (1H，s) 〇 實施例287 5-「6-氨基-7-(2-甲氣乙氣基）4啉-4-基氣1&lt;哚-1-#酸環 丙醯胺 以與實施例310同樣之方法，從4-( 1H-峋哚-5-基氧）-7-(2-甲氧乙氧基）喹啉-6-甲腈（450 mg)，得到為固體之標題 化合物（210 mg)。 1H-NMR 光譜（01^30-(16)5(??111):0.59-0.65 (211，111)，0.71-0.77 (2H, m), 2.74-2.82 (1H, m), 3.76-3.80 (2H, m)3 0.59-0·65 (2H，m)，4.39-4.43 (2H，m)，6·47 (1H，d，J=5.2 Hz)， 6.68 (1H, d5 J=3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7·52 (1H，d，J=2.4 Hz)，7·62 (1H，s)，7.90 (1H，d，J=3.6 Hz)， 8.30 (1H，d，J=2.8 Hz)，8.35 (1H，d，J=8.8 Hz)，8.68 (1H，d， J=5.2 Hz)，8·79 (1H，s)。 如下述合成中間體。 398 本紙張尺度適用中國國家標準(CNS) A4規格（210X297公釐） 裝 訂 線 1304061 〜(1H, dd, J=2.4 Hz, J=8.8 Hz), 7.44-7.46 (2H, m), 7·52 (1Η· d J=8.8 Hz), 7.62 (1H, s), 8.67 (1H, d , J=5.2 Hz), 8.82 (iH s), 11.31 (1H, br s). ' 5 ' f Example 285 Hydroxy-3-(pyrrolidin-1-even, 氲]g?丨哚-1 - anthracene propylamine 7-((2R)_2-hydroxy-3-(pyrrole) Pyridin-1-yl)propoxy)_4·(1Η-4 嗓-5-yloxy)quinoline-6-carbonitrile (0.56 g) was etherified with tridecyl chloride and imidazole to give hydrazine. 48 g of the object. The amide was obtained from triethoxydecane (〇·2 g) in the same manner as in Example 31, and deprotected at 50 ° C in a mixed solution of acetic acid, tetrahydrofuran and water. The title compound (3 5 mg) was obtained as a solid. </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> 1.84-1.94 (2H, m), 1.98-2.06 (2H, m), 2.73-2.79 (1H, m)5 3.07-3.16 (2H, m), 3.33-3.38 (2H, m), 3.57-3.64 (2H , m), 4.28-4.36 (3H, m), 6.55 (1H, d, J=5.6 Hz), 6.70 (1H, d, J=3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, J= 8.8 Hz), 7.53 (1H, d, J=2.4 Hz), 7.66 (1H, s), 7.88 (1H, d, J=3.6 Hz), 8.32 (1H, d, J=2.8 Hz), 8.35 (1H , d, J = 8.8 Hz), 8.74 (1H, d, J = 5.6 Hz), 8·87 (1H, s). Example 286 5- "6-Amino-7-n-Ub-r-pyridin-1- a) rain gas phenyl phenyl-4-yloxy 〖4 -1 - #acid cyprodinil was applied in the same manner as in Example 310 from the Chinese National Standard (CNS) A4 from 4-(1Η-θ丨哚-5-yloxy)-7--397 - paper scale. Specification (210 X 297 mm) 1304061 A7 B7 V. Inventive Note (392 ) (3-(Pyrrolidin-1-yl)propoxy)quinoline-6-carbonitrile (150 mg), titled as solid Compound (35 mg). iH-NMR spectrum (0^^0-heart) 5 (??111): 0.59-0.64 (211,111), 0.71-0.76 (2H5 m), 1.64-1.72 (4H?m) , 1.95-2.03 (2H, m), 2.38-2·48 (4H, m), 2·59 (2H, d, J=6.8 Hz), 2·74-2·81 (1H, m), 4.33 ( 2H,d,J=6.4 Hz), 6.47 (1H,d,J=5.2 Hz), 6.68 (1H,d, J=3.6 Hz), 7.19 (1H,dd,J=2.4 Hz,8.8 Hz),7.52 (1H, d, J = 2.4 Hz), 7.58 (1H, s), 7.90 (1H, d, J = 3.6 Hz), 8.23 (1H, d, J = 2.8 Hz), 8.35 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 5.2 Hz), 8·79 (1H, s) 〇 Example 287 5-"6-Amino-7-(2-methylethane) 4 olin-4-yl gas 1 &lt;哚-1-# acid cyclopropanamide in the same manner as in Example 310, from 4-( 1H-indol-5-yloxy)-7-(2-methoxy Ethoxy)quinoline-6- Carbonitrile (450 mg), to give the title compound as a solid (210 mg). 1H-NMR spectrum (01^30-(16)5(??111):0.59-0.65 (211,111), 0.71-0.77 (2H, m), 2.74-2.82 (1H, m), 3.76-3.80 ( 2H, m)3 0.59-0·65 (2H,m), 4.39-4.43 (2H,m),6·47 (1H,d,J=5.2 Hz), 6.68 (1H, d5 J=3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7·52 (1H, d, J=2.4 Hz), 7·62 (1H, s), 7.90 (1H, d, J=3.6 Hz) ), 8.30 (1H, d, J = 2.8 Hz), 8.35 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 5.2 Hz), 8.79 (1H, s). Intermediate 398 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) Gutter 1304061 ~

、 AT B7 五、發明説明（393 ) 事造例287- 1 4-(11^-口亏卜果-5-基乳）-7，（2讀甲乳乙氧某）口奎口林-6-甲月青 以與實施例309同樣地，浞4-氯-7-甲氧乙氧基-卜氰基口奎 啉（1·〇 g)及5-羥基嘀哚，得到為固體之標題化合物（〇8 g) 0 W-NMR 光譜（DMSO-d6)5(ppm): 3-37 (3H，s)，3.76-3.79 (2H， m), 4.39-4.43 (2H, m), 6.43 (1H, d, J=5.6 Hz), 6.45-6.49 (1H, m), 6.99 (1H, dd, J=2.4 Hz, J=8-S Hz), 7.43-7.47 (2H, m), 7.52 (1H, d, J=8.8 Hz), 7.61 (lHr s), 8.66 (1H, d, J=5.6 Hz)5 8·79 (1H，s)，11.31 (1H，br s)。 實施例288 4-( 1H- 口朵-5 -基乳）-7-(3-( 口比洛矣-1-某）丙氧基）0奎琳-6 - 甲腈 以與實施例7同樣地，從4-(1Η-啕哚-5-基氧）-7-羥基4 琳-6-甲腈（1.98 g)及1-(3-氯丙基）说哈淀之鹽酸鹽，得到 為固體之標題化合物（1.27 g)。 W-NMR 光譜（01^0-〇16)5(??111): 1.64-1.72 (411，111)，1.95- 2.03 (2H, m), 2.42-2.48 (4H, m), 2.59 (2H, t, J=7.2 Hz), 4.32 (2H，t，J=6.4 Hz)，6·43 (1H，d，J=5-2 Hz)，6.46-6.48 (1H，m)， 6.99 (1H, dd5 ]=2A Hz, J=8.8 Hz)? 7.43-7.47 (2H, m), 7.51 (1H, d, J=8.8 Hz), 7.57 (1H, s), 8.66 (1H, d, J=5.2 Hz), 8.78 (1H，s)，11.30 (1H，br s)。 實施例289 . -氣基- 7- (3-( 口比洛咬-1-基)内氧某)g林麵4 -基氣lg弓卜果- -399 - 木紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐； 1304061 A7 B7 394 五、發明説明（ 1-讀酸（峰峻-2-基）酿胺 以與實施例312同樣之方法，從4-(1Η-啕哚-5-基氧）-7-(3-(吡咯啶-1-基）丙氧基）喹啉-6-甲腈（200 mg)，得到為固 體之標題化合物（155 mg)。 W-NMR 光譜（01^046)5(|31)111):1.66-1.76 (41^111)，1.98-2.07 (2H, m), 2.52-2.61 (4H, m)3 2.70 (2H, t5 J=7.2 Hz), 4.34 (2H，t，J=6.4 Hz)，6.51 (1H，d，J=5.2 Hz)，6·63 (1H，d，J=3.6 Hz), 6.95 (1H, d, J=4.4 Hz), 7.16 (1H, dd5 J=2.4 Hz, J=8.8 Hz), 7.38 (1H, d, J=4.4 Hz), 7.50 (1H3 d, J=2.4 Hz), 7.59 (1H3 s)，8·09 (1H，d，J=3.6 Hz)，8·68 (1H，d，J=5.2 Hz)，8·72 (1H， d，J=8.8 Hz)，8.81 (1H，s)。 實施例290 5 - [ 6-氰基-7- (2-甲氧乙氧基）4 g株-4-基氣g朵-1 -藉酸（g塞 唑-2-基）醯胺 以與實施例312同樣之方法，從4-(1Η-吲嗓-5-基氧）-7-(2-甲氧乙氧基）喹啉-6-曱腈（1〇〇 mg)，得到為固體之標題 化合物（3 1 mg)。 iH-NMR光譜（DMSO-d6)(5(ppm): 3·37 (3H，s)，3.77-3.80 (2H， m)，4.41 (2Η，m)，6·51 (1Η，d，J=5.2 Hz), 6.59-6.64 (1Η，m)， 6·88_6·95 (1H，m)，7·12,7·18 (1H，m)，7.32-7.39 (1H，m)， 7.48-7.51 (1H，m)，7.62 (1H，s)，8.06-8.13 (1H，m)，8.69 (1H， d，J=5.2 Hz)，8.69-8.77 (1H，m)，8.81 (1H，s) 〇 實施例291 . 5-〔7-芊氣基-6-氨基4：琳-4-基氯）4丨嗓-1-遵酸（2-氣乙基）- -400 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐) 1304061 A7 B7 395 五、發明説明（ 醯胺 從與實施例310同樣之方法，從5-(7-芊氧基-6-氰基喹啉- 4- 基氧）啕哚（4.5 g)及（2-氟乙基）羧酸苯酯，得到為固體之 標題化合物（3.6 g)。 iH-NMR 光譜（DMSO-d6)5(ppm): 3·54-3·61 (1H，m)，3.61-3.66 (1H，m)，4.53 (1H，t，J=4.8 Ηζ)，4·65 (1H，t，J=4.8 Hz)， 5·45 (2H，s)，6.48 (1H，d，J=5.2 Hz)，6·73 (1H，d，J=3.6 Hz), 7.20 (1H, dd3 J=2.4 Hz, J=8.8 Hz), 7.34-7.39 (1H5 m), 7.42-7.47 (2H，m)，7.53-7.57 (3H，m)，7.70 (1H，s)，7.98 (1H，d， J=3.6 Hz)，8.36 (1H，d，J=8.8 Hz)，8.50 (1H，t，J=5.2 Hz)， 8·68 (1H，d，J=5.2 Hz)，8·82 (1H，s)。 實施例292 5- (6-氰基-7-羥基4啉-4-基氣）㈣哚-1-藉酸（2-氣乙基）醯 龜 以與製造例21同樣之方法，用三氟乙酸從5-(7-芊氧基-6-氰基喹咻-4-基氧）啕哚-1-羧酸（2-氟乙基）醯胺（3 g)，得到 為固體之標題化合物（2.17 g)。 iH-NMR 光譜（01^30-〇16)(?(??111):3.54-3.59 (111，111)53.61-3.65 (1H, m), 4.53 (1H, t, J=5.2 Hz), 4.65 (1H, t3 J=5.2 Hz), 6.39 (1H，d，J=5.2 Hz)，6.73 (1H，d，J=3.6 Hz)，7.19 (1H，dd， J=2.4 Hz，J=8.8 Hz)，7.41 (1H，s)，7·53 (1H，d，J=2.4 Hz)， 7.98 (1H，d，J=3.6 Hz)，8·35 (1H，d，J=8.8 Hz)，8.50 (1H，t， J=5.2 Hz)，8.61 (1H，d，J=5.2 Hz)，8.71 (1H, s)。 實施例293 -401 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（396 ) U 6-氣基-7-(六氫叶1：咬-4-基）甲氣某1 4 g抹-4-基氧弓丨吟： 1-藉酸（2-氣乙基）酿胺 以與實施例301同樣之方法，從5-(6-氰基-7-羥基喹啉-4-基氧）啕哚-1-羧酸（2-氟乙基）醯胺（1 g)及4-溴乙基六氫吡 啶-1-羧酸第三丁酯，得到第三丁氧羰基體（150 mg)後，用 三氟乙酸將第三丁氧羰基脫保護，得到為固體之標題化合 物（97 mg) 〇 W-NMR 光譜（01^0-(16)5(??111):1.48-1.61(211，111)，1,95-2.02 (2H, m), 2.16-2.26 (1H, m), 2.92-3.01 (2H, m), 3.28-3.38 (2H, m), 3.54-3.59 (1H, m), 3.61-3.66 (1H, m), 4.02- 4.07 (1H, m), 4.22 (2H, d, J=6.4 Hz), 4.53 (1H, t, J=5.2 Hz), 4.65 (1H, t, J=5.2 Hz), 6.49 (1H, d, J=5.2 Hz), 6.74 (1H3 d5 J=4.0 Hz), 7.19 (1H5 dd, J=2.4 Hz, J=8.8 Hz), 7.54 (1H, d5 J=2.4 Hz)，7.64 (1H，s)，7.99 (1H，d，J=4.0 Hz)，8·36 (1H，d， J=8.8 Hz)，8.51 (1H，t，J=5.6 Hz), 8·82 (1H，s)。 實施例294 _5-『6-氰基- 7-( 1-(甲基六新p比咬-4·某）甲氣基）4 g株氧1 嗓-1-致酸（2-氣乙基）酿脖 以與貫施例302同樣之方法，從5-[6-氰基- 7- (六氫7比症-4-基曱氧基）喹啉氧]啕哚-；μ羧酸（2-氟乙基）醯胺（97 mg)， 得到為固體之標題化合物（35 mg)。 H-NMR 光譜（01\/180-(16)(5(卩卩111):1.52-1.61(211，111)，1.89- 2.07 (5H, m), 2,31 (3H, s), 2.92-2.98 (2H, m), 3.69-3.74 (1H, m)，3·76-3·81 (1H，m)，4.30 (2H，d，J=6.0 Hz)，4·68 (1H，t， -402 - 本畝張尺度適用中國國家標準(CNS) A4規格(210 x 297公爱） 裝 訂 線 1304061 A7 B7 五、發明説明（397 J=5.2 Hz)，4.80 (1H，t，J=5.2 Ηζ)，6·63 (1H，d，J=5.2 Hz)， 6.88 (1H，d，J=4.0 Hz)，7.35 (1H，dd，J=2.4 Hz，J=8.8 Hz)， 7·69 (1H，d，J=2.4 Hz)，7.73 (1H，s)，8.13 (1H，d，J=4.0 Hz)， 8·51 (1H，d，J=8.8 Hz)，8,65 (1H，t，J=5.2 Hz)，8.83 (1H，d， J=5.2 Hz)，8·94 (1H，s) 〇 實施例295 1ιΙ·6-氣基乙氣基奎啉-4-基氣i吲哚-丨-羧酸 乙醯胺· 以與實施例310同樣之方法，從7-(甲氧基乙氧基）-4-(1H-巧嗓-5-基氧）喹啉· 6-曱腈（1〇〇 mg)，得到為固體之標 題化合物（77 mg)。 iH-NMR 光譜（DMSO-dOS^pm): ι·ΐ8 (3H，t，J=7.2 Hz)， 3.28-3.33 (2H，m)，3.37(iH，s)，3.76-3.80 (2H，m)，4.40-4.44 (2H，m)，6·48 (1H，d，J=5.2 Hz)，6·71 (1H，d，J=3.6 Hz)， 7.19 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.53 (1H, d, J-2.4 Hz)5, AT B7 V. Invention Description (393) Case 287- 1 4-(11^- mouth loss fruit-5-base milk)-7, (2 reading methyl milk ethoxy) mouth Kuikoulin-6 -Methyl chloroform, in the same manner as in Example 309, 4-chloro-7-methoxyethoxy-cyano-cyanoquinoline (1·〇g) and 5-hydroxyindole to give the title compound as a solid. (〇8 g) 0 W-NMR spectrum (DMSO-d6) 5 (ppm): 3-37 (3H, s), 3.76-3.79 (2H, m), 4.39-4.43 (2H, m), 6.43 (1H , d, J=5.6 Hz), 6.45-6.49 (1H, m), 6.99 (1H, dd, J=2.4 Hz, J=8-S Hz), 7.43-7.47 (2H, m), 7.52 (1H, d, J=8.8 Hz), 7.61 (lHr s), 8.66 (1H, d, J=5.6 Hz) 5 8·79 (1H, s), 11.31 (1H, br s). Example 288 4-(1H-oral-5-based milk)-7-(3-(mouthpyridin-1-one)propoxy)0 quinolin-6-carbonitrile was the same as in Example 7. From 4-(1Η-啕哚-5-yloxy)-7-hydroxy-4-lin-6-carbonitrile (1.98 g) and 1-(3-chloropropyl) The title compound (1.27 g) was obtained as a solid. W-NMR spectrum (01^0-〇16)5(??111): 1.64-1.72 (411,111), 1.95-2.03 (2H, m), 2.42-2.48 (4H, m), 2.59 (2H, t, J=7.2 Hz), 4.32 (2H, t, J=6.4 Hz), 6.43 (1H, d, J=5-2 Hz), 6.46-6.48 (1H, m), 6.99 (1H, dd5 ]=2A Hz, J=8.8 Hz)? 7.43-7.47 (2H, m), 7.51 (1H, d, J=8.8 Hz), 7.57 (1H, s), 8.66 (1H, d, J=5.2 Hz) , 8.78 (1H, s), 11.30 (1H, br s). Example 289 . - gas base - 7- (3-( 口比洛 bit-1-yl) inner oxygen) g forest face 4 - base gas lg bow fruit - -399 - wood paper scale applies to Chinese national standards ( CNS) A4 specification (210 X 297 mm; 1304061 A7 B7 394 V. Description of the invention (1-reading acid (peak-jun-2-yl)-bristamine in the same manner as in Example 312, from 4-(1Η-啕) Indole-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-6-carbonitrile (200 mg) gave NMR spectrum (01^046)5(|31)111):1.66-1.76 (41^111), 1.98-2.07 (2H, m), 2.52-2.61 (4H, m)3 2.70 (2H, t5 J=7.2 Hz), 4.34 (2H, t, J = 6.4 Hz), 6.51 (1H, d, J = 5.2 Hz), 6.63 (1H, d, J = 3.6 Hz), 6.95 (1H, d, J=4.4 Hz), 7.16 (1H, dd5 J=2.4 Hz, J=8.8 Hz), 7.38 (1H, d, J=4.4 Hz), 7.50 (1H3 d, J=2.4 Hz), 7.59 (1H3 s),8· 09 (1H, d, J = 3.6 Hz), 8.68 (1H, d, J = 5.2 Hz), 8.72 (1H, d, J = 8.8 Hz), 8.81 (1H, s). 5-[6-Cyano-7-(2-methoxyethoxy)4 g strain-4-based gas g-l-acid (g-s-zol-2-yl)guanamine as in Example 312 The same method, from 4-(1Η-吲Indole-5-yloxy)-7-(2-methoxyethoxy)quinolin-6-indolecarbonitrile (1 mg) gave the title compound (3 1 mg) as a solid. DMSO-d6) (5 (ppm): 3·37 (3H, s), 3.77-3.80 (2H, m), 4.41 (2Η, m), 6·51 (1Η, d, J=5.2 Hz), 6.59 -6.64 (1Η,m), 6·88_6·95 (1H,m),7·12,7·18 (1H,m),7.32-7.39 (1H,m), 7.48-7.51 (1H,m), 7.62 (1H, s), 8.06-8.13 (1H, m), 8.69 (1H, d, J = 5.2 Hz), 8.69-8.77 (1H, m), 8.81 (1H, s) 〇 Example 291 . [7-helium-based-6-amino 4:lin-4-yl chloride) 4丨嗓-1-benzoic acid (2-gasethyl)- -400 This paper scale is applicable to China National Standard (CNS) A4 specification ( 210 X 297 mm) 1304061 A7 B7 395 V. Description of the invention (Indoleamine in the same manner as in Example 310, from 5-(7-decyloxy-6-cyanoquinolin-4-yloxy)anthracene (4.5 g) and (2-fluoroethyl)carboxylate as the title compound (3.6 g). iH-NMR spectrum (DMSO-d6) 5 (ppm): 3·54-3·61 (1H, m), 3.61-3.66 (1H, m), 4.53 (1H, t, J = 4.8 Ηζ), 4· 65 (1H, t, J = 4.8 Hz), 5·45 (2H, s), 6.48 (1H, d, J = 5.2 Hz), 6.73 (1H, d, J = 3.6 Hz), 7.20 (1H , dd3 J=2.4 Hz, J=8.8 Hz), 7.34-7.39 (1H5 m), 7.42-7.47 (2H,m), 7.53-7.57 (3H,m), 7.70 (1H,s),7.98 (1H, d, J=3.6 Hz), 8.36 (1H, d, J=8.8 Hz), 8.50 (1H, t, J=5.2 Hz), 8·68 (1H, d, J=5.2 Hz), 8.82 ( 1H, s). Example 292 5-(6-Cyano-7-hydroxy-4-phenyl-4-yl gas) (IV) Indole-1-Acid acid (2-ethylethyl) anthraquinone In the same manner as in Production Example 21, trifluorobenzene was used. Acetic acid from 5-(7-decyloxy-6-cyanoquinoxalyl-4-yloxy)indole-1-carboxylic acid (2-fluoroethyl)decylamine (3 g) afforded the title compound (2.17 g). iH-NMR spectrum (01^30-〇16) (?(??111):3.54-3.59 (111,111)53.61-3.65 (1H, m), 4.53 (1H, t, J=5.2 Hz), 4.65 (1H, t3 J=5.2 Hz), 6.39 (1H, d, J=5.2 Hz), 6.73 (1H, d, J=3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, J=8.8 Hz) , 7.41 (1H, s), 7·53 (1H, d, J = 2.4 Hz), 7.98 (1H, d, J = 3.6 Hz), 8.35 (1H, d, J = 8.8 Hz), 8.50 ( 1H, t, J = 5.2 Hz), 8.61 (1H, d, J = 5.2 Hz), 8.71 (1H, s). Example 293 -401 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Inventive Note (396) U 6-Gasyl-7-(Hexane Leaf 1: Bite-4-yl) Methane A certain 1 4 g wipe-4-yl oxygen bow: 1-(6-Cyano-7-hydroxyquinolin-4-yloxy)indole-1-carboxylic acid (5-(6-cyano-7-hydroxyquinolin-4-yloxy)indole-1-carboxylic acid) 2-fluoroethyl)decylamine (1 g) and 4-bromoethylhexahydropyridine-1-carboxylic acid tert-butyl ester to obtain a third butoxycarbonyl group (150 mg), then treated with trifluoroacetic acid Deprotection of the tributoxycarbonyl group to give the title compound as a solid (97 mg) 〇W-NMR spectrum (01^0-(16)5 (??111): 1.48-1.61 (211,11 1), 1, 95-2.02 (2H, m), 2.16-2.26 (1H, m), 2.92-3.01 (2H, m), 3.28-3.38 (2H, m), 3.54-3.59 (1H, m), 3.61-3.66 (1H, m), 4.02- 4.07 (1H, m), 4.22 (2H, d, J=6.4 Hz), 4.53 (1H, t, J=5.2 Hz), 4.65 (1H, t, J= 5.2 Hz), 6.49 (1H, d, J=5.2 Hz), 6.74 (1H3 d5 J=4.0 Hz), 7.19 (1H5 dd, J=2.4 Hz, J=8.8 Hz), 7.54 (1H, d5 J=2.4 Hz), 7.64 (1H, s), 7.99 (1H, d, J = 4.0 Hz), 8.36 (1H, d, J = 8.8 Hz), 8.51 (1H, t, J = 5.6 Hz), 8· 82 (1H, s). Example 294 _5-"6-Cyano- 7-(1-(methylhexa-p-biti-4) methyl group) 4 g strain of oxygen 1 嗓-1-acid (2-gas ethyl The brewing neck was the same as in Example 302, from 5-[6-cyano-7-(hexahydro-7-pyrimidin-4-ylindoleoxy)quinolineoxy]indole; 2-Fluoroethyl)guanamine (97 mg) gave the title compound (35 mg). H-NMR spectrum (01\/180-(16)(5(卩卩111):1.52-1.61(211,111), 1.89-2.07 (5H, m), 2,31 (3H, s), 2.92- 2.98 (2H, m), 3.69-3.74 (1H, m), 3·76-3·81 (1H, m), 4.30 (2H, d, J=6.0 Hz), 4·68 (1H, t, - 402 - The standard of the acre is applicable to the Chinese National Standard (CNS) A4 specification (210 x 297 public) Gutter 1304061 A7 B7 V. Invention description (397 J=5.2 Hz), 4.80 (1H, t, J=5.2 Ηζ) ,6·63 (1H,d,J=5.2 Hz), 6.88 (1H,d,J=4.0 Hz), 7.35 (1H,dd,J=2.4 Hz, J=8.8 Hz), 7·69 (1H, d, J = 2.4 Hz), 7.73 (1H, s), 8.13 (1H, d, J = 4.0 Hz), 8·51 (1H, d, J = 8.8 Hz), 8, 65 (1H, t, J = 5.2 Hz), 8.83 (1H, d, J = 5.2 Hz), 8·94 (1H, s) 〇 Example 295 1ιΙ·6-gas-based ethane quinoid -4-yl gas i吲哚-丨-Carboxylic acid acetamide. In the same manner as in Example 310, from 7-(methoxyethoxy)-4-(1H-Chloro-5-yloxy)quinoline·6-indolecarbonitrile (1) 〇〇mg), gave the title compound (77 mg) as a solid. iH-NMR spectrum (DMSO-dOS^pm): ι·ΐ8 (3H, t, J=7.2 Hz), 3.28-3.33 (2H, m) , 3.37 (iH, s), 3.76- 3.80 (2H, m), 4.40-4.44 (2H, m), 6·48 (1H, d, J = 5.2 Hz), 6.71 (1H, d, J = 3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.53 (1H, d, J-2.4 Hz)5

7·62 (1H，s)，7.93 (1H，d，J=3.6 Hz)，8·24 (1H，d，J=5.2 Hz) 8.35 (1H，d，J=8.8 Hz)，8·69 (1H，d，&gt;5·2 Hz)，8.80 (1H s) 0 ’ 實施例296 L： (3-二乙胺丙氧-基）-4-Π H-吲哚-5-基氩毗，r 以與實施例7同樣之方法，從4- ( 1 Η-啕哚-5-基氧）7罗一 基峻琳-6-甲猜（〇·8 g)及3 -二乙胺基丙基氯，得到為固触、 標題化合物（0.46 g)。 lH-NMR 光譜（DMSO-d6)5(ppm): 0·95 (6H，t j=7o τ 5 1Hz), -403 - 本紙張尺度適用中國國家搮準(CNS) A4規格(210 x 297公釐) 1304061 、 A7 ______ B7_ 五、發明説明（398) 1.88-1.94 (2H, m), 2.43^2.49 (4H, m), 2.59 (2H, t, J=6.8 Hz), 4.30 (2H, t, J=6.0 Hz), 6.42 (1H, d, J=5.2 Hz), 6.45-6.48 (1H, m), 6.98 (1H, dd5 J=2.4 Hz, J=8.8 Hz), 7.43-7.47 (2H, m), 7.51 (1H, d, J=8.8 Hz), 7.55 (1H, s), 8.65 (1H, d, J=5.2 Hz), 8.77 (1H, s)，11.30 (1H，br s)。 實施例297 .氛基-7 - (3 乙霞羞^丙氣基）崦嗾· 4 -基氣吲哚-t _藉 酸乙酿胺 以與實施例3 10同樣之方法，從7-(3-二乙胺基丙氧基卜4- (1H-4丨哚-5-基氧）喹啉-6-甲腈（230 mg)，得到為固體之標 題化合物（35 mg)。 W-NMR 光譜（DMSO-d6)5(ppm): 0·95 (6H，t，J=7.2 Hz)， 1.18 (3H，t, J=7.2 Hz)，1.89-1.94 (2H，m)，2.43-2.49 (4H，m)， 2.59 (2H, t, J=7.2 Hz), 3.29-3.37 (2H, m), 4.31 (2H, t, J=6.0 Hz), 6.47 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.6 Hz), 7.18 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.52 (1H, d5 J=2.4 Hz), 7.57 (1H3 s), 7.93 (1H3 d, J=3.6 Hz), 8.24 (1H, t, J=5.2 Hz), 8.35 (1H, d, J=8.8 Hz)，8·67 (1H，d，J=5.2 Hz)，8·78 (1H，s) 〇 實施例298 5 -「6-氰基-7- ( 3 -二乙胺基丙爱.基）4 g汰_4-某氧i s卜朵-^•淼 酸環丙醯胺 以與實施例310同樣之方法，從7-(3_二乙胺基丙氧基）_‘ (1H-啕哚-5.-基氧）+淋-6-曱腈（〇·5 g)，得到為固體之標題 化合物（0.21 g)。 -404 - ^紙張尺度適用中國國家標準(CNS) A4規格（21〇 x 297公釐） 1304061 A7 B7 五、發明説明（399) iH-NMR 光譜（01^3〇-(16)5(??111):0.59-0.64 (211，111)，0.71-0.76 (2H, m), 0.95 (6H,-t, J=7.2 Hz), 1.87-1.95 (2H, m), 2.43-2.49 (4H，m)，2·59 (2H，t，J=6.8 Hz)，2.74-2.81 (1H，m)， 4.31 (2H, t5 J=6.0 Hz), 6.46 (1H, d, J=5.2 Hz), 6.68 (1H, d, J=3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.52 (1H, d, J=2.4 Hz), 7.56 (1H, s), 7.90 (1H5 d, J=3.6 Hz), 8.30 (1H3 d, J=3.2 Hz)5 8.35 (1H, d, J=8.8 Hz), 8.67 (1H, d, J=5.2 Hz), 8·78 (1H，s)。 實施例299 5-「6-氨基-7-(3-(吡咯啶-1-基）丙氣基V套啉-4-基氣1钊哚-1-羧酸乙醯胺 以與實施例310同樣之方法，從7-(3-(吡咯啶-1-基）丙氧 基）-4-( 1H-啕哚-5-基氧）喹啉-6-甲腈（100 mg)，得到為固 體之標題化合物（31 mg)。 iH-NMR 光譜（DMSO-d6)5(ppm): 1.18 (3H，t，J=7.2 Hz)， 1.85-1.99 (4H, m), 2.40-2.49 (2H, m), 3.01-3.48 (8H, m), 4.39 (2H，t，J=6.0 Hz)，6·50 (1H，d，J=5.2 Hz)，6.71 (1H，d， J=3.6 Hz)，7.18 (1H，dd，J=2.4 Hz, J=8.8 Hz)，7·53 (1H，d， J=2.4 Hz)，7.62 (1H，s)，7.96 (1H，d，J=3.6 Hz)，8.28 (1H，t， J=5.2 Hz), 8.36 (1H, d, J=8.8 Hz), 8.70 (1H, d5 J=5.2 Hz), 8.82 (1H，s)。 實施例300 5-「6-氰基-&lt;7-(’3-二乙胺基丙氣基）4啉-4-基氣1钊哚-1-藉 酸唑-2-基）醯胺 -405 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂 線 1304061 A7 B7 400 ) 五、發明説明（ 以與實施例312同樣之方法，從M3-二乙胺基丙氧基）-4-(1H-吲哚-5-基氧）喹啉-6-甲腈（8〇 mg)，得到為固體之標 題化合物（5 mg)。 iH-NMR 光譜（DMS〇-d6)5(pPm): 1·〇〇 (6H，t，J=7.2 Hz)， 1·93-2·01 (2H，m)，2·59 (4H，q，J=7.2 Hz)，2·72 (2H，t，J=6.8 Hz)，4:33 (2H，t，J=6.0 Hz)，6:51 (1H，d，J=5.2 Hz)，6.64 (1H， d, J=3.6 Hz), 6.98 (1H, d5 J=4.0 Hz), 7.16 (1H, dd, J=2.4 Hz, J-8.8 Hz), 7.40 (1H, d, J=4.0 Hz), 7.50 (1H, d, J=2.4 Hz), 7.58 (1H，s)，8.09 (1H，d，J=3.6 Hz)，8.68 (1H，d，J=5.2 Hz)， 8·70 (1H，d，J=8.8 Hz)，8·81 (1H，s)。 t施例301 LA基-4·ΠΗ-㈤哚-5-莘n7-(六氤吡啶-4-某）甲氧4啉 將6-氰基-4-(1Η-啕哚-5-基氧）-7-[(1-(第三丁氧羰氧基） 六氫说啶-4-基）甲氧基]喹啉（0·25 g，0.5015 mmol)溶於乙 酵（2 ml)及四氫呋喃（2 ml)，於室溫加入濃鹽酸（0.2 mi), 並將其授拌17小時。減壓餾去溶媒，加入飽和碳酸氫制水 溶液，將其用四氫呋喃與乙酸乙酯之混合溶媒萃取，用飽 和食鹽水洗淨，用無水硫酸鎂乾燥並減壓餾去溶媒。並使 殘餘物吸著於ΝΗ矽凝膠，然後ffiNH矽凝膠層析（乙酸乙 醋·甲醇系）精製，將得到之結晶懸浮於乙醇中，將其用乙 _及己烷稀釋。濾取結晶，用乙醚洗淨，藉由吸引乾燥得 到為淡叉色結晶之標題化合物（15 mg，0.0376 mmol， 7.51%)。 * H-NMR 光讀（DMSO〇 (5 (ppm): 1.23-1.29 (2Η，m)，1 74· -406 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 〜 ' ' A7 _____ B7 五、發明説 1.77 (2Η, m), 1.95 (1H, br s), 2.48-2.55 (2H, m), 2.97-3.00 (2H, m)? 4.12 (2H5 d5 J=5.6 Hz), 6.43 &lt;1H, d5 J=5.2 Hz), 6.47 (1H，s)，6.88 (1H，dd，J=2.4, 9.2 Hz)，7·45 (1H，d，J=2.4 Hz)， 7.46 (1H，s)，7·52 (1H，d，J=9.2 Hz)，7·57 (1H，s)，8·66 (1H， d，J=5.2 Hz)，8·79 (1H，s)，11.31 (1H，s)。 如下述合成原料。 掣造例3 01 - 1 7-苄氧基·τ6二氰某-4-ΠΗ-W哚-5-某惫.V杳啉 將7-芊氧基-6-氰基-4-氯喹啉（23 g，78.03 mmol)懸浮於 N-甲基吡咯啶酮（15·8 ml)，加入5-羥基吲哚（12.5 g , 83.64 mmol)及一異丙基乙胺（15·8 ml)，並於150°C加熱禮拌10小 時。放冷至室溫後，加入水及四氫呋喃，以使結晶完全溶 解。用四氫呋喃萃取，用飽和食鹽水洗淨，用無水疏酸鎂 乾燥及減壓餘去溶媒後，使殘餘物吸著於碎凝膠^用碎凝 膠管柱層析精製（己燒·四氫吱喃系），加入濃鹽酸（〇.2 ml) ’並將其攪拌17小時。減壓餾去溶媒，加入飽和竣酸氫 鈉水溶液，將其用四氫呋喃與乙酸乙酯之混合溶媒萃取， 用飽和食鹽水洗淨，用無水硫酸鎂乾燥並減壓餾去溶媒。 將得到之結晶懸浮於乙酸乙酯中，將其用乙醚及己烷稀 釋。遽取結晶，用乙醚及己烷洗淨，藉由吸引乾燥得到為 淡黃色結晶之標題化合物（12.5 g，31.93 mm〇l，40.92%)。 iH-NMR光譜（DMSO-d6)5(ppm): 5.45 (2H，s)，6.44 (1H，d， J=5.2 Ηζ)，6·47 (1H，m)，6.99 (1H，dd，J=2.4，8·8 Ηζ)，7·37 (1H，t，J=7.4 Hz)，7.42-7.46 (4H，m)，7.51-7.56 (3H，m)，7.69 -407 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） 1304061 五、發明説明（402) A7 B7 (1H，s)，8.66 (1H，d，J=5.2 Ηζ)，8·82 (1H，s)，11.29 (1H，s)。 製造例301-2 i:·乱基-4 - (1Η -卜果-5 -基氣）-7 H某4说 將7-芊氧基-6-氰基- 4-( 1 Η-啕嗓-5-基氧）4淋（3 g , 76·642 mmol)溶於四氫呋喃（250 ml),加入10%鈀/碳粉末 (500 mg，含水品），於氫氣蒙氣及室溫下攪拌丨丨小時。加 入10%鈀/碳粉末（300 mg ’含水品），於氫氣蒙氣及室溫下 攪拌9小時後，加入10%鈀/碳粉末（2〇〇 mg，含水品），然 後於氫氣蒙氣及室溫下攪拌5小時。濾去觸媒，將其用乙醇 洗淨後，將濾液減壓蒸餾。將得到之結晶懸浮於乙醇中， 將其用己燒稀釋’滤取結晶，用己燒：乙酵=3 : 1洗淨，萨 由吸引乾燥’仔到為淡叉色結晶之標題化合物（1.8 2 g , 6.0402 mmol, 79.12%) ° iH-NMR 光譜（DMSO-d6)5(ppm): 6·34 (1H，d，J=5.4 Hz) 6.46 (1H，m)，6·98 (1H，dd，J=2.4，8.8 Hz)，7·40-7·46 (3H m), 7.51 (1H, d, J=8.8 Hz), 8.58 (1H, d, J=5.4 Hz), 8.70 (ifj s)，11.29 (1H，s)，11.58 (1H，s)。 ’ 製造例301-3 6-氨某-4-Π Η-Θ丨哚-5-基氣）-7-「（W第三丁 口比咬-4 -基）甲氧1 口奎口林 將6-氨基- 4- (1Η-α?丨嗓-5-基氧）-7-^基峻琳（1 72 σ , 5.7084 mmol)溶於Ν，Ν-二甲基甲醯胺（20 ml),加入後酸名甲 (0.87 g，6/2792 mmol)以及4-溴甲基六氫咕淀-1-幾酸第二 丁酯（1.75 g，6.2792 mmol)，並於70°C加熱攪拌7小時。放 -408 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐）7·62 (1H, s), 7.93 (1H, d, J = 3.6 Hz), 8·24 (1H, d, J = 5.2 Hz) 8.35 (1H, d, J = 8.8 Hz), 8.69 ( 1H,d,&gt;5·2 Hz), 8.80 (1H s) 0 'Example 296 L: (3-diethylaminepropoxy-yl)-4-oxime H-indole-5-yl argon r In the same manner as in Example 7, from 4-(1 Η-啕哚-5-yloxy)7-l-yl-Junlin-6--------------- The chloro group was obtained as the title compound (0.46 g). lH-NMR spectrum (DMSO-d6) 5 (ppm): 0·95 (6H, tj=7o τ 5 1Hz), -403 - This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 , A7 ______ B7_ V. Description of invention (398) 1.88-1.94 (2H, m), 2.43^2.49 (4H, m), 2.59 (2H, t, J=6.8 Hz), 4.30 (2H, t, J =6.0 Hz), 6.42 (1H, d, J=5.2 Hz), 6.45-6.48 (1H, m), 6.98 (1H, dd5 J=2.4 Hz, J=8.8 Hz), 7.43-7.47 (2H, m) , 7.51 (1H, d, J=8.8 Hz), 7.55 (1H, s), 8.65 (1H, d, J=5.2 Hz), 8.77 (1H, s), 11.30 (1H, br s). Example 297. Azyl-7 - (3, Ethylene, propylene, propylene, propylene, propylene, ketone, ketone, ketone, ketone, ketone, ketone, ketone, ketone, ketone 3-Diethylaminopropoxy-4-(1H-4丨哚-5-yloxy)quinolin-6-carbonitrile (230 mg), m. Spectrum (DMSO-d6) 5 (ppm): 0·95 (6H, t, J = 7.2 Hz), 1.18 (3H, t, J = 7.2 Hz), 1.89-1.94 (2H, m), 2.43-2.49 ( 4H,m), 2.59 (2H, t, J=7.2 Hz), 3.29-3.37 (2H, m), 4.31 (2H, t, J=6.0 Hz), 6.47 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.6 Hz), 7.18 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.52 (1H, d5 J=2.4 Hz), 7.57 (1H3 s), 7.93 (1H3 d , J=3.6 Hz), 8.24 (1H, t, J=5.2 Hz), 8.35 (1H, d, J=8.8 Hz), 8.67 (1H, d, J=5.2 Hz), 8·78 (1H , s) 〇 Example 298 5 - "6-Cyano-7-(3-diethylaminopropyl-propyl) 4 g _4-an oxygen is pulo-^• ciprofloxacin In the same manner as in Example 310, from 7-(3-diethylaminopropoxy)_'(1H-indole-5.-yloxy)+lead-6-indoleonitrile (〇·5 g), The title compound was obtained as a solid (0.21 g). Applicable to China National Standard (CNS) A4 specification (21〇x 297 mm) 1304061 A7 B7 V. Description of invention (399) iH-NMR spectrum (01^3〇-(16)5(??111):0.59- 0.64 (211,111), 0.71-0.76 (2H, m), 0.95 (6H,-t, J=7.2 Hz), 1.87-1.95 (2H, m), 2.43-2.49 (4H,m),2·59 (2H, t, J = 6.8 Hz), 2.74 - 2.81 (1H, m), 4.31 (2H, t5 J = 6.0 Hz), 6.46 (1H, d, J = 5.2 Hz), 6.68 (1H, d, J =3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.52 (1H, d, J=2.4 Hz), 7.56 (1H, s), 7.90 (1H5 d, J=3.6 Hz) ), 8.30 (1H3 d, J=3.2 Hz) 5 8.35 (1H, d, J=8.8 Hz), 8.67 (1H, d, J=5.2 Hz), 8·78 (1H, s). Example 299 5-"6-Amino-7-(3-(pyrrolidin-1-yl)propane-based V-carboxolin-4-yl gas 1-indole-1-carboxylic acid acetamide as Example 310 The same procedure was obtained from 7-(3-(pyrrolidin-1-yl)propoxy)-4-(1H-indol-5-yloxy)quinolin-6-carbonitrile (100 mg). The title compound of the solid (31 mg). iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.18 (3H, t, J = 7.2 Hz), 1.85-1.99 (4H, m), 2.40-2.49 (2H, m), 3.01-3.48 (8H, m), 4.39 (2H, t, J = 6.0 Hz), 6.50 (1H, d, J = 5.2 Hz), 6.71 (1H, d, J = 3.6 Hz), 7.18 (1H, dd, J = 2.4 Hz, J = 8.8 Hz), 7·53 (1H, d, J = 2.4 Hz), 7.62 (1H, s), 7.96 (1H, d, J = 3.6 Hz), 8.28 (1H, t, J = 5.2 Hz), 8.36 (1H, d, J = 8.8 Hz), 8.70 (1H, d5 J = 5.2 Hz), 8.82 (1H, s). Example 300 5-"6- Cyano-&lt;7-('3-diethylaminopropenyl) 4 phenyl-4-yl gas 1 钊哚-1-oxazolyl-2-yl) decylamine-405 - This paper size is applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) Gutter 1304061 A7 B7 400 ) V. Description of the Invention (In the same manner as in Example 312, from M3-diethylaminopropoxy)-4-( 1H-吲哚-5-yloxy)quinoline-6-carbonitrile (8 mg) gave the title compound (5 mg) as a solid. iH-NMR spectrum (DMS 〇-d6) 5 (pPm): 1 〇 〇(6H,t,J=7.2 Hz), 1·93-2·01 (2H,m),2·59 (4H,q,J=7.2 Hz), 2·72 (2H,t,J=6.8 Hz), 4:33 (2H, t, J = 6.0 Hz), 6:51 (1H, d, J = 5.2 Hz), 6.64 (1H, d, J = 3.6 Hz), 6.98 (1H, d5 J= 4.0 Hz), 7.16 (1H, dd, J=2.4 Hz, J-8.8 Hz), 7.40 (1H, d, J=4.0 Hz), 7.50 (1H, d, J=2.4 Hz), 7.58 (1H, s ), 8.09 (1H, d, J = 3.6 Hz), 8.68 (1H, d, J = 5.2 Hz), 8·70 (1H, d, J = 8.8 Hz), 8.81 (1H, s). t Example 301 LA--4-ΠΗ-(5)哚-5-莘n7-(hexa-pyridin-4-one)methoxytetraline 6-cyano-4-(1Η-啕哚-5-yloxy) -7-[(1-(Tertidinoxycarbonyloxy)hexahydron-4-yl)methoxy]quinoline (0·25 g, 0.5015 mmol) is dissolved in ethyl acetate (2 ml) Tetrahydrofuran (2 ml) was added with concentrated hydrochloric acid (0.2 mi) at room temperature and stirred for 17 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of hydrogen carbonate was added, and the mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate. The mixture was washed with saturated aqueous sodium sulfate and dried over anhydrous magnesium sulfate. The residue was incubated with a hydrazine gel, and then purified by ffi NH(R) gel chromatography (ethyl acetate-methanol). The obtained crystals were suspended in ethanol and diluted with ethyl acetate and hexane. The title compound (15 mg, 0.0376 mmol, 7.51%) was obtained. * H-NMR optical reading (DMSO 〇 (5 (ppm): 1.23-1.29 (2Η, m), 1 74· -406 - This paper size applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) 1304061 ~ ' ' A7 _____ B7 V. Invention 1.77 (2Η, m), 1.95 (1H, br s), 2.48-2.55 (2H, m), 2.97-3.00 (2H, m)? 4.12 (2H5 d5 J=5.6 Hz), 6.43 &lt;1H, d5 J=5.2 Hz), 6.47 (1H, s), 6.88 (1H, dd, J=2.4, 9.2 Hz), 7·45 (1H, d, J=2.4 Hz), 7.46 (1H, s), 7.52 (1H, d, J = 9.2 Hz), 7·57 (1H, s), 8.66 (1H, d, J = 5.2 Hz), 8.79 (1H, s), 11.31 (1H, s). Synthetic starting materials as described below. Example 3 01 - 1 7-Benzyloxy·τ6 dicyandi-4- ΠΗ-W哚-5- 惫.V porphyrin 7 -decyloxy-6-cyano-4-chloroquinoline (23 g, 78.03 mmol) was suspended in N-methylpyrrolidone (15·8 ml), and 5-hydroxyindole (12.5 g, 83.64 mmol) was added. And isopropylethylamine (15·8 ml), and heat-mixed at 150 ° C for 10 hours. After cooling to room temperature, add water and tetrahydrofuran to completely dissolve the crystals. Extract with tetrahydrofuran, with saturated salt Washed with water, dried with anhydrous magnesium sulfate and decompressed to remove solvent The residue was sorbed on a crushed gel. The residue was purified by a gel column chromatography (hexane, tetrahydrofuran), and concentrated hydrochloric acid (2 ml) was added and stirred for 17 hours. The solvent was distilled off, and a saturated aqueous solution of sodium hydrogencarbonate was added thereto, and the mixture was extracted with a mixed solvent of tetrahydrofuran and ethyl acetate, and washed with brine, dried over anhydrous magnesium sulfate and evaporated. The title compound (12.5 g, 31.93 mm ,l, 40.92%) was obtained as a pale yellow crystals. iH-NMR spectrum (DMSO-d6) 5 (ppm): 5.45 (2H, s), 6.44 (1H, d, J = 5.2 Ηζ), 6·47 (1H, m), 6.99 (1H, dd, J =2.4,8·8 Ηζ),7·37 (1H,t,J=7.4 Hz),7.42-7.46 (4H,m),7.51-7.56 (3H,m),7.69 -407 - This paper size is applicable to China National Standard (CNS) A4 Specification (21〇x 297 mm) 1304061 V. Description of Invention (402) A7 B7 (1H, s), 8.66 (1H, d, J=5.2 Ηζ), 8·82 (1H, s ), 11.29 (1H, s). Production Example 301-2 i:·Chaotic-4 - (1Η-Buguo-5-base gas)-7 H 4 says 7-decyloxy-6-cyano-4-(1 Η-啕嗓-5-yloxy) 4 leaching (3 g, 76.642 mmol) dissolved in tetrahydrofuran (250 ml), 10% palladium on carbon powder (500 mg, hydrated), stirred under hydrogen atmosphere and room temperature Hour. Add 10% palladium/carbon powder (300 mg 'aqueous product), stir for 9 hours under hydrogen atmosphere and room temperature, add 10% palladium/carbon powder (2 〇〇mg, hydrated product), then hydrogen Stir at room temperature for 5 hours. The catalyst was filtered off, washed with ethanol, and the filtrate was distilled under reduced pressure. The obtained crystal was suspended in ethanol, and it was diluted with hexane to 'filter and crystallize. It was washed with hexane: ethyl acetate = 3:1, and the title was compounded by dry-staining. 2 g , 6.0402 mmol, 79.12%) ° iH-NMR spectrum (DMSO-d6) 5 (ppm): 6·34 (1H, d, J = 5.4 Hz) 6.46 (1H, m), 6·98 (1H, Dd, J=2.4, 8.8 Hz), 7·40-7·46 (3H m), 7.51 (1H, d, J=8.8 Hz), 8.58 (1H, d, J=5.4 Hz), 8.70 (ifj s ), 11.29 (1H, s), 11.58 (1H, s). ' Manufacturing Example 301-3 6-Ammonia-4-Π Η-Θ丨哚-5-base gas)-7-"(W third Dingkou than bite-4-yl) methoxy 1 mouth Kuipulin 6-Amino-4-(1Η-α?丨嗓-5-yloxy)-7-^ jijunlin (1 72 σ , 5.7084 mmol) is soluble in hydrazine, hydrazine-dimethylformamide (20 ml) After the addition, the acid name (0.87 g, 6/2792 mmol) and the 4-butyl bromide hexahydroindol-1-carboxylic acid (1.75 g, 6.2792 mmol) were added and heated and stirred at 70 ° C. Hour - 408 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂Binding

線 1304061 〜 Λ7 ^ ： _ ___B7 五、發明説明（403) 冷至立》後’加入水’用乙酸乙S旨·四氫p夫喃萃取，用飽 和食鹽水洗淨，用無水硫酸鎂乾燥及減壓餾去溶媒後，使 殘餘物吸著於矽凝膠。用矽凝膠管柱層析（己烷·乙酸乙酯 系）而精製’將得到之黃色油狀物加至乙酸乙|旨·乙醇·己 烷中，並使結晶析出。濾取結晶，用己烷··乙醇==i 0 : 1洗 淨，藉由吸引乾燥得到為淡黃色結晶之標題化合物（丨.786 g，3.3852 mmol，59.30%) 〇 h-NMR 光譜（DMSO-d6) 5 (ppm): 1.20-1.33 (2H，m)，1.39 (9H，s)，1.78-1.82 (2H，m)，2.06(lH，m)，2.78(2H，m)，3.98-4.02 (2H, n), 4.17 (2H, d5 J=6.4 Hz), 6.43 (1H, d, J=5.2 Hz)5 6.49 (1H, s), 6.98 (1H, dd5 J=2.4 Hz, 8.8 Hz), 7.44-7.46 (2H, m)，7.51 (1H，d，J=8.8 Hz)，7·58 (1H，s)，8·66 (1H，d，J=5.2 Hz)，8·79 (1H，s)，11.30 (1H，s)。 實施例302 氣基-心（1 H-啕哚，5-基氣-曱某六氤毗啶-4-基）甲 氧杳成 將6-氰基-4-( 1H-吲哚-5-基氧）-7-[(1-甲基六氫吡啶-4-基）甲氧]口奎淋（30 mg，0.0753 mmol)溶於四氫峡喃（2.5 ml) 及甲醇（2.5 ml)，並加入乙酸（0.009 ml)及甲醛水溶液 (0.047 ml，0.5648 mmol，12N)。然後於室溫加入氰基硼氫 鈉（10 mg)，並於室溫攪拌丨小時。加入飽和碳酸氫鈉水溶 液，用乙酸乙酯及四氫呋喃萃取，用飽和食鹽水洗淨，用 無水硫酸鎂乾燥及減壓餾去溶媒後，使殘餘物吸著於NH型 矽凝膠。藉NH型矽凝膠管柱層析（乙酸乙酯··甲醇=i〇: u _ - 409 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 1304061 A7 ： _____ B7 五、發明説明（4〇4) 精I ’然後將得到之結晶懸浮於乙趟。濾、取結晶，藉由吸 引乾燥，得到為無色結晶之標題化合物（7 mg，0.0170 mmol » 22.54%) 〇 H-NMR 光譜（〇1^〇46)5(??111):1.35-1.44 (211，111)，1.76- 1.91 (5H, m), 2.15 (3H, s), 2.78-2.82 (2H, m), 4.14 (2H, d, J=6.0 Hz), 6.42 (1H, d3 J=5.2 Hz), 6.47 (1H, s), 6.98 (1H5 dd? J=2.4, 8.8 Hz)，7.44-7.46 (2H，m)，7.51 (1H，d，JN8.8 Hz)， 7·57 (1H，s)，8.66 (1H，d，J=5.2 Hz)，8·78 (1H，s)，11.31 (1H， s)。 ’ ί施例303 乙基胺甲醯基啕哚-5-基氣7-吖士舒a咗_4- 基）甲氲嗾 將6-氰基-4-(1-乙基胺甲醯基啕哚-5-基氧）(第三 丁氧k氧基）六氫p比淀-4-基）甲氧]峻琳（18〇 mg，0.0753 mmol)溶於三氟乙酸（1 ml)，並於室溫攪拌〇 5小時。加入 飽和碳酸氫鈉水溶液，用乙酸乙酯及四氫咬喃萃取，用飽 和食鹽水洗淨，用無水硫酸鎂乾燥及減壓餾去溶媒後，在 所得不定形物中加入乙醇並結晶化。將其用己燒稀釋後， 濾取結晶，用己烷洗淨，藉由吸引乾燥，得到為無色結晶 之標題化合物（132 mg，0.2811 mmol，88,96%)。 W-NMR 光譜（DMSO-d6)(5(ppm): 1·18 (3H，t，J=7.2 Hz)， 1.50-1.59 (2H, m), 1.96-2.01 (2H, m), 2.21 (1H, br s), 2.93- 2.99 (2H，m)，3.28-3.37 (4H，m)，4·22 (2H，d，J=6.0 Hz)， 6·49 (1H，d，J=5.6 Hz)，6.71 (1H，d，J=3.6 Hz)，7.17 (1H，dd， -410- 本·紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) '' ' 1304061 A7 -- ____ B7 五、發明説明（405) j=2.4, 8.8 Hz), 7.53 (1H, d, J=2.4 Hz), 7.64 (1H, s), 7.95 (1H，d，J=8.8 Hz)，8.26 (1H，t，J=5.4 Hz)，8·36 (1H，d，J=8.8 Hz)，8·42 (1H，br s)，8.69 (1H，d，J=5.6 Hz)，8·81 (1H，s)。 如下述合成起始原料。 f ;告例 3 03 - 1 6-氣胺甲醯某㈤哚-5-某氫第三丁 $ 羰氧—基啶-4-某）甲氧1 4呲 使用6-氰基-4-( 1H-吲哚-5-基氧）-7-[(1-(第三丁氧羰氧 基）六氫p比淀-4-基）甲氧]p奎淋（350 mg，0.7062 mmol)及N-乙基胺基甲酸苯酯（140 mg)，藉由與實施例310同樣之反 應，得到為無色結晶之標題化合物（180 mg，〇 316〇 mmol，44.74%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 1.18 (3H，t，J=7.〇 Hz)， 1.18-1.35 (2H，m)，1·40 (9H，s)，1·78-1·82 (2H，m)，2·16 (1H， m)，2·79 (2H，m)，3.32 (2H，q，J=7.0 Hz)，3·98-4·02 (2H，m)， 4.18 (2H，d，J=6.0 Hz)，6.48 (1H，d，J=5.2 Hz)，6·70 (1H，d， J=3.8 Hz)，7.18 (1H，dd，J=2.4, 9·2 Hz)，7·52 (1H，d，J=2.4 Hz)，7.59 (1H，s)，7.93 (1H，d，J=3.8 Hz)，8.22 (1H，br* s)， 8,35 (1H，d，J=9.2 Hz)，8.68 (1H，d，J=5.2 Hz)，8.79 (1H， s)。 實施例304 6-¾基- 4- (1-乙基胺甲酷基嗓-5-基乳-甲基六尋I 也啶-4-基）甲氣&gt;奎啉 使用6-氰基-4-(1-乙基胺甲醯基啕哚-5-基氧）-7-[(六氫 -411 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂Line 1304061 ~ Λ7 ^ : _ ___B7 V. Description of the invention (403) After the cold to the end, the 'addition of water' is extracted with acetic acid, ethyl acetate, tetrahydrop-propanol, washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was absorbed in a hydrazine gel. It was purified by a gel column chromatography (hexane-ethyl acetate). The obtained yellow oil was added to ethyl acetate, ethyl alcohol and hexane, and crystals were precipitated. The crystals were collected by filtration, washed with EtOAc EtOAc EtOAc EtOAc (EtOAc) -d6) 5 (ppm): 1.20-1.33 (2H, m), 1.39 (9H, s), 1.78-1.82 (2H, m), 2.06 (lH, m), 2.78 (2H, m), 3.98-4.02 (2H, n), 4.17 (2H, d5 J=6.4 Hz), 6.43 (1H, d, J=5.2 Hz)5 6.49 (1H, s), 6.98 (1H, dd5 J=2.4 Hz, 8.8 Hz), 7.44-7.46 (2H, m), 7.51 (1H, d, J = 8.8 Hz), 7·58 (1H, s), 8.66 (1H, d, J = 5.2 Hz), 8.79 (1H, s), 11.30 (1H, s). Example 302 Gas-based (1H-indole, 5-based gas-曱6-hexyridin-4-yl)methoxyoxane to 6-cyano-4-(1H-indole-5- Base oxy)-7-[(1-methylhexahydropyridin-4-yl)methoxy] quinine (30 mg, 0.0753 mmol) was dissolved in tetrahydroglycol (2.5 ml) and methanol (2.5 ml). Acetic acid (0.009 ml) and aqueous formaldehyde solution (0.047 ml, 0.5648 mmol, 12 N) were added. Sodium cyanoborohydride (10 mg) was then added at room temperature and stirred at room temperature for a few hours. After adding a saturated aqueous solution of sodium hydrogencarbonate, the mixture was extracted with ethyl acetate and tetrahydrofuran, and washed with brine, dried over anhydrous magnesium sulfate and evaporated. Chromatography by NH-type gel column chromatography (ethyl acetate··methanol=i〇: u _ - 409 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 : _____ B7 V. Inventive Description (4〇4) The title compound (7 mg, 0.0170 mmol » 22.54%) was obtained as a colorless crystals. H-NMR spectrum (〇1^〇46)5(??111):1.35-1.44 (211,111), 1.76- 1.91 (5H, m), 2.15 (3H, s), 2.78-2.82 (2H, m ), 4.14 (2H, d, J=6.0 Hz), 6.42 (1H, d3 J=5.2 Hz), 6.47 (1H, s), 6.98 (1H5 dd? J=2.4, 8.8 Hz), 7.44-7.46 (2H , m), 7.51 (1H, d, JN8.8 Hz), 7·57 (1H, s), 8.66 (1H, d, J = 5.2 Hz), 8.78 (1H, s), 11.31 (1H, s). ' ί Example 303 ethylamine carbaryl 啕哚-5-based gas 7-吖士舒 a咗_4-yl) formazan 6-cyano-4-(1-ethylamine Mercaptopurine-5-yloxy)(t-butoxykoxy)hexahydrop-precipitate-4-yl)methoxy]junlin (18〇mg, 0.0753 mmol) is dissolved in trifluoroacetic acid (1 Ml) and stir for 5 hours at room temperature. After adding a saturated aqueous solution of sodium hydrogencarbonate, the mixture was extracted with ethyl acetate and tetrahydrohexane, and washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove solvent, and ethanol was added to the obtained amorphous material and crystallized. The title compound (132 mg, 0.2811 mmol, 88, 96%) was obtained as a colorless crystals. W-NMR spectrum (DMSO-d6) (5 (ppm): 1.18 (3H, t, J = 7.2 Hz), 1.50-1.59 (2H, m), 1.96-2.01 (2H, m), 2.21 (1H , br s), 2.93- 2.99 (2H,m), 3.28-3.37 (4H,m),4·22 (2H,d,J=6.0 Hz), 6·49 (1H,d,J=5.6 Hz) , 6.71 (1H, d, J = 3.6 Hz), 7.17 (1H, dd, -410- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) '' ' 1304061 A7 -- ____ B7 V. INSTRUCTIONS (405) j=2.4, 8.8 Hz), 7.53 (1H, d, J=2.4 Hz), 7.64 (1H, s), 7.95 (1H, d, J=8.8 Hz), 8.26 (1H ,t,J=5.4 Hz),8·36 (1H,d,J=8.8 Hz),8·42 (1H,br s),8.69 (1H,d,J=5.6 Hz),8·81 (1H , s). Synthetic starting materials as described below. f ; Illustrative 3 03 - 1 6 - valine formazan (5) 哚-5 - a hydrogen third butyl $ carbonyl oxy-pyridin-4-one) methoxy 1 4呲 using 6-cyano-4-(1H-indol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)hexahydrop-p-but-4-yl)methoxy] The title compound (180 mg, 〇 316 为) was obtained as the colorless crystals from m. M, 44.74%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.18 (3H,t,J=7.〇Hz), 1.18-1.35 (2H,m),1·40 (9H,s),1·78- 1·82 (2H,m),2·16 (1H, m), 2·79 (2H,m), 3.32 (2H,q,J=7.0 Hz),3·98-4·02 (2H,m ), 4.18 (2H, d, J = 6.0 Hz), 6.48 (1H, d, J = 5.2 Hz), 6.70 (1H, d, J = 3.8 Hz), 7.18 (1H, dd, J = 2.4, 9·2 Hz), 7·52 (1H, d, J=2.4 Hz), 7.59 (1H, s), 7.93 (1H, d, J=3.8 Hz), 8.22 (1H, br* s), 8, 35 (1H,d,J=9.2 Hz), 8.68 (1H,d,J=5.2 Hz), 8.79 (1H, s). Example 304 6-3⁄4 base- 4-(1-ethylamine methyl carbazino-5-yl-milk-methylhexa-I-pyridin-4-yl)methyl gas &gt; quinoline using 6-cyano- 4-(1-ethylamine-methylindolyl-5-yloxy)-7-[(hexahydro-411 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding

1304061 A7 B7 五、發明説明（406) 吡啶-4-基）甲氧]喹啉（122 mg，〇·2598 mmol)，進行與實施 例302同樣之反應後，用NH型矽凝膠管柱層析（乙酸乙酯： 甲醇=10 : 1)精製。將得到之結晶懸浮於乙醇，用己烷稀 釋，濾取結晶，藉由吸引乾燥，得到為無色結晶之標題化 合物（28 mg，0.0579 mmol，22.29%)。 h-NMR 光譜（DMSO-d6)(5(ppm): ΐ·2〇 (3H，t，J=7 2 Hz)， 1·38-1·47 (2H，m)，1.78-1.93 (5H，m)，2.18 (3H，s)，2·8〇_ 2·84 (2H，m)，3·33-3·37 (2H，m)，4·η (2H，d，卜6 〇 Hz)， 6.49 (1H, d, J=5.2 Hz), 6.72 (1H5 d5 J，3.6 Hz), 7.20 (1H5 dd! 9.2 Hz), 7.54 (1H, d, J=2.4 Hz), 7.60 (1H) s) 7 95 (1H，d，J=3.6 Hz)，8.25 (1H，m)，8·37 (1H，d，J=9.〇 Hz)’，8 7〇 (1H，d，J=5.2 Hz), 8.80 (1H，s)。 ’ 實施例305 •氰基-4-Π-環丙墓胺甲醯基吲嘴= 4-基）曱負杏嗾 使用6-夜基- 4- (1-環丙基胺甲酶基叫嗓长 基氧）-7-[(1- (第三丁氧羰氧基）六氫吡啶-4-基）甲备Ί + 氧]嗜琳（965 mg， 1.6590 mmol)，以與實施例301同樣之士 4 L 、 万式，得到為淡黃色 結晶之標題化合物（962 mg，定量）。 iH-NMR 光譜（DMS046) 5 (ppm): 〇·6〇·〇 64 (2h ^ 0.74 (2H，m)，1.50-1.60 (2H，m)，ι·96 ) ，叫’ 0.71 Ο、2.〇〇 (2Η，m)，2.21 (1Η，m)，2.75-2.81 (1Η，m)，2.90-2 9R ^ 〜T 、 . * m)3 3.28-3.36 (2H, m), 4.21 (2H, d, J=6.0 Hz), 6.49 rm ,1TT 、H，d，&gt;5.2 Hz)，6.69 (1H，d，J=3.8 Hz), 7.19 (1H, dd，J二2·4 。 8.8 Hz), 7.52 (1H, -412 - 本故張尺度適用中國國家標準(CNS) A4規格（210 x 297公爱1 '〜·、〜' 1304061 〜 、 A7 _—___B7 五、發明説明（407) d, J=2.4 Hz), 7.64 (1H, s), 7.92 (1H, d, J=3.8 Hz), 8.33 (1H, m)，8·36 (1H，d，J=8.8 Hz)，8·51 (1H，br s)，8·69 (1H，d， J=5.2 Hz)，8.81 (1H，s)。 如下述合成起始原料。 芻造例301-1 6-氨1-環丙某胺甲醯某蜊哚某氧「n•(篥三 1羰氣基)六氫吡啶-4-某）甲氣1,杏毗 使用6_氰基- 4-( 1H-啕哚-5-基氧）-7- [( 1-(第三丁氧羰氧 基）六氫吡啶-4-基）甲氧]喹啉（ι·〇 g , 2.0056 mmol)及N-環 丙基胺基甲酸苯酯（426 mg)，藉由與實施例310同樣之方 式’付到為淡紅色結晶之標題化合物（9 6 5 m g，1.6 5 9 0 mmol，82.72%) 〇 iH-NMR 光譜（01^0-〇16)5(??111):0.59-0.64 (211，111)，0.71-0.76 (2H，m)，1·21-1·33 (2H，m)，1·40 (9H，s)，1.78-1.82 (2H， m)，2.07 (1Η，m)，2·40-2·70 (3Η，m)，3.95-4.15 (2Η，m)，4·18 (2H, d, J=6.0 Hz), 6.48 (1H, d, J=5.2 Hz)5 6.80 (1H, d, J=3.6 Hz)，7·19 (1H，dd，J=2.4 Hz, 8.8 Hz)，7.52 (1H，d，J=2.4 Hz)， 7·59 (1H，s)，7.90 (1H，d，J=3.6 Hz)，8.29 (1H，br s)，8.35 (1H，d，J=8.8 Hz)，8.68 (1H，d，Hz)，8.79 (1H，s)。 實施例306 6-氰基-4-Π-環丙基胺甲醯某巧哚-5-基氣）-7-「Π -甲基 氤吡啶-4-基）甲氣1崦啉 使用6-氰'基-4-( 1-環丙基胺甲醯基啕哚-5-基氧）-7-[(六 氫吡啶-4-基）甲氧]喹啉（862 mg，1.7900 mmol)，以與實施 -413 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱） A7 B7 1304061 五、發明説明（408) 例3 02同樣之方法，得到為無色結晶之標題化合物（335 mg，0.6760 mmol，37.76%) 0 1H-NMR 光譜（0^^〇-〇16)5(??111):0.59-0.64 (2氏111)，0.71-0·76 (2H，m)，1·35-1·45 (2H，m)，1·76-1·91 (5H，m)，2·16 (3H，s)，2·74-2·82 (3H，m)，4·15 (2H，d，J=6.0 Hz)，6·47 (1H， d, J=5,2 Hz)，6·68 (1H，d，J=3.8 Hz)，7.19 (1H，dd，J=2.4 Hz， 8·8 Hz)，7·52 (1H，d，J=2.4 Hz)，7·58 (1H，s)，7.90 (1H，d， J=3.8 Hz)，8·30 (1H，d，J=2.4 Hz)，8·35 (1H，d，J=8.8 Hz)， 8.68 (1H，d，J=5.2 Hz)，8.78 (1H，s)。 實施例307 6-氨基-7-K六氫吡啶-4-基）甲氣基l-4-「l-(2-達唑胺甲醯 基）钊哚-5-基氣啉 使用6-氰基- 4-[ 1-(2-噻唑胺甲醯基）啕哚-5-基氧]-7-[(1-(第三丁氧談氧基）六氫p比咬-4-基）甲氧]p奎琳（220 mg， 0.3522 mmol)，以與實施例301同樣之方式，得到為無色結 晶之標題化合物（114 mg，0.2136 mmol)。 1H-NMR 光譜（01^30-〇16)5(??111):1.50-1.60 (211，111)，1.97-2·01 (2H，m)，2.22 (1H，br s)，2.93-2.99 (2H，m)，3.31-3.37 (2H，m)，4·22 (2H，d，J=5.6 Hz)，6·53 (1H，d，J=5.2 Hz)，6.70 (1H，d，J=3.0 Hz)，7·09 (1H，d，J=4.2 Hz)，7.20 (1H，dd， J=2.4 Hz，8.8 Hz)，7·47 (1H，d，J=4.2 Hz)，7·53 (1H，d，J=2.4 Hz)，7.65 (1H，s)，8.09 (1H，d，J=3.0 Hz)，8.10-8.67 (1H，br s)，8·67 (I.H.，d，J=8.8 Hz)，8.70 (1H，d, J=5.2 Hz)，8.83 (1H， -414 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 〜 A7 _______B7 ____ 五、發明説明（4〇9) 如下述合成起始原料。 Μ造例307- 1 基-4-「1-(2-嘧唑胺甲醯甚w?丨唤-5-幕氫第三 氧羰氣基）六藍.吡啶-4-某）甲氲某1违啉 使用6-氰基-4-( 1H-啕哚-5-基氧）-7-[(1-(第三丁氧羰氧 基）六氫口比淀-4 -基）甲氧基]pr奎琳（3〇〇 mg，0.6017 mmol)， 氫化鈉（51 mg，1.2636 mmol，60%，在油中）及N-(2_喳唑 基）胺基甲酸苯g旨（146 mg，0.6619 mmol)，藉由與實施例 312同樣之反應，得到為淡黃色結晶之標題化合物（220 mg，0.3522 mmo卜 58.53%)。 H-NMR 光譜（DMSO-d6) 5 (ppm): 1.21-1.33 (2H，m)，1.39 (9H, s), 1.78-1.82 (2H, m), 2.06 (1H, m)5 2.78 (2H, m), 3.98-4.02 (2H，m)，4.17 (2H，d, J=6.4 Hz)，6.51 (1H，d，J=5.2 Hz)， 6·69 (1H, d，J=3.4 Hz)，7.08 (1H，d，J=4.6 Hz)，7·20 (1H，dd， J=2.4 Hz，9.2 Hz)，7·47 (1H，d，J=4.6 Hz)，7·53 (1H，d，J=2.4 Hz)，7.59 (1H，s)，8.08 (1H，d，J=3.4 Hz)，8·67 (1H，d，J=9.2 Hz)，8·69 (1H，d，J=5.2 Hz)，8.80 (1H，s)。 實施例308 6-氰某-7-ΓΠ -甲基六羡毗啶-4-基）甲氣某1-4-「1-(2-_岫 基胺曱醯基）啕哚-5-基氛啉 使用6-氨基-7-[(ττ風ρ比淀-4-基）甲氧]-4-[1-(2-σ塞唆胺 甲酿基）吲嗓-5-基氧]4：淋（104 mg，0.1982 mmol)，進行與 實施例302同樣之反應，藉NH矽凝膠管柱層析（乙酸乙醋·· 甲醇=10 : 1)精製，將得到之結晶懸浮於乙醇中，將其用己 -415 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱） 1304061 A7 B7 五、發明説明（41〇) 垸稀釋，濾取結晶，及藉由吸引乾燥，得到為無色結晶之 標題化合物（38 mg，0.0705 mmol，35.60%)。 lH-kMR 光譜（〇]\/[3〇-(16)(5(?0111):1.45-1.48(211，111)，1.83-!·95 (3Η, m), 2.08-2.15 (2H, m), 2.29 (3H, s), 2.93-2.96 (2H, m), 4.19 (2H, d, J=5.6 Hz), 6.53 (1H, d, J=5.2 Hz), 6.67 (1H, d，J=3:4 Hz)，7·01 (1H，d，J=4.4 Hz)，7.19 (1H，dd，J=2.4 Hz， 9·2 Hz)，7·42 (1H，d，J=4.4 Hz)，7·53 (1H，d，J=2.4 Hz)，7.62 UH，s)，7.81 (1H，d，J=3,4 Hz)，8.71 (1H，d，J=5.2 Hz)，8.73 (1H，d，J=9.2 Hz)，8·83 (1H，s)。 f施例309 將6-胺甲醯基-4-氯-7-甲氧基峻淋（2 〇 g，8 45〇9 mmol)，5-羥基啕哚（1.68 g)，二異丙基乙胺（2·2 ml)及N-曱基说咯啶酮（2.2 ml)混合，於150。(：加熱攪拌5小時。放冷 後將一部分固化反應溶液溶解於二甲基亞颯後，使其吸著 於NH型矽凝膠，用nh型矽凝膠管柱層析（乙酸乙酯：甲醇） 精製。將得到之結晶懸浮於乙醇中，將其用乙醚及己烷稀 釋’濾取結晶，用乙醚：己烷=1 : 5洗淨結晶，及藉由吸引 乾燥’得到為淡黃色結晶之標題化合物（1.2 9 1 g，3 β 8 6 9 8 mmol » 45.79%) 〇 1H-NMR 光譜（DMS〇-d6)c5(PPm): 4.02 (3H，s)，6·37 (1H，d， J=5.2 Hz), 6.46 (1H, br s)5 6.98 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.43-7.45 (2H，m)，7·48 (1H，s)，7·51 (1H，d，J=8.4 Hz)，7.71 〇H, br s), 7.84 (1H, br s), 8.58 (1H, d, J=5.2 Hz), 8.74 (1H, ___ - 416 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（411 s)，11·29 (1H，s) 〇 f施例3 10 t-胺甲醯基-4-Π-(2,4-二氣笨基胺甲醯某）-1H_ 4丨哚-5-某 氧1-7-甲氫某4说1304061 A7 B7 V. Inventive Note (406) Pyridin-4-yl)methoxy]quinoline (122 mg, 〇·2598 mmol), after the same reaction as in Example 302, using a NH-type ruthenium gel column It was purified by chromatography (ethyl acetate: methanol = 10:1). The obtained crystals were suspended in ethanol, diluted with hexanes, and crystals were crystallised eluted to afford crystals (yield: 28 mg, 0.0579 mmol, 22.29%). H-NMR spectrum (DMSO-d6) (5 (ppm): ΐ·2〇(3H, t, J=7 2 Hz), 1.38-1·47 (2H, m), 1.78-1.93 (5H, m), 2.18 (3H, s), 2·8〇_ 2·84 (2H, m), 3·33-3·37 (2H, m), 4·η (2H, d, Bu 6 〇 Hz) , 6.49 (1H, d, J=5.2 Hz), 6.72 (1H5 d5 J, 3.6 Hz), 7.20 (1H5 dd! 9.2 Hz), 7.54 (1H, d, J=2.4 Hz), 7.60 (1H) s) 7 95 (1H,d,J=3.6 Hz), 8.25 (1H,m),8·37 (1H,d,J=9.〇Hz)',8 7〇(1H,d,J=5.2 Hz) , 8.80 (1H, s). Example 305: Cyano-4-indole-cyclopropylamine methylmercaptopurine = 4-base) 曱 嗾 嗾 嗾 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 Long-formoxy)-7-[(1-(t-butoxycarbonyloxy)hexahydropyridin-4-yl)methyl oxime + oxy] lin (965 mg, 1.6590 mmol), same as Example 301 The title compound (962 mg, quantitative) was obtained as pale yellow crystals. iH-NMR spectrum (DMS046) 5 (ppm): 〇·6〇·〇64 (2h ^ 0.74 (2H, m), 1.50-1.60 (2H, m), ι·96 ), called '0.71 Ο, 2. 〇〇(2Η,m), 2.21 (1Η,m), 2.75-2.81 (1Η,m), 2.90-2 9R ^ 〜T , . * m)3 3.28-3.36 (2H, m), 4.21 (2H, d, J=6.0 Hz), 6.49 rm , 1TT , H, d, &gt; 5.2 Hz), 6.69 (1H, d, J = 3.8 Hz), 7.19 (1H, dd, J 2·4. 8.8 Hz) , 7.52 (1H, -412 - The original Zhang scale applies the Chinese National Standard (CNS) A4 specification (210 x 297 public love 1 '~·, ~' 1304061 ~, A7 _-___B7 V, invention description (407) d, J=2.4 Hz), 7.64 (1H, s), 7.92 (1H, d, J=3.8 Hz), 8.33 (1H, m), 8.36 (1H, d, J=8.8 Hz), 8·51 ( 1H, br s), 8·69 (1H, d, J = 5.2 Hz), 8.81 (1H, s). The starting material was synthesized as follows. 30Example 301-1 6-Ammonia 1-cyclopropylamine A醯 蜊哚 蜊哚 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧 氧-7-[(1-(Tertidinoxycarbonyloxy)hexahydropyridin-4-yl)methoxy]quinoline (ι·〇g, 2.0056 mmol) and N-cyclopropylaminocarbamate ( 426 The title compound (9 6 5 mg, 1.6 5 9 0 mmol, 82.72%) was obtained as a pale red crystal in the same manner as Example 310. 〇iH-NMR spectrum (01^0-〇16) 5(??111): 0.59-0.64 (211,111), 0.71-0.76 (2H,m),1·21-1·33 (2H,m),1·40 (9H,s),1.78-1.82 (2H, m), 2.07 (1Η, m), 2·40-2·70 (3Η, m), 3.95-4.15 (2Η, m), 4·18 (2H, d, J=6.0 Hz), 6.48 (1H, d, J=5.2 Hz)5 6.80 (1H, d, J=3.6 Hz), 7·19 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.52 (1H, d, J=2.4 Hz) ), 7·59 (1H, s), 7.90 (1H, d, J = 3.6 Hz), 8.29 (1H, br s), 8.35 (1H, d, J = 8.8 Hz), 8.68 (1H, d, Hz) ), 8.79 (1H, s). Example 306 6-Cyano-4-anthracene-cyclopropylamine formazan-5-base gas)-7-"Π-methylpyridin-4-yl)methane 1 porphyrin using 6- Cyanopyl-4-(1-cyclopropylaminecarbamimidin-5-yloxy)-7-[(hexahydropyridin-4-yl)methoxy]quinoline (862 mg, 1.7900 mmol), In the same manner as in the implementation of -413 - This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 public interest) A7 B7 1304061 V. Inventive Note (408) Example 3 02, the title compound is obtained as colorless crystals ( 335 mg, 0.6760 mmol, 37.76%) 0 1H-NMR spectrum (0^^〇-〇16)5(??111):0.59-0.64 (2 of 111), 0.71-0.76 (2H,m), 1·35-1·45 (2H,m),1·76-1·91 (5H,m),2·16 (3H,s),2·74-2·82 (3H,m),4· 15 (2H,d,J=6.0 Hz),6·47 (1H, d, J=5,2 Hz),6·68 (1H,d,J=3.8 Hz), 7.19 (1H,dd,J= 2.4 Hz, 8·8 Hz), 7·52 (1H, d, J=2.4 Hz), 7·58 (1H, s), 7.90 (1H, d, J=3.8 Hz), 8·30 (1H, d, J = 2.4 Hz), 8.35 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 5.2 Hz), 8.78 (1H, s). Example 307 6-Amino-7- K hexahydropyridin-4-yl)methyl group l-4- "1-(2-Dazozinylcarbenyl) indol-5-yl aeroline uses 6-cyano-4-[1-(2-thiazolylmethylindenyl)indole-5-yloxy]- 7-[(1-(T-butoxy)oxyhexanhydrop-pept-4-yl)methoxy]p-quine (220 mg, 0.3522 mmol) was obtained in the same manner as in Example 301. The title compound (114 mg, 0.2136 mmol) was obtained as colorless crystals. 1H-NMR spectrum (01^30-〇16)5 (??111): 1.50-1.60 (211,111), 1.97-2·01 (2H,m ), 2.22 (1H, br s), 2.93-2.99 (2H, m), 3.31-3.37 (2H, m), 4·22 (2H, d, J = 5.6 Hz), 6.53 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.0 Hz), 7·09 (1H, d, J=4.2 Hz), 7.20 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.47 (1H, d, J = 4.2 Hz), 7·53 (1H, d, J = 2.4 Hz), 7.65 (1H, s), 8.09 (1H, d, J = 3.0 Hz), 8.10-8.67 (1H, Br s),8·67 (IH,d,J=8.8 Hz), 8.70 (1H,d, J=5.2 Hz),8.83 (1H, -414 - This paper size applies to the Chinese National Standard (CNS) A4 specification ( 210 x 297 mm) 1304061 ~ A7 _______B7 ____ V. INSTRUCTIONS (4〇9) The starting materials were synthesized as follows. 307例例307- 1 base-4-"1-(2- thiazolylamine 醯 醯 w 丨 -5 -5 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 1 using a 6-cyano-4-(1H-indol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)hexahydroperoxy-p--4-yl) methoxy group Base]pr-quine (3〇〇mg, 0.6017 mmol), sodium hydride (51 mg, 1.2636 mmol, 60% in oil) and N-(2-carbazolyl) carbamic acid phenyl g (146 mg) The title compound (220 mg, 0.3522 mmol, 58.53%) was obtained as pale-yellow crystals. mp. 1.33 (2H, m), 1.39 (9H, s), 1.78-1.82 (2H, m), 2.06 (1H, m)5 2.78 (2H, m), 3.98-4.02 (2H, m), 4.17 (2H, d, J=6.4 Hz), 6.51 (1H, d, J=5.2 Hz), 6·69 (1H, d, J=3.4 Hz), 7.08 (1H, d, J=4.6 Hz), 7·20 ( 1H, dd, J=2.4 Hz, 9.2 Hz), 7·47 (1H, d, J=4.6 Hz), 7·53 (1H, d, J=2.4 Hz), 7.59 (1H, s), 8.08 ( 1H, d, J = 3.4 Hz), 8.67 (1H, d, J = 9.2 Hz), 8.69 (1H, d, J = 5.2 Hz), 8.80 (1H, s). Example 308 6- Cyanide-7-ΓΠ-A Hexa-pyridin-4-yl)methyl 1-4-"1-(2--mercaptoamine fluorenyl) indol-5-yl phenyl phenanthroline using 6-amino-7-[(ττ风ρ淀四-4-) methoxy]-4-[1-(2-σ serotoninyl) 吲嗓-5-yloxy] 4: leaching (104 mg, 0.1982 mmol), and examples 302 The same reaction was carried out by NH(R) gel column chromatography (acetic acid ethyl acetate·methanol = 10:1), and the obtained crystal was suspended in ethanol, and it was applied to the Chinese country with hex-415 - paper scale. Standard (CNS) A4 size (210 X 297 public) 1304061 A7 B7 V. Description of the invention (41〇) 垸Dilution, crystallization, and by suction drying to give the title compound (38 mg, 0.0705 mmol , 35.60%) lH-kMR spectrum (〇]\/[3〇-(16)(5(?0111):1.45-1.48(211,111),1.83-!·95 (3Η, m), 2.08- 2.15 (2H, m), 2.29 (3H, s), 2.93-2.96 (2H, m), 4.19 (2H, d, J=5.6 Hz), 6.53 (1H, d, J=5.2 Hz), 6.67 (1H , d, J=3:4 Hz), 7·01 (1H, d, J=4.4 Hz), 7.19 (1H, dd, J=2.4 Hz, 9·2 Hz), 7·42 (1H, d, J=4.4 Hz), 7·53 (1H, d, J=2.4 Hz), 7.62 UH, s), 7.81 (1H, d, J=3, 4 Hz), 8.71 (1H, d, J = 5.2 Hz), 8.73 (1H, d, J = 9.2 Hz), 8.83 (1H, s). f Example 309 6-Aminomethylmercapto-4-chloro-7-methoxysulfan (2 〇g, 8 45 〇 9 mmol), 5-hydroxyindole (1.68 g), diisopropyl B The amine (2.2 ml) and the N-mercapto rsqualonone (2.2 ml) were mixed at 150. (: heating and stirring for 5 hours. After cooling, a part of the curing reaction solution was dissolved in dimethyl hydrazine, and then sorbed on a NH-type hydrazine gel, and chromatographed with an nh-type hydrazine gel column (ethyl acetate: Methanol) was purified. The obtained crystals were suspended in ethanol, diluted with diethyl ether and hexanes, and the crystals were collected by filtration, washed with diethyl ether:hexane = 1:5, and dried by suction to give pale yellow crystals. The title compound (1.2 9 1 g, 3 β 8 6 9 8 mmol » 45.79%) 〇1H-NMR spectrum (DMS 〇-d6) c5 (PPm): 4.02 (3H, s), 6·37 (1H, d , J=5.2 Hz), 6.46 (1H, br s)5 6.98 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.43-7.45 (2H,m),7·48 (1H,s),7· 51 (1H,d,J=8.4 Hz), 7.71 〇H, br s), 7.84 (1H, br s), 8.58 (1H, d, J=5.2 Hz), 8.74 (1H, ___ - 416 - paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of invention (411 s), 11·29 (1H, s) 〇f Example 3 10 t-Aminomethylmercapto- 4-Π-(2,4-two gas stupylamine carbenium)-1H_ 4丨哚-5-an oxygen 1-7-methylhydrogen 4

將6-胺甲醯基-4-(1H-吲哚-5-基氧）-7-甲氧基喹啉（1〇〇 mg，0.3 mmol)溶於N，N-二甲基甲醯胺（0.5 ml)中，於冰冷 下加入氫化鈉（12 mg，0.3 mmol)，並於室溫攪掉15分鐘。 在其中加入N-(2,4-二氟苯基）胺基甲酸苯酯（79 mg，0.3150 mmol) ’並於室溫攪拌2小時。在反應溶液中加入水，用乙 酸乙酯及四氫呋喃萃取，用飽和食鹽水洗淨，用無水硫酸 鎂乾燥並將濾液減壓蒸餾。將得到之結晶懸浮於乙醇中， 將其用己烷稀釋後濾取結晶，用己烷洗淨結晶及吸引乾 燥’得到為無色結晶之標題化合物（84 mg，〇. 171 8 mmol， 57.28%)。Dissolving 6-amine-mercapto-4-(1H-indol-5-yloxy)-7-methoxyquinoline (1 mg, 0.3 mmol) in N,N-dimethylformamide (0.5 mg, 0.3 mmol) was added under ice-cooling (0.5 ml) and stirred at room temperature for 15 min. Phenyl N-(2,4-difluorophenyl)carbamate (79 mg, 0.3150 mmol) was added thereto and stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate and EtOAc. The obtained crystals are suspended in ethanol, and the crystals are diluted with hexane, and the crystals are crystallized, washed with hexanes, and dried to give the title compound (84 mg, y. 171 8 mmol, 57.28%). .

W-NMR 光譜（DMSO-d6)(5(ppm): 4·03 (3H，s)，6.45 (1H，J， J=5.2 Ηζ)，6·81 (1Η，d，J=3.8 Ηζ)，7·14-7·19 (1Η，m)，7.23 (1H，dd，J=2.4 Hz，8.8 Hz)，7.39-7.49 (1H，m)，7.51 (1H，s)， 7.50-7.58 (2H, m), 7.72 (1H, br s), 7.85 (1H, br s), 8.11 (1H, d, J=3.8 Hz), 8.32 (1H, d, J=8.8 Hz), 8.62 (1H, d, J=5.2 Hz), 8.73 (1H，s)，10.03 (1H，s)。 如下述合成起始原料。 率造例3 10-—1 2,4-二氣苯墓）胺某甲酸笨酯 將2,4-二氟苯胺（10 ml，98.21 mmol)溶於四氫呋喃（2〇〇 -417 - 國家標準(CNS) μ規格(210X297公釐) 1304061 ' A7 ____B7 ___ 五、發明説明（412) ml)中，在其中於室溫加入吡啶（8 7 ，108.33 mmol)及攪 拌。將其冰冷，經15分鐘滴入氯甲酸苯酯（13.6 ml，108.33 mmol)，然後於室溫攪拌24小時。在反應溶液中加入水， 用乙酸乙酯及四氫呋喃萃取，用飽和食鹽水洗淨，用無水 硫酸鎂乾燥並將濾液減壓蒸餾。將得到之結晶懸浮於乙醇 中’將其用己烷稀釋後濾取結晶，用己烷洗淨結晶，及吸 引乾燥後，得到為薄紫色結晶之標題化合物（21.00 g， 84·26 mmol，85.80%)。 iH-NMR 光譜（DMSO-d6) 5 (ppm): 7.05-7.12 (1H，m)，7·19 (2H，d，&gt;7·6 Hz)，7·24 (1H，t，J=7.6 Hz)，7.33 (1H，m)，7.41 (2H，t，J=7.6 Hz)，7·59-7·68 (1H，m)，9·91 (1H，br s)。實施例3 11 1-_胺甲醯基-4··[ 1 - (二氟苯基胺甲醯某）〗H_ P?|哚-5•其 氣1-7-甲氫某崦嗾使用6-胺曱酿基- 4-( 1H-喇哚-5 -基氧）_ 7-甲氧基4：琳（1〇〇 mg，0.3 mmol)及N-(4-氟苯基）胺基甲酸苯酯（86 mg)，進 行與實施例3 10同樣之反應，得到為無色結晶之標題化合物 (60 mg，0.1275 mmol，42.51%)。 iH-NMR 光譜（DMSO-d6)5(ppm)·· 4·03 (3H，s)，6·45 (1H d J=5.2 Ηζ)，6·79 (1Η，d，J=3.6 Ηζ)，7.21-7.26 (3Η，m)，7.51 (1H, s), 7.57 (1H, d, J=2.0 Hz), 7.67 (2H, dd, J=5.2 Hz, 8.8Hz)，7·73 (1H，br s)，7·85 (1H，br s)，8.13 (1H，d，J=3,6 Hz)， 8·33 (1H，d，J=8.8 Hz)，8·62 (1H，d，J=5.2 Hz)，8·73 (1H，s) 10·16 (1H，s)。 -418 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1304061 — A7 …___ —_B7____ 五、發明説明（413) 如下述合成起始原料。 製造例3 11 -1 N - (4 --一乱尽基）fe·幕甲酸笨醋 使用4-氟苯胺（5 m卜52.78 mmol)，藉由與製造例310-1 同樣之方法，得到為薄紫色結晶之標題化合物（10·03 1 g， 43.38 mmol，82·190/〇) 〇 iji-NMR 光譜（01^18〇-(16)5(卩卩111):7.13-7.27(511，111)，7.39-7·44 (2Η，m)，7.48-7.52 (2Η，m)，10.26 (1Η，s)。 音施例312 6- 胺甲醯基-4-「1- (2-唓峻基胺甲醯基）-1H- 41嗓-5 -基氲1 - 7- 甲氫基4:啉 將氫化鈉（50 mg，1.2524 mmol)懸浮於Ν，Ν·二曱基甲醯 胺（0·5 ml)中，在其中，於室溫加入Ν-(2,4-二氟苯基）胺基 甲酸苯酯（79 mg，0.3 150 mmol)，繼而加入6-胺甲醯基-4-(1H- W 哚-5-基氧）-7-甲氧喹啉（2〇〇 mg，0.5964 mmol), 然後’在室溫揽摔10小時。在其中加入水及飽和食鹽水， 用乙酸乙醋及四氫呋喃萃取，用飽和食鹽水洗淨，用無水 硫酸鎂乾燥並將濾液減壓蒸餾。使殘餘物吸著於矽凝膠， 然後付諸於矽凝膠管柱層析（己烷-四氫吱喃）。將得到之結 晶用1滴二甲基亞颯濕潤後，懸浮於乙醇及濾取結晶，用乙 酵洗淨結晶及吸引乾燥後’得到為淡黃色結晶之標題化合 物（138 mg，0.3003 mmol，50.36%) 〇 iH-NMR 光譜（DMS〇-d6)5(Ppm): 4·03 (3H，s)，6 46 (1H，d J-5.2 Hz)，6.69 (1H，d，J=3,6 Hz)，7.09 (1H，d，j=4 4 hz)， -419 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 x 297公釐） 1304061 A7 B7W-NMR spectrum (DMSO-d6) (5 (ppm): 4·03 (3H, s), 6.45 (1H, J, J = 5.2 Ηζ), 6.81 (1 Η, d, J = 3.8 Ηζ), 7·14-7·19 (1Η, m), 7.23 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.39-7.49 (1H, m), 7.51 (1H, s), 7.50-7.58 (2H, m), 7.72 (1H, br s), 7.85 (1H, br s), 8.11 (1H, d, J=3.8 Hz), 8.32 (1H, d, J=8.8 Hz), 8.62 (1H, d, J = 5.2 Hz), 8.73 (1H, s), 10.03 (1H, s). The starting material was synthesized as follows. Rate Example 3 10-1 2,4-di-benzene benzene tomb) Amine acid cumyl ester 2 , 4-difluoroaniline (10 ml, 98.21 mmol) dissolved in tetrahydrofuran (2〇〇-417 - National Standard (CNS) μ size (210X297 mm) 1304061 ' A7 ____B7 ___ V. Description of invention (412) ml) Pyridine (8 7 , 108.33 mmol) was added thereto at room temperature and stirred. It was ice-cooled, and phenyl chloroformate (13.6 ml, 108.33 mmol) was added dropwise over 15 minutes, and then stirred at room temperature for 24 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate and EtOAc. The obtained crystals are suspended in ethanol. The crystals are diluted with hexane, and the crystals are filtered, washed with hexane, and dried to give the title compound (21.00 g, 84.26 mmol, 85.80. %). iH-NMR spectrum (DMSO-d6) 5 (ppm): 7.05-7.12 (1H, m), 7·19 (2H, d, &gt; 7·6 Hz), 7·24 (1H, t, J=7.6 Hz), 7.33 (1H, m), 7.41 (2H, t, J = 7.6 Hz), 7·59-7·68 (1H, m), 9·91 (1H, br s). Example 3 11 1-_Aminomethylmercapto-4··[ 1 - (difluorophenylamine methyl hydrazine) 〗 H_ P?|哚-5• Its gas 1-7-methylhydrogen hydrazine uses 6 -amine aryl- 4-(1H-rhodium-5-yloxy)-7-methoxy 4:lin (1 mg, 0.3 mmol) and N-(4-fluorophenyl)urethane The title compound (60 mg, 0.1275 mmol, 42.51%) was obtained. iH-NMR spectrum (DMSO-d6) 5 (ppm)·· 4·03 (3H, s), 6·45 (1H d J=5.2 Ηζ), 6.79 (1Η, d, J=3.6 Ηζ), 7.21-7.26 (3Η,m), 7.51 (1H, s), 7.57 (1H, d, J=2.0 Hz), 7.67 (2H, dd, J=5.2 Hz, 8.8Hz), 7.73 (1H, br s),7·85 (1H,br s),8.13 (1H,d,J=3,6 Hz), 8·33 (1H,d,J=8.8 Hz),8·62 (1H,d,J =5.2 Hz), 8.73 (1H, s) 10·16 (1H, s). -418 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1304061 — A7 ... ___ — _B7____ V. Inventive Note (413) The starting materials are synthesized as follows. Production Example 3 11 -1 N - (4 - a chaotic base) Fe. Curcummic acid acetal was obtained by the same method as in Production Example 310-1 using 4-fluoroaniline (5 m, 52.78 mmol). The title compound of thin purple crystals (10·03 1 g, 43.38 mmol, 82·190/〇) 〇iji-NMR spectrum (01^18〇-(16)5(卩卩111):7.13-7.27(511,111 ), 7.39-7·44 (2Η, m), 7.48-7.52 (2Η, m), 10.26 (1Η, s). Example 312 6-Aminomethyl-4-yl-1-"2-唓胺 醯 ) ) -1 -1 - - - - - - - - - - - - - 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化 氢化· 5 ml), in which phenyl-(2,4-difluorophenyl)carbamate (79 mg, 0.3150 mmol) was added at room temperature, followed by the addition of 6-aminomethylindol-4- (1H-W 哚-5-yloxy)-7-methoxyquinoline (2 〇〇 mg, 0.5964 mmol), then 'fall at room temperature for 10 hours. Add water and saturated brine, use acetic acid The vinegar and tetrahydrofuran were extracted, washed with saturated brine, dried over anhydrous magnesium sulfate and the filtrate was evaporated under reduced pressure. The residue was applied to a gel and then applied to a gel. Column chromatography (hexane-tetrahydrofuran). The obtained crystals were wetted with 1 drop of dimethyl hydrazine, suspended in ethanol and filtered to crystallize, washed with ethyl acetate and dried and attracted to dryness. The title compound (138 mg, 0.3003 mmol, 50.36%) 〇iH-NMR spectrum (DMS 〇-d6) 5 (Ppm): 4·03 (3H, s), 6 46 (1H, d J-5.2 Hz), 6.69 (1H, d, J=3, 6 Hz), 7.09 (1H, d, j=4 4 hz), -419 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297) PCT) 1304061 A7 B7

五、發明説明（414) 7.20 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.47 (1H, d, J=4.4 Hz), 7.51 (1H, s), 7.52 (1H, d, J=2.4 Hz), 7.73 (1H, br s), 7.86 (lH, br s)，8.08 (1H，d，J=3.6 Hz)，8·62 (1H，d，J=5.2 Hz)，8.67 (lH, d，J=8.8 Hz)，8·74 (1H，s)，13.16 (1H，s)。 實施例313 胺甲基丙基胺•㈣哚基氳1 氧口奎口林 使用6-胺甲醯基- 4-( 1 Η-啕嗓-5 -基氧）-7-甲氧4淋（1〇〇 g，0.3 mmol)及N-(4-氟苯基）胺基甲酸苯酯（56 mg),造行 與實施例3 10同樣之反應，得到為無色結晶之標題化合物 (35 mg » 0.0840 mmol » 28.02%) 〇 1H-NMR 光譜（DMSO-d6)5(ppm): 0.62 (2H，m)，0.73 (2H，m)， 2.78 (1H，m)，4.02 (3H，s)，6.42 (1H，d，J=5.2 Hz)，6·68 (1H， d，J=3.2 Hz)，7·18 (1H，d，J=9.0 Hz)，7.50 (2H，m)，7.73 (1H， s)，7·85 (1H，s)，7.89 (1H，d，J=3.2 Hz)，8.30 (1H，s)，8.34 (1H，d，J=9.0 Hz)，8·61 (1H，d，J=5.2 Hz)，8.72 (1H，s)。 如下述合成起始原料e 製造例313-1 N-環丙某胺基甲酸笨酯V. INSTRUCTIONS (414) 7.20 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.47 (1H, d, J=4.4 Hz), 7.51 (1H, s), 7.52 (1H, d, J=2.4 Hz), 7.73 (1H, br s), 7.86 (lH, br s), 8.08 (1H, d, J = 3.6 Hz), 8.62 (1H, d, J = 5.2 Hz), 8.67 (lH, d , J = 8.8 Hz), 8.74 (1H, s), 13.16 (1H, s). Example 313 Aminomethylpropylamine • (IV) Mercaptopurine 1 Oxygen port queryrin using 6-aminocarbazino-4-(1 Η-啕嗓-5-yloxy)-7-methoxy 4 ( The title compound (35 mg) was obtained as a colorless crystals. 0.0840 mmol » 28.02%) 〇1H-NMR spectrum (DMSO-d6) 5 (ppm): 0.62 (2H, m), 0.73 (2H, m), 2.78 (1H, m), 4.02 (3H, s), 6.42 (1H, d, J = 5.2 Hz), 6.68 (1H, d, J = 3.2 Hz), 7·18 (1H, d, J = 9.0 Hz), 7.50 (2H, m), 7.73 (1H, s), 7.85 (1H, s), 7.89 (1H, d, J = 3.2 Hz), 8.30 (1H, s), 8.34 (1H, d, J = 9.0 Hz), 8.61 (1H, d , J = 5.2 Hz), 8.72 (1H, s). Synthetic starting material e as described below. Production Example 313-1 N-cyclopropylaminomethanecarboxylate

装 訂Binding

線 使用環丙胺（3 ml ’ 43.29 mmol)進行與製造例3 ι〇_ 1同樣 之反應，將4于到之結晶懸洋於乙酸·己燒=1 : 2，減取|士 晶，用乙醚：己烷==1 : 2洗淨，藉由吸引乾燥，得到為淡黃 色結晶之標·題化.合物（5.832 g，32·9 1 mmol，76.03%)。 iH-NMR 光譜（CDCl3)5(Ppm): 0.60-0.65 (2H，m)，〇·7&quot;8〇 -420 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 '， A7 ^__ B7 五、發明説明（415) (2H, m), 2.69 (1H, br s), 5.23 (1H, br s), 7.13 (2H, d, J=7.6 Hz), 7.19 (1H, t5 1=7.6 Hz), 7.35 (2H, t, J=7.6 Hz) 〇 實施例314 胺甲酿基土.11-(2二乙基胺甲歐吲哚_5·某氪^ 7-曱氫基崦啉 實施Θ 3 1 5 U 1 - (2-氣腔^^!-出二啕隻二^某氫16· Γ 2_ # Λ葚 遞胺甲醯基）-_7-甲氯甚 使用6-胺甲醯基-4-(1Η-吲哚-5-基氧）_7•曱氧基喹啉（8〇〇 mg，2.3 998 mmol)，氫化鈉㈠ 〇4 mg , 2 5918 mm〇1)及 Ν· (2-氟乙基）胺基甲酸苯酯（483 mg , 2 6398 mm〇1),進行與 實施例310同樣之反應，用乙酸乙酯及四氫呋喃萃取，用飽 和食鹽水洗淨’用無水硫酸鎂乾燥並減壓餾去溶媒。使殘 餘物吸著於矽凝膠，然後付諸於矽凝膠管柱層析（乙酸乙 醋·四氫吱喃·甲醇），除去原料後，再使所得者吸著於 ΝΗ型矽凝膠，及付諸於ΝΗ型矽凝膠管柱層析（乙酸乙酯· 四氫呋喃·甲醇系），得到分別為低極性及高極性之化合 物。將其分別懸浮於乙醇，並用己烷稀釋。濾取結晶，用 己烷洗淨結晶及吸引乾燥後，得到為無色結晶之低極性化 合物4-[ 1-(2-氟乙基胺甲醯基）-n吲哚-5-基氧]-6-(2-氟 乙基脉胺甲酿基）-7-甲乳基峻琳（49 mg，0.0958 mmol， 3.99%);以及為淡黃色結晶之高極性化合物6-胺甲酿基- 4-[1-(2-氟乙基腠甲醯基丨哚-5-基氧]-7-甲氧基喹啉 (632 mg，1.4961 mmol » 62.34%) ° -421 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜 A7 '· B7 ------*-- 五、發明説明（416) 低極性（實施例315) lH-NMR 光譜（DMSO-d6)占（ppm): 3.59 (4H，m)，4.01 (3H，s)， 4.47 (1H，m)，4.53 (1H，m)，4.59 (1H，m)，4.65 (1H，m)，6 46 (1H，d，J=4.4 Hz)，6·73 (1H，d，J=2.0 Hz)，7,19 (1H，d，J=8 8 Hz)，7·53 (2H，s)，7.97 (1H，d，J=2.0 Hz)，8·35 (1H，d，J=8 8 Hz)，8」0 (1H，m)，8·51 (1H，s)，8·63 (1H，m)，8·64 (ih，d J=4.4 Hz)，10.62 (1H，s)。 高極性（.實施例314)The line was reacted with cyclopropylamine (3 ml '43.29 mmol) in the same manner as in Production Example 3 ι〇_1, and 4 crystals were suspended in acetic acid, hexane = 1 : 2 , minus | :hexane = 1:1: 2 Washed, and dried by suction to give the title compound (5.832 g, 32·9 1 mmol, 76.03%) as pale yellow crystals. iH-NMR spectrum (CDCl3) 5 (Ppm): 0.60-0.65 (2H, m), 〇·7&quot;8〇-420 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 ', A7 ^__ B7 V. INSTRUCTIONS (415) (2H, m), 2.69 (1H, br s), 5.23 (1H, br s), 7.13 (2H, d, J=7.6 Hz), 7.19 ( 1H, t5 1 = 7.6 Hz), 7.35 (2H, t, J = 7.6 Hz) 〇 Example 314 Amine-based base soil. 11-(2 diethylaminomethyl guanidine _5· 氪^ 7- Hydrazine-based porphyrins are carried out Θ 3 1 5 U 1 - (2-air cavity ^^!- out of two 啕 only two ^ a hydrogen 16 · Γ 2_ # Λ葚 胺 醯 ) )) -_7-methyl chloride even use 6-Aminomercapto-4-(1Η-吲哚-5-yloxy)_7•decyloxyquinoline (8〇〇mg, 2.3 998 mmol), sodium hydride (I) 〇4 mg , 2 5918 mm〇1 And phenyl (2-fluoroethyl) carbamic acid phenyl ester (483 mg, 2 6398 mm 〇 1), the same reaction as in Example 310, and ethyl acetate and tetrahydrofuran were extracted and washed with saturated brine. Drying with anhydrous magnesium sulfate and distilling off the solvent under reduced pressure. The residue was sorbed on a ruthenium gel, and then applied to a gel column chromatography (acetic acid ethyl acetate, tetrahydrofuran, methanol) to remove the raw materials, and then the resultant was sorbed on a ΝΗ-type gel. And it was applied to a gel column chromatography (ethyl acetate, tetrahydrofuran, methanol) to obtain compounds having low polarity and high polarity, respectively. They were separately suspended in ethanol and diluted with hexane. The crystals were collected by filtration, washed with hexanes, and then dried to afford crystals of 4-[1-(2-fluoroethylamine-carbamoyl)-n-5-yloxy]- 6-(2-Fluoroethyl sulphate)-7-Methyl carbaryl (49 mg, 0.0958 mmol, 3.99%); and a highly polar compound 6-amine-branthyl- 4 -[1-(2-Fluoroethylindenylindol-5-yloxy]-7-methoxyquinoline (632 mg, 1.4961 mmol » 62.34%) ° -421 - This paper size applies to China Standard (CNS) A4 size (210 X 297 mm) 1304061 ~ A7 '· B7 ------*-- V. Description of invention (416) Low polarity (Example 315) lH-NMR spectrum (DMSO-d6 ) (ppm): 3.59 (4H, m), 4.01 (3H, s), 4.47 (1H, m), 4.53 (1H, m), 4.59 (1H, m), 4.65 (1H, m), 6 46 (1H, d, J = 4.4 Hz), 6.73 (1H, d, J = 2.0 Hz), 7, 19 (1H, d, J = 8 8 Hz), 7·53 (2H, s), 7.97 (1H,d,J=2.0 Hz),8·35 (1H,d,J=8 8 Hz), 8”0 (1H,m),8·51 (1H,s),8·63 (1H, m), 8·64 (ih, d J=4.4 Hz), 10.62 (1H, s). High polarity (. Example 314)

1H-NMR 光譜（DMSO-d6)5(ppm): 3·56 (1H，dt，J=5.〇 Hz，5 〇 Hz)，3.63 (1H，dt，J=5.0 Hz，5.0 Hz)，4.02 (3H，s)，4·53 (1H t, J=5.0 Hz), 4.65 (1H, t, J=5.0 Hz), 6.43 (1H, d, J-5.2 Hz) 6·73 (1H, d，J=3.8 Hz)，7.19 (1H，dd，J=2.4 Hz，8·8 HZ)，7·5〇 (1H，s)，7·52 (1H，d，J=2.4 Hz)，7·72 (1H，br s)，7.85 (ih，br s)，7.98 (1H，d，J=3.8 Hz)，8.35 (1H，d，J=8.8 Hz)，8.49 (1H t，J=5.0 Hz)，8·61 (1H，d，J=5.2 Hz)，8·72 (1H，s)。 如下述合成起始原料。 製造例314-1 N-(2-氟乙基）胺某甲酸茉酯 將2-氟乙胺（0.5 g，5.0321 mmol)溶於二甲基甲酿胺（1〇 ml)，於室溫加入吡啶（0.87 ml，10.5674 mmol)並攪拌。將 其冰冷’滴入氯甲酸苯酯（0.67 ml，5·2837 mm〇1)，滴入終 了後於室溫攪拌2.5小時。在反應液中加入水，用乙酸乙醋 萃取，用飽·和食鹽水洗淨，用無水硫酸鎂乾燥及減壓餾去 溶媒。殘餘物用矽凝膠管柱層析（己烷：乙酸乙酯=2 : ”精 -422 - 本紙張尺度適用中國國各標準(CNS) A4規格(210 X 297公爱) —&quot; '~ -:— 1304061 -- A7 … ___ B7 五、發明説明（417) 製，得到為淡黃色結晶之標題化合物（0.797 g，4.3509 mmol，86.46%) 0 iH-NMR 光譜（CDCl3)5(ppm)·· 3.55 (1H，q，J=4.8 Ηζ)，3·62 (1H，q，J=4.8 Hz)，4·51 (1H，t，J=4.8 Hz)，4·62 (1H，t，J=4.8 Hz)，5.39 (1H，br s)，7·13 (2H，d，J=7.6 Hz)，7.21 (1H，t， &gt;7·6 kz)，7·37 (2H，t，J=7.6 Hz)。 f施例3 1 6 k胺甲醯基-4-(1-乙基胺甲醯某-1H-㈤哚-5-基氣）-7-甲氧 基口奎淋 實施例3 17 i^l-乙基胺甲醯基-1H-吲哚-5-某氫）-6-乙基脲胺甲醯甚 7-甲氣基4啉 將6-胺甲醯基-4-( 1H-吲哚-5-基氧）-7-甲氧基喹啉（1.2 g，3.6141 mmol)，N-4-乙基胺基甲酸苯酯（822 mg， 4.9761 mmol)及氫化納（195 mg，4.8799 mmol)進行與實施 例3 10同樣之反應，得到各為無色結晶之低極性化合物4-(1-乙基胺甲醯基-1H-吲哚-5-基氧）-6-乙基脲胺甲醯基-7-甲氧基喹啉（105 mg，0.220 8 mmol，6.11%)以及高極性化 合物6 -胺甲酿基-4 - ( 1 -乙基胺甲酿基-1Η - 丨。木-5 -基氧）-7 · 甲氧基 口奎淋（506 mg，1.2511 mmol，34.62%)。 低極性（實施例317) lH-NMR 光譜（DMS〇-d6)5(ppm): 1·11 (3H，t，J=7.2 Hz)， 1.77 (3H, t, J=7；2 Hz), 3.23 (2H, q, J=7.2 Hz), 3.29 (2H, q, J=7.2 Hz), 4.01 (3H, s), 6.45 (1H, d, J=5.2 Hz), 6.70 (1H, d, 猶 423 -_ 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 1304061 :〜 '.· A7 ___B7 五、發明説明（418) J=3.6 Hz), 7.17 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.51 (1H, d, J=2.4 Hz)，.7.52 (1H，s)，7.93 (1H，d，J=3.6 Hz)，8·24 (1H，t， J=5.6 Hz), 8.35 (1H, d, J=8.8 Hz), 8.44 (1H5 m), 8.52 (1H, s), 8·64 (1H，d，J=5.2 Hz), 10.46 (1H，s)。 高極性（實施例3 1 6) h-NMR 光譜（DMSO-d6)5(Ppm): 1.18 (3H，t，J=7.2 Hz)， 3.32 (2H，q，J=7.2 Hz)，4·02 (3H，s)，6·42 (1H，d，J=5.2 Hz)， 6.70 (1H，d，J=3.6 Hz)，7.17 (1H，dd，J=2.4 Hz，8·8 Hz)，7.50 (1H，s)，7_51 (1H，d，J=2.4 Hz)，7.71 (1H，br s)，7·84 (1H，br s)5 7.93 (1H，d，J=3.6 Hz)，8.23 (1H，t，J=5.6 Hz)，8·34 (1H， d，J=8.8 Hz)，8·61 (1H，d，J=5.2 Hz)，8.72 (1H，s)。 如下述合成起始原料。 製造例316-1 N-乙基胺基甲酸苯酯 使用乙胺鹽酸鹽（20.3 g，0.25 mol)進行與製造例310-1同 樣之反應，將得到之結晶懸浮於己烷中，濾取結晶，用己 烷洗淨及吸引乾燥，得到為無色結晶之標題化合物（33.33 g，0.2018 mol，80.71%) 〇 iH-NMR 光譜（CDCl3)5(ppm): 1·21 (3H，t，J=7.2 Hz)，3.31 (2H5 m)5 5.02 (1H, br s), 7.12 (2H, d5 J=7.6 Hz)3 7.19 (1H, t, J=7.6 Hz)，7.35 (2H，t，J=7.6 Hz)。 實施例3 1 8 6-胺甲醯‘基~-7-甲氣某-4-Π -丙基胺甲疫基-1H-峭哚-5-某 氧）口奎g林 -424 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜 A7 ________357_ 五、發明説明（419) 實施例3 1 9 甲氧基丙基_胺甲醯某-1H-W哚-5-某氬）-6-丙某胧 胺甲醯基喹啉 將6-胺甲醯基-4-(1H-W哚-5-基氧）-7-甲氧基喹啉（400 mg，1.2 mmol)，N-正丙基胺基甲酸苯酯（237 mg，1.3199 mmol)·及風化鋼（55 mg，1.3199 mmol)進行與實施例310同 樣之反應’仔到各為淡黃色結晶之低極性化合物7 -甲氧基_ 4-(1-丙基胺甲醯基-1H-嘀哚-5-基氧）-6-丙基脲胺甲醯基 喹啉（49 mg，0.0973 mmol，8.11%)以及高極性化合物6-胺甲醯基-7-甲氧基-4-(1-正丙基胺甲醯基-1H-4哚-5-基 氧）口奎淋（218 mg，0.5210 mmol，43.41%)。 低極性（實施例319) iH-NMR 光譜（DMSO-d6) 5 (ppm): 0.89 (3H，t，J=7.2 Hz)， 0·91 (3H，t，J=7.2 Hz)，1·51 (2H，q，J=7.2 Hz)，1·59 (2H，q， J=7.2 Hz), 3.18 (2H, t, J=7.2 Hz), 3.25 (2H, t5 J=7.2 Hz), 4.02 (3H，s)，6.45 (1H，d，J=5.2 Hz)，6·70 (1H，d，J=3.6 Hz)， 7.27 (1H, dd5 J=2A Hz, 8.8 Hz), 7.51 (1H, d, J=2.4 Hz), 7.52 (1H，s)，7·95 (1H，d，J=3.6 Hz)，8·22 (1H，m)，8.34 (1H，d， J=8.8 Hz)，8·47 (1H，br s)，8.54 (1H，s)，8·64 (1H，d，J=5.2 Hz)，10.45 (1H，s)。 高極性（實施例318) h-NMR 光譜（DMSO-d6)(5(ppm): 0.92 (3H，t，J=7.2 Hz)， 1.58 (2H, q； J=7,2 Hz), 3.24 (2H, q, J=7.2 Hz), 4.02 (3H, s), 6.42 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.6 Hz), 7.17 (1H, dd, -425 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 裝 訂1H-NMR spectrum (DMSO-d6) 5 (ppm): 3·56 (1H, dt, J=5.〇Hz, 5 〇Hz), 3.63 (1H, dt, J=5.0 Hz, 5.0 Hz), 4.02 (3H, s), 4·53 (1H t, J=5.0 Hz), 4.65 (1H, t, J=5.0 Hz), 6.43 (1H, d, J-5.2 Hz) 6.73 (1H, d, J=3.8 Hz), 7.19 (1H, dd, J=2.4 Hz, 8·8 HZ), 7·5〇(1H, s), 7·52 (1H, d, J=2.4 Hz), 7.72 (1H, br s), 7.85 (ih, br s), 7.98 (1H, d, J = 3.8 Hz), 8.35 (1H, d, J = 8.8 Hz), 8.49 (1H t, J = 5.0 Hz), 8·61 (1H, d, J=5.2 Hz), 8.72 (1H, s). The starting materials were synthesized as described below. Production example 314-1 N-(2-Fluoroethyl)amine a certain methyl methacrylate 2-fluoroethylamine (0.5 g, 5.0321 mmol) was dissolved in dimethyl amide (1 〇ml) and added at room temperature. Pyridine (0.87 ml, 10.5674 mmol) and stirred. This was ice-cooled into phenyl chloroformate (0.67 ml, 5·2837 mm 〇1), and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with EtOAc EtOAc. The residue was chromatographed on a gel column (hexane: ethyl acetate = 2: s) - 422 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) -&quot; '~ -: - 1304061 - A7 ... ___ B7 5. Inventive (417), the title compound (0.797 g, 4.3509 mmol, 86.46%) obtained as pale yellow crystals. iH-NMR spectrum (CDCl3) 5 (ppm) · 3.55 (1H, q, J=4.8 Ηζ), 3·62 (1H, q, J=4.8 Hz), 4·51 (1H, t, J=4.8 Hz), 4·62 (1H, t, J =4.8 Hz), 5.39 (1H, br s), 7·13 (2H, d, J = 7.6 Hz), 7.21 (1H, t, &gt; 7·6 kz), 7·37 (2H, t, J =7.6 Hz) f Example 3 1 6 k-aminomethylmercapto-4-(1-ethylamine-methylhydrazine-1H-(penta)-5-yl gas)-7-methoxy hydroxyquinone Example 3 17 i^l-ethylamine-mercapto-1H-indole-5-hydrogen-6-ethylureaaminecarboxamide-7-methylphenoline 4-pheneline 6-amine-mercapto-4- (1H-Indol-5-yloxy)-7-methoxyquinoline (1.2 g, 3.6141 mmol), phenyl N-4-ethylcarbamate (822 mg, 4.9761 mmol) and sodium hydride (195) Mg, 4.8799 mmol) The same reaction as in Example 3 10 was carried out to obtain low polarities each of which was colorless crystals. Compound 4-(1-Ethylaminomethylhydrazino-1H-indole-5-yloxy)-6-ethylureacarbamoyl-7-methoxyquinoline (105 mg, 0.220 8 mmol, 6.11 %) and the highly polar compound 6-amine-mercapto-4 - (1-ethylamine-mercapto-1Η-丨.木-5-yloxy)-7 ·methoxy quinine (506 mg, 1.2511 M, 34.62%). Low polarity (Example 317) lH-NMR spectrum (DMS 〇-d6) 5 (ppm): 1·11 (3H, t, J = 7.2 Hz), 1.77 (3H, t, J= 7;2 Hz), 3.23 (2H, q, J=7.2 Hz), 3.29 (2H, q, J=7.2 Hz), 4.01 (3H, s), 6.45 (1H, d, J=5.2 Hz), 6.70 (1H, d, 423-_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 :~ '.· A7 ___B7 V. Invention description (418) J=3.6 Hz), 7.17 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.51 (1H, d, J=2.4 Hz), .7.52 (1H, s), 7.93 (1H, d, J=3.6 Hz), 8·24 ( 1H,t, J=5.6 Hz), 8.35 (1H, d, J=8.8 Hz), 8.44 (1H5 m), 8.52 (1H, s), 8·64 (1H,d,J=5.2 Hz), 10.46 (1H, s). High polarity (Example 3 1 6) h-NMR spectrum (DMSO-d6) 5 (Ppm): 1.18 (3H, t, J = 7.2 Hz), 3.32 (2H, q, J = 7.2 Hz), 4·02 (3H, s), 6.42 (1H, d, J = 5.2 Hz), 6.70 (1H, d, J = 3.6 Hz), 7.17 (1H, dd, J = 2.4 Hz, 8·8 Hz), 7.50 (1H, s), 7_51 (1H, d, J = 2.4 Hz), 7.71 (1H, br s), 7.84 (1H, br s) 5 7.93 (1H, d, J = 3.6 Hz), 8.23 ( 1H, t, J = 5.6 Hz), 8·34 (1H, d, J = 8.8 Hz), 8.61 (1H, d, J = 5.2 Hz), 8.72 (1H, s). The starting materials were synthesized as described below. Production Example 316-1 N-ethylcarbamic acid phenyl ester The same reaction as in Production Example 310-1 was carried out using ethylamine hydrochloride (20.3 g, 0.25 mol), and the obtained crystals were suspended in hexane and filtered. Crystallization, washing with hexanes and EtOAc (EtOAc:EtOAc:jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj =7.2 Hz), 3.31 (2H5 m)5 5.02 (1H, br s), 7.12 (2H, d5 J=7.6 Hz)3 7.19 (1H, t, J=7.6 Hz), 7.35 (2H, t, J= 7.6 Hz). Example 3 1 8 6-Aminomethyl hydrazide '~7-Methane -4- Π propyl acetaminophen-1H- 哚-5-an oxygen) mouth quinine g-424 - paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ~ A7 ________357_ V. Description of the invention (419) Example 3 1 9 methoxypropyl-amine methyl hydrazine-1H-W哚-5 - argon)-6-propanylguanidinomethylquinoline 6-Aminomethylmercapto-4-(1H-W哚-5-yloxy)-7-methoxyquinoline (400 mg, 1.2 Methyl) N-n-propyl propyl carbamate (237 mg, 1.3199 mmol) and weathered steel (55 mg, 1.3199 mmol) were subjected to the same reaction as in Example 310, to the low polarity of each of the pale yellow crystals. Compound 7-Methoxy-4-(1-propylaminecarbamido-1H-indol-5-yloxy)-6-propylureacarbamicinylquinoline (49 mg, 0.0973 mmol, 8.11% And the highly polar compound 6-aminoformamido-7-methoxy-4-(1-n-propylaminecarbomethyl-1H-4哚-5-yloxy) quinine (218 mg, 0.5210 mmol) , 43.41%). Low polarity (Example 319) iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.89 (3H, t, J = 7.2 Hz), 0·91 (3H, t, J = 7.2 Hz), 1. 51 (2H,q,J=7.2 Hz),1·59 (2H,q, J=7.2 Hz), 3.18 (2H, t, J=7.2 Hz), 3.25 (2H, t5 J=7.2 Hz), 4.02 ( 3H, s), 6.45 (1H, d, J = 5.2 Hz), 6.70 (1H, d, J = 3.6 Hz), 7.27 (1H, dd5 J=2A Hz, 8.8 Hz), 7.51 (1H, d , J=2.4 Hz), 7.52 (1H, s), 7.95 (1H, d, J=3.6 Hz), 8·22 (1H, m), 8.34 (1H, d, J=8.8 Hz), 8 · 47 (1H, br s), 8.54 (1H, s), 8.64 (1H, d, J = 5.2 Hz), 10.45 (1H, s). Highly polar (Example 318) h-NMR spectrum (DMSO-d6) (5 (ppm): 0.92 (3H, t, J = 7.2 Hz), 1.58 (2H, q; J = 7, 2 Hz), 3.24 ( 2H, q, J=7.2 Hz), 4.02 (3H, s), 6.42 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.6 Hz), 7.17 (1H, dd, -425 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) binding

1304061 、 ' ' A7 __ B7 五、發明説明（42〇) J=2.4 Hz, 8.8 Hz), 7.50 (1H, s), 7.51 (1H, d3 J=2.4 Hz), 7.72 (1H, br s),.7.49 (1H, br s)3 7.95 ( 1H, d, J=3.6 Hz), 8.23 (1H? t5 J=5.2 Hz), 8.34 (1H, d, J=8.8 Hz)5 8.61 (1H, d, J=5.2 Hz), 8·72 (1H，s)。 如下述合成起始原料。 N-(正H 基甲酸苯酯 使用正丙胺（4.1 mi，50 mmol)進行與製造例310-1同樣之 反應’將得到之結晶懸浮於己燒中，遽取結晶，用己燒洗 淨及吸引乾燥，得到為無色結晶之標題化合物（4.5〇2 g，25.12 mmol，50.24%)。 1H-NMR 光譜（DMS〇-d6)5(ppm)·· 0.86 (3H，t，J=7.4 Hz)， 1.41-1.50 (2H5 m)3 3.00 (2H, q, J=6.8 Hz)5 7.06 (2H, d, J=8.0 Hz), 7.17 (1H, t, J=8.0 Hz), 7.36 (2H, t3 J=8.0 Hz), 7.72 (1H, m) 0 實施例320 胺甲酿棊二7-甲氧基-4二fl-Π -甲基）乙某胺甲醯基-1H-吲 嗓-5 -基氣In争太 實施例321 t甲氧基-4-Π-Π -甲基）乙基胺甲醯基-1H- W哚-5-基氣μ 甲基）乙某脲胺甲醯基4啉 使用6-胺甲醯基-4-( 1Η-4Ι哚-5-基氧）-7-甲氧基喹啉（400 mg，1.2 mmol)，N-(l -甲基）乙基胺基甲酸苯酯（237 mg)及 氫化鈉（55 mg，1.3 199 mmol)，藉由與實施例310同樣之方 -426 - 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐)1304061 , ' ' A7 __ B7 V. Description of invention (42〇) J=2.4 Hz, 8.8 Hz), 7.50 (1H, s), 7.51 (1H, d3 J=2.4 Hz), 7.72 (1H, br s), .7.49 (1H, br s)3 7.95 ( 1H, d, J=3.6 Hz), 8.23 (1H? t5 J=5.2 Hz), 8.34 (1H, d, J=8.8 Hz) 5 8.61 (1H, d, J = 5.2 Hz), 8·72 (1H, s). The starting materials were synthesized as described below. N-(p-H-formic acid phenyl ester was subjected to the same reaction as in Production Example 310-1 using n-propylamine (4.1 mi, 50 mmol). The obtained crystal was suspended in hexane, and crystals were taken and washed with hexane. The title compound (4.5 〇 2 g, 25.12 mmol, 50.24%) was obtained as colorless crystals. 1H-NMR spectrum (DMS 〇-d6) 5 (ppm)·· 0.86 (3H, t, J=7.4 Hz) , 1.41-1.50 (2H5 m)3 3.00 (2H, q, J=6.8 Hz)5 7.06 (2H, d, J=8.0 Hz), 7.17 (1H, t, J=8.0 Hz), 7.36 (2H, t3 J = 8.0 Hz), 7.72 (1H, m) 0 Example 320 Amines, 7-methoxy-4, difl-indole, methyl, ethylamine, methylamino-1H-indole-5 Base gas Into the exemplified Example 321 t methoxy-4-hydrazone-fluorene-methyl)ethylamine-mercapto-1H-W哚-5-based gas μ methyl) ethylureacarbamyl group 4 6-Aminomethylmercapto-4-(1Η-4Ι哚-5-yloxy)-7-methoxyquinoline (400 mg, 1.2 mmol), N-(1-methyl)ethylamine Phenyl formate (237 mg) and sodium hydride (55 mg, 1.3 199 mmol) by the same method as in Example 310 - 426 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

裝 訂Binding

線 1304061 - A7 Β7 五、發明説明（421) 法，得到為淡黃色結晶之低極性化合物7-甲氧基-4-f lqt 甲基）乙基.胺甲酿基卜朵-5-基氧]-6-(1-甲基）乙基踩 胺甲醯基口奎琳（62 mg，0.123 1 mmol，10.26%)以及為無色 結晶之南極性化合物6 -胺甲酿基-7-甲氧基- -甲基） 乙基胺甲酿基- ΙΗ-Θ丨嗓-5-基氧]p奎，林（309 mg，0.73 84 mmol，43 .41 %)。 可得標題化合物之無色結晶（60 mg，0.1275 mmol， 61.54%)。 低極性（實施例321) W-NMR 光譜（DMSO-d6)5(ppm): 1·17 (6H，d，J=5.8 Hz)， 1·22 (6H，d，J=5.8 Hz)，3.88 (1H，m)，4·01 (3H，s)，4.03 (1H， m)，6.45 (1H，d，J=5.4 Hz)，6.69 (1H，d，JN3.4 Hz)，7.16 (1H， dd，J=2.4 Hz，8·6 Hz)，7·50 (1H，d，J=2.4 Hz)，7·52 (1H，s)， 7.98 (1H，s)，7·99 (1H，d，J=3.4 Hz), 8.33 (2H，m)，8.52 (1H， s)，8·64 (1H，d，J=5.4 Hz)，10.46 (1H，s)。 高極性（實施例320) iH-NMR 光譜（DMSO-d6)5(ppm): 1.23 (6H，d，J=6.4 Hz)， 4.00 (1H，m)，4.33 (3H，s)，6.42 (1H，d，J=5.4 Hz)，6·69 (1H， d，J=3.6 Hz)，7.17 (1H，dd，J=2.4 Hz，8.8 Hz)，7.50 (1H，s)， 7.51 (1H5 d, J=2.4 Hz), 7.72 (1H, br s)3 7.85 (1H, br s)? 7.97 (1H，s)，7.99 (1H，d，J=3.5 Hz)，8.33 (1H，d，J=8.8 Hz)，8.61 (1H，d，J=5.4 Hz)，8·72 (1H，s)。 如下述合成起始原料e 製造例320-1 -427 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公爱） 1304061 A7 B7 五、發明説明（422) N-(異丙基）胺篡甲酸笨酯 使用異丙胺（4.3 ml，50 mmol)進行與製造例310-1同樣之 反應’將得到之結晶懸浮於己烷中，濾取結晶，用己烷洗 淨及吸引乾燥，得到為無色結晶之標題化合物（5.丨05 g， 28.48 mol &gt; 56.97%) ° iH-NMR 光譜（DMSO-d6)(5(ppm): 1β〇ι (6H，d，J=6 4 Hz)， 3.58-3.67 (1H，m)，7·07 (2H，d，J=7.6 Hz)，7.17 (1H，t，J=7.6 Hz)，7·3·5 (2H，t，J=7.6 Hz)，7.65 (1H，m)。 實施例322 4-( 1-正丁基胺甲醯基-1H-吲哚-5-甚氣）-6-胺甲醯基-7-甲 氣基g林 使用6_胺甲酿基-4-( 1H-峭哚-5-基氧）-7-甲氧基喹啉（335 g，1·〇 mmol)，N-正丁基胺基甲酸苯酯（213 mg，1·1 mmol) 及氫化鈉（44 mg，1·1 mmol)，藉由與實施例310同樣之反 應，得到為無色結晶之標題化合物（203 mg，0.4694 mmol，46.94%) 0 iH-NMR 光譜（DMS〇-d6)5(ppm): 0.92 (3H，t，J=7.2 Hz), 1.36 (2H, m), 1.55 (2H, m), 3.29 (2H, m), 4.02 (3H, s), 6.42 (1H, d? J=5.4 Hz), 6.70 (1H, d, J=3.6 Hz)? 7.17 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.50-7.52 (2H, m), 7.73 (1H, br s)5 7.85 (1H, br s), 7.94 (1H, d, J=3.6 Hz), 8.22 (1H, t, J=5.4 Hz), 8.34 (1H, d, 1=8.8 Hz), 8.61 (1H, d, J=5.4 Hz), 8.72 (1H, s)。 . · 起始原料如下述合成e -428 - 本紙張尺度適用中國國家標举(CNS) A4規格(210 X 297公爱）Line 1304061 - A7 Β7 V. Inventive Note (421) Method, obtaining a low-polarity compound 7-methoxy-4-f lqt methyl)ethyl. Amine-branched-5-yloxy ]-6-(1-methyl)ethyl-t-amidoxime-based quinine (62 mg, 0.123 1 mmol, 10.26%) and a colorless crystalline south polar compound 6-amine-mercapto-7-methoxy Base--methyl) ethylamine-branched-indole-5-yloxy]p-quine, lin (309 mg, 0.73 84 mmol, 43.41%). The title compound was obtained as colorless crystals (60 mg, 0.1275 mmol, 61.54%). Low polarity (Example 321) W-NMR spectrum (DMSO-d6) 5 (ppm): 1·17 (6H, d, J = 5.8 Hz), 1·22 (6H, d, J = 5.8 Hz), 3.88 (1H,m),4·01 (3H,s),4.03 (1H, m), 6.45 (1H,d,J=5.4 Hz), 6.69 (1H,d,JN3.4 Hz), 7.16 (1H, Dd, J=2.4 Hz, 8·6 Hz), 7·50 (1H, d, J=2.4 Hz), 7·52 (1H, s), 7.98 (1H, s), 7·99 (1H, d , J = 3.4 Hz), 8.33 (2H, m), 8.52 (1H, s), 8.64 (1H, d, J = 5.4 Hz), 10.46 (1H, s). High polarity (Example 320) iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.23 (6H, d, J = 6.4 Hz), 4.00 (1H, m), 4.33 (3H, s), 6.42 (1H ,d,J=5.4 Hz),6·69 (1H, d,J=3.6 Hz), 7.17 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.50 (1H, s), 7.51 (1H5 d, J=2.4 Hz), 7.72 (1H, br s)3 7.85 (1H, br s)? 7.97 (1H, s), 7.99 (1H, d, J=3.5 Hz), 8.33 (1H, d, J=8.8 Hz), 8.61 (1H, d, J = 5.4 Hz), 8.72 (1H, s). Synthetic starting material e as follows. Production example 320-1 -427 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 public) 1304061 A7 B7 V. Description of invention (422) N-(isopropyl The amine hydrazine carboxylic acid ester was subjected to the same reaction as in Production Example 310-1 using isopropylamine (4.3 ml, 50 mmol). The obtained crystals were suspended in hexane, and the crystals were collected by filtration, washed with hexane and suction dried. The title compound was obtained as colorless crystals (5. 丨05 g, 28.48 mol &gt; 56.97%) ° iH-NMR spectrum (DMSO-d6) (5 (ppm): 1β〇ι (6H, d, J=6 4 Hz ), 3.58-3.67 (1H,m),7·07 (2H,d,J=7.6 Hz), 7.17 (1H,t,J=7.6 Hz),7·3·5 (2H,t,J=7.6 Hz), 7.65 (1H, m). Example 322 4-(1-n-butylamine-carbamoyl-1H-indole-5-carbamate)-6-aminecarboxamyl-7-methyl group g 6-Amino-mercapto-4-( 1H-threo-5-yloxy)-7-methoxyquinoline (335 g, 1·〇mmol), phenyl N-n-butylcarbamate (213 mg, 1.1 mmol) and sodium hydride (44 mg, EtOAc). 94 mmol, 46.94%) 0 iH-NMR spectrum (DMS 〇-d6) 5 (ppm): 0.92 (3H, t, J = 7.2 Hz), 1.36 (2H, m), 1.55 (2H, m), 3.29 ( 2H, m), 4.02 (3H, s), 6.42 (1H, d? J=5.4 Hz), 6.70 (1H, d, J=3.6 Hz)? 7.17 (1H, dd, J=2.4 Hz, 8.8 Hz) , 7.50-7.52 (2H, m), 7.73 (1H, br s)5 7.85 (1H, br s), 7.94 (1H, d, J=3.6 Hz), 8.22 (1H, t, J=5.4 Hz), 8.34 (1H, d, 1=8.8 Hz), 8.61 (1H, d, J=5.4 Hz), 8.72 (1H, s). · The starting materials are as follows: e-428 - This paper scale applies to the Chinese national standard Lift (CNS) A4 specification (210 X 297 public)

訂Order

線 1304061 、 … A7 ______Β7 五、發明説明（423) 一 &quot; 〜 製造例322- 1 Ν- C孟一丁棊J胺基甲醴苯酯 使用正丁胺（4.9 ml，50 mmol)進行與製造例31〇-1同樣之 反應’用矽膠管柱層析（己垸：乙酸乙酯^#:丨）精製，得到 為無色油狀物之標題化合物（8.U g，4197 mm〇1， 71.97%) 〇 iH-NMR 光譜（〇〇(：13)5 0?111):〇.95(311，11=7.2 112)，1.35-1.45 (2H, m)3 1.52-1.60 (2H, m), 3.27 (2H5 q, J=7.2 Hz), 5.01 (1H, br s)5 7.12 (2H, d5 J=7.2 Hz), 7.19 (1H, t, J=7.2 Hz)，7·35 (2H，t，J=7.2 Hz)。 實施例323 $二胺甲醯基-4-Π _ Π, 1-二甲某乙基胺甲醯甚）-1H-W哚-5-基氧卜7-甲氳某违呲 使用6-胺甲醯基-4-( 1H-吲哚-5-基氧）-7-甲氧基喹啉（335 mg，1·0 mm〇l)，N-(l，l-二甲基乙基）胺基甲酸苯酯（213 mg，1.1 mmol)及氫化鈉（44 mg，1.1 mmol)，藉由與實施 例3 10同樣之方法，得到為無色結晶之標題化合物（225 mg，0.5203 mmo卜 52.03%卜 iH-NMR 光譜（DMSO-d6)5(PPm): 1.42 (9H，s)，4.02 (3H，s)， 6.41 (1H, d, J=5.0 Hz), 6.65 (1H, d, J=3.8 Hz), 7.15 (1H, dd, J=2.4 Hz，9·2 Hz)，7.50 (2H，s)，7·63 (1H，s)，7.72 (1H，br s)， 7.85 (1H，br s)，7·95 (1H，d，J=3.8 Hz)，8·26 (1H，d，J=9.2 Hz)，8.61 (iH，d，J=5.0 Hz), 8.73 (1H，s)。 出發原料如下述合成e ____ - 429 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）Line 1304061, ... A7 ______Β7 V. Inventive Note (423) One &quot; ~ Manufacturing Example 322- 1 Ν-C Meng Yi Ding 棊J-aminomethyl phenyl phenyl ester was prepared and manufactured using n-butylamine (4.9 ml, 50 mmol) The title compound (8. U g, 4197 mm 〇 1, 71.97) was obtained as a colorless oil. %) 〇iH-NMR spectrum (〇〇(:13)5 0?111): 〇.95 (311,11=7.2 112), 1.35-1.45 (2H, m)3 1.52-1.60 (2H, m), 3.27 (2H5 q, J=7.2 Hz), 5.01 (1H, br s)5 7.12 (2H, d5 J=7.2 Hz), 7.19 (1H, t, J=7.2 Hz), 7·35 (2H, t, J = 7.2 Hz). Example 323: Diamine, hydrazinyl-4-indole, 1-dimethylethylamine, hydrazinium-1H-W哚-5-yloxybutene, 7-methyl hydrazine, 6-amine Methyl 4-(1H-indol-5-yloxy)-7-methoxyquinoline (335 mg, 1.0 mm), N-(l,l-dimethylethyl) The title compound (225 mg, 0.5203 mmo, 52.03%) was obtained as the colorless crystals. iH-NMR spectrum (DMSO-d6) 5 (PPm): 1.42 (9H, s), 4.02 (3H, s), 6.41 (1H, d, J = 5.0 Hz), 6.65 (1H, d, J = 3.8 Hz), 7.15 (1H, dd, J=2.4 Hz, 9·2 Hz), 7.50 (2H, s), 7·63 (1H, s), 7.72 (1H, br s), 7.85 (1H, br s ), 7.95 (1H, d, J = 3.8 Hz), 8.26 (1H, d, J = 9.2 Hz), 8.61 (iH, d, J = 5.0 Hz), 8.73 (1H, s). The raw materials are as follows: e ____ - 429 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)

五、發明説明（424 ) I造例323-1 第三丁基）胺基甲酸笨酯 使用第三丁胺（5.3 ml，50 mmol)，藉由與製造例3 10· i同 樣之方法，得到為粉紅色結晶之標題化合物（3.910 g， 23 mol，40.46%) 〇 i-NMR 光譜（DMSO-d6)5(ppm): 1·26 (9H，s)，7·05 (2H，d， J-8.0 Hz), 7.16 (1H, t, J=8.0 Hz), 7.35 (2H, t, J=8.0 Hz), 7,53 (1H，s)。 t施例3 24 k胺甲醯基-4-『1-( 3 -氣丙基胺甲醯基）-1Η-吲唤-5-某氳1 -h甲氣基4啉 使用6-胺曱醯基-4-(1 H-啕哚-5-基氧）-7-甲氧基喹啉（280 mg，0.8349 mmol)，N-(3-氟丙基）胺基甲酸苯酯（181 mg， 0.9184 mmol)及氫化鈉（37 mg，0.9184 mmol)，藉由與實施 例3 1 0同樣之方法，得到為無色結晶之標題化合物（丨〇 5 mg，0.2406 mmol , 28.82%) 〇 iH-NMR 光譜（DMS〇-d6) 5 (ppm): 1.89-2.03 (2H，m)，3.39 (2H，m)，4·02 (3H，s)，4.49 (1H，t，J=6.0 Hz)，4·61 (1H，d， J=6.0 Hz), 6.42 (1H, d, J=5.2 Hz), 6.71 (1H, d, J=3.6 Hz), 7.18 (1H，dd，J=2.4 Hz，8.8 Hz)，7.50 (1H，s)，7·52 (1H，d， J=2.4 Hz)，7.72 (1H，br s)，7·85 (1H，br s)，7.94 (1H，d， J=3.6 Hz)，8.32 (1H，t，J=5.4 Hz)，8·34 (1H，d，J=8.8 Hz)， 8.61 (1H，d，· J=5.2 Hz)，8.72 (1H，s)。 如下述合成起始原料。 ______ - 430 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 425 五、發明説明（ 製造例324-1 (3-氣丙基）胺某甲酸茉酯 使用3-氟丙胺鹽酸鹽（0.92 g(濕重），8 1〇 mm〇i)，進行與 製造例310-1同樣之反應，藉由矽凝膠管柱層析（己烷-乙酸 乙酯系）精製，得到為粉紅色結晶之標題化合物（〇.47〇 g， 2.3832 mmo卜 29.42%)。 i-NMR 光譜（CDCl3)(5(PPm): h96 (1H，m)，2〇3 (1H，m)， 3.44 (2H，q，J=6.4 Hz)，4·54 (1H，t，J=5.6 Hz)，4·65 (1H，t， &gt;5·6 Hz)，5·22 (1H，br s)，7.12 (2H，d，J = 7.6 Hz)，7.20 (1H， t，J=7.6 Hz)，7.36 (2H，t，J=7.6 Hz)。 實施例325 甲醯，.基Π-(·3·氣丙基胺甲醯某）-1H-H卜朵-5-某氳卜 甲氣基4啉 使用6-胺曱醯基-4-( 1Η-啕哚-5-基氧）-7-甲氧基喹啉（280 mg，〇·8349 mmol) , N-(3-氯丙基）胺基甲酸苯酯（197 mg , 0.9184 mmol)及氫化鈉（37 mg，0.9184 mmol)，藉由與實施 例3 10同樣之方法’得到為無色結晶之標題化合物（13 6 mg，0.3003 mmol，35.97%)。 H-NMR 光譜（DMSO-d6)6(ppm): 2·03 (2H，q，J=6.4 Hz)， 3.42 (2H，q，J=6.4 Hz)，3·74 (2H，t，J=6.4 Hz)，4.02 (3H，s)， 6.42 (1H，d，J=5.2 Hz)，6.71 (1H，d，J=3.6 Hz)，7·18 (1H，dd， J=2.4 Hz, 8.8 Hz), 7.50 (1H, s), 7.52 (1H, d, J=2.4 Hz), 7.72 (1H，bi: s)，7·85 (1H，br s)，7.94 (1H, d，J=3.6 Hz)，8.30 (1H， d, J=5.4 Hz), 8.34 (1H, d, J=8.8 Hz), 8.61 (1H, d, J=5.2 Hz), -431 - 本紙張尺度通用中國國家標準(CNS) A4規格(210 x 297公釐) 裝 訂 A7V. INSTRUCTION DESCRIPTION OF THE INVENTION (424) I. Example 323-1 The tert-butyl) carbamic acid methacrylate was obtained by the same method as in Production Example 3 10·i using a third butylamine (5.3 ml, 50 mmol). The title compound (3.910 g, 23 mol, 40.46%) 粉i-NMR spectrum (DMSO-d6) 5 (ppm): 1·26 (9H, s), 7·05 (2H, d, J) -8.0 Hz), 7.16 (1H, t, J=8.0 Hz), 7.35 (2H, t, J=8.0 Hz), 7,53 (1H, s). t Example 3 24 k-aminomethylmercapto-4-"1-(3-propanolamine-methyl)-hydrazinyl-5-anthracene-5-anthene-1-h-methyl-based 4 phenyl group using 6-amine hydrazine Mercapto-4-(1 H-indol-5-yloxy)-7-methoxyquinoline (280 mg, 0.8349 mmol), phenyl N-(3-fluoropropyl)carbamate (181 mg , the title compound (丨〇5 mg, 0.2406 mmol, 28.82%) 〇iH-NMR was obtained as the colorless crystals. Spectrum (DMS〇-d6) 5 (ppm): 1.89-2.03 (2H, m), 3.39 (2H, m), 4·02 (3H, s), 4.49 (1H, t, J = 6.0 Hz), 4 ·61 (1H,d, J=6.0 Hz), 6.42 (1H, d, J=5.2 Hz), 6.71 (1H, d, J=3.6 Hz), 7.18 (1H, dd, J=2.4 Hz, 8.8 Hz ), 7.50 (1H, s), 7.52 (1H, d, J = 2.4 Hz), 7.72 (1H, br s), 7.85 (1H, br s), 7.94 (1H, d, J = 3.6) Hz), 8.32 (1H, t, J = 5.4 Hz), 8.34 (1H, d, J = 8.8 Hz), 8.61 (1H, d, J = 5.2 Hz), 8.72 (1H, s). The starting materials were synthesized as described below. ______ - 430 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 425 V. Description of invention (Production Example 324-1 (3-Actylpropyl) Amine 3-fluoropropylamine hydrochloride (0.92 g (wet weight), 8 1 〇mm〇i), the same reaction as in Production Example 310-1 was carried out by gel column chromatography (hexane-ethyl acetate) The title compound (〇.47〇g, 2.3832 mmob 29.42%) was obtained as a pink crystal. i-NMR spectrum (CDCl3) (5 (PPm): h96 (1H, m), 2〇3 ( 1H,m), 3.44 (2H,q,J=6.4 Hz),4·54 (1H,t,J=5.6 Hz), 4·65 (1H,t, &gt;5·6 Hz),5·22 (1H, br s), 7.12 (2H, d, J = 7.6 Hz), 7.20 (1H, t, J = 7.6 Hz), 7.36 (2H, t, J = 7.6 Hz). Example 325 Hyperthyroidism, Π-(····················································· Base oxy)-7-methoxyquinoline (280 mg, 〇·8349 mmol), phenyl N-(3-chloropropyl)carbamate (197 mg, 0.9184 mmol) and sodium hydride (37 mg, 0.9184) Ment), by way of example 3 The title compound (13 6 mg, 0.3003 mmol, 35.97%) was obtained as colorless crystals. </ br </ br> </ br> ), 3.42 (2H, q, J = 6.4 Hz), 3.74 (2H, t, J = 6.4 Hz), 4.02 (3H, s), 6.42 (1H, d, J = 5.2 Hz), 6.71 (1H ,d,J=3.6 Hz),7·18 (1H,dd, J=2.4 Hz, 8.8 Hz), 7.50 (1H, s), 7.52 (1H, d, J=2.4 Hz), 7.72 (1H,bi : s), 7.85 (1H, br s), 7.94 (1H, d, J = 3.6 Hz), 8.30 (1H, d, J = 5.4 Hz), 8.34 (1H, d, J = 8.8 Hz), 8.61 (1H, d, J=5.2 Hz), -431 - This paper is the standard Chinese National Standard (CNS) A4 specification (210 x 297 mm) Binding A7

1304061 五、發明説明（ 8.72 (1H，s) 〇 如下述合.成起始原料。 Ν-Γ3-氯丙基）胺基甲酩笨g旨 使用3-氯丙胺鹽酸鹽（6.5 g，5〇mm〇i)，進行盘製造例 BO-丨词樣之反應，用碎凝膠管柱層析（己烷.乙酸乙醋系） 精製’將得到之結晶懸浮於乙㈣，用己料釋，滤取結 晶，用己燒洗淨及吸引乾燥，得到為無色結晶之標題化合 物（4.316 g，20·20 mmol，40.40%)。 #麵11光譜（腹犯〇5(1)1)111):191(211，叫11如，卜601304061 V. INSTRUCTIONS ( 8.72 (1H, s) 〇 下述 . 成 成 成 成 。 。 。 Γ Γ Γ Γ Γ Γ 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨〇mm〇i), perform the BO-丨-like reaction of the disk manufacturing example, and purify it by crushing gel column chromatography (hexane. acetic acid ethyl acetate). The crystal obtained is suspended in B (four) and released with the drug. The title compound (4.316 g, 20·20 mmol, 40.40%) was obtained as crystals. #面11谱(腹腹〇5(1)1)111):191(211,叫11如,卜60

Hz), 3.18 (2H, q, J=6.0 Hz), 3.68 (2H, t, J=6.0 Hz), 7.08 (2H, d5 J=8.0 Hz), 7.18 (1H, t, J=8.0 Hz), 7.35 (2H? t3 J=8.0 Hz), 7.81 (1H，t，J=6.0 Hz)。 實施例326 6:释平一罐基...乙氧丙幕醯某1H- W哚-5-某 氣1- 7-甲氣某4啉 使用6-胺甲醯基-4-( 1H-啕哚-5-基氧）-7-甲氧基喹淋（280 mg，0.8349 mmol)，N-(3-乙氧丙基）胺基甲酸苯酯（！97 mg ’ 0.9184 mmol)及氫化制（37 mg，0.9184 mmol)，藉由 與實施例3 10同樣之方法，得到為無色結晶之標題化合物 (103 mg，0.2227 mmol，26.67%) 〇 iH-NMR 光譜（DMS〇-d6)5(ppm): 1.01 (3H，t，J=6.8 Hz)， 1.80 (2H, t,*J=6.8 Hz), 3.34 (2H, q, J=6.8 Hz), 3.39-3.46 (4H, m), 4.02 (3H5 s), 6.24 (1H, d, J=5.2 Hz), 6.70 (1H? d5 J=3.6 -432 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）Hz), 3.18 (2H, q, J=6.0 Hz), 3.68 (2H, t, J=6.0 Hz), 7.08 (2H, d5 J=8.0 Hz), 7.18 (1H, t, J=8.0 Hz), 7.35 (2H? t3 J=8.0 Hz), 7.81 (1H, t, J = 6.0 Hz). Example 326 6: Release a tank base... Ethoxypropyl sulfonate 1H-W哚-5-a gas 1- 7-methyl gas A 4 phenoline using 6-amine-mercapto-4-( 1H-啕哚-5-yloxy)-7-methoxyquinone (280 mg, 0.8349 mmol), N-(3-ethoxypropyl)carbamic acid phenyl ester (!97 mg '0.9184 mmol) and hydrogenated ( The title compound (103 mg, 0.2227 mmol, 26.67%) was obtained as the colorless crystals of ydH-NMR spectrum (DMS 〇-d6) 5 (ppm). : 1.01 (3H,t,J=6.8 Hz), 1.80 (2H, t,*J=6.8 Hz), 3.34 (2H, q, J=6.8 Hz), 3.39-3.46 (4H, m), 4.02 (3H5 s), 6.24 (1H, d, J=5.2 Hz), 6.70 (1H? d5 J=3.6 -432 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

裝 訂Binding

1304061 A7 B7 五、發明説明（427 )1304061 A7 B7 V. Description of invention (427)

Hz), 7.18 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.50 (1H, s), 7.51 (1H, d, J=2.4 Hz), 7.72 (1H, br s), 7.85 (1H, br s), 7.93 (1H, d, 1=3.6 Hz), 8.22 (1H, t, J=5.2 Hz), 8.34 (1H, d, J=8.8 Hz), 8.61 (1H，d，J=5.2 Hz)，8·72 (1H，s)。 如下述合成起始原料。 製造例326- 1 N-(3-乙氧基丙基）胺某甲酸笨醋 將3-乙氧基丙胺（6.0 ml，50 mmol)溶於二甲基甲酿胺 (100 ml)，進行與製造例310-1同樣之反應，用NH型矽凝膠 管柱層析（己烷·乙酸乙酯系）精製，得到為淡黃色油狀物 之標題化合物（10·76 g，48.19 mmol，96.39%)。 iH-NMR 光譜（CDCl3)5(ppm): 1·22 (3H，t，J=7.0 Ηζ)，1·85 (2H，quintet, J=6.0 Hz)，3·40 (2H，q，J=6.0 Hz)，3·51 (2H，q， J=7.0 Hz), 3.56 (2H, t3 J=6.0 Hz), 5.58 (1H, br s), 7.12 (2H, d，J=7.6 Hz)，7·18 (1H，t，J=7.6 Hz)，7·32 (2H，t，J=7.6 Hz)。 實施例327 匕胺曱醯基-4-Π-(3-二乙胺基丙某胺甲醯基）-1 H-〃?丨哚-5-基氣1- 7-甲氲基4啉 使用6-胺甲醯基-4-(1 H-啕哚-5-基氧）-7-甲氧基喹啉（240 mg，0.7157 mmol)，N-(3 -二乙胺丙基）胺基甲酸苯酯（197 mg，0.7872 mmol)及氫化納（31 mg，0.7872 mmol)，進行 與實施例3 10同樣之反應，得到為無色結晶之標題化合物 (65 mg » 0.1328 mmol J 18.55%) 〇 W-NMR 光譜（DMS〇-d6)d(ppm): 0.94 (6H，t，J=7.2 Hz), -433 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂 線 1304061 … A7 _B7_ 五、發明説明（428 ) 1·69 (2H，m)，2.42-2.48 (6H，m)，3·27-3.30 (2H，m)，4.02 (3H，s), 6·4.2 (1H，d，J=5.4 Hz)，6.70 (1H，d，J=3.6 Hz)，7·17 (1H，dd，J=2.4 Hz，8·8 Hz)，7·50 (1H，s)，7·51 (1H，d，J=2.4 Hz), 7.72 (1H, br s)5 7.84 (1H, br s), 7.91 (1H5 d5 J=3.6 Hz), 8.26 (lH，t，J=5.6 Hz)，8·33 (1H，d，J=8.8 Hz)，8·61 (1H，d， J=5.4 Hz)，8·72 (1H，s)。 製造例327-1 K- (3-二乙胺基丙某）賒某τ酸笨氣 將3 -二乙胺基丙胺（7.9 ml，50 mmol)溶於二甲基甲醯胺 (100 ml)，進行與製造例310-1同樣之反應，用NH型矽凝膠 管柱層析（己烷·乙酸乙酯系）精製，得到為淡黃色油狀物 之標題化合物（7.21 g，28.80 mmol，57.60%)。 h-NMR 光譜（CDC13) 5(ppm): 1·〇6 (6H，t，J=7.0 Hz), 1.71 (2H，quintet，J=6.0 Hz)，2.49-2.57 (6H，m)，3.36 (2H，q，J=6 Hz)，6·83 (1H，br s)，7.12 (2H，t，J=7.6 Hz)，7.17 (1H，t， J=7.6 Hz)，7·34 (2H，t，J=7.6 Hz)。 實施例328 L胺甲醯基-7-甲氣某-4- Π-Π-甲硫某雨甚1H- W哚-5-某 氧1 口奎淋 使用6-胺甲醯基-4-( 1H-啕哚-5-基氧）-7-甲氧基喹啉（280 mg，0.8349 mmol)，N-(3-甲硫基丙基）胺基曱酸苯酯（2〇7 mg，0.9184 mmol)及氫化鈞（37 mg，0.9184 mmol),藉由 與實施例3 10同樣之方法，得到為無色結晶之標題化合物 (177 mg，0.3810 mmo卜 45.64%) ° -434 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 B7 五、發明説明（429 )Hz), 7.18 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.50 (1H, s), 7.51 (1H, d, J=2.4 Hz), 7.72 (1H, br s), 7.85 (1H, br s), 7.93 (1H, d, 1 = 3.6 Hz), 8.22 (1H, t, J = 5.2 Hz), 8.34 (1H, d, J = 8.8 Hz), 8.61 (1H, d, J = 5.2 Hz) , 8.72 (1H, s). The starting materials were synthesized as described below. Production Example 326-1 N-(3-Ethoxypropyl)amine A carboxylic acid of acetoacetate 3-Ethyl propylamine (6.0 ml, 50 mmol) was dissolved in dimethylamine (100 ml). The title compound (10·76 g, 48.19 mmol, 96.39) was obtained as a pale yellow oil. %). iH-NMR spectrum (CDCl3) 5 (ppm): 1·22 (3H, t, J=7.0 Ηζ), 1.85 (2H, quintet, J=6.0 Hz), 3·40 (2H, q, J= 6.0 Hz), 3·51 (2H, q, J=7.0 Hz), 3.56 (2H, t3 J=6.0 Hz), 5.58 (1H, br s), 7.12 (2H, d, J=7.6 Hz), 7 · 18 (1H, t, J = 7.6 Hz), 7·32 (2H, t, J = 7.6 Hz). Example 327 Amidoxime-4-indole-(3-diethylaminopropylaminocarbamoyl)-1 H-indole-5-yl gas 1- 7-carboxyl 4 phenyl 6-Aminomethylmercapto-4-(1 H-indol-5-yloxy)-7-methoxyquinoline (240 mg, 0.7157 mmol), N-(3-diethylaminopropyl)amine Phenyl formate (197 mg, 0.7872 mmol) and sodium hydride (31 mg, 0.7872 mmol). -NMR spectrum (DMS〇-d6)d (ppm): 0.94 (6H, t, J = 7.2 Hz), -433 - This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) gutter 1304061 ... A7 _B7_ V. INSTRUCTIONS (428 ) 1·69 (2H, m), 2.42-2.48 (6H, m), 3·27-3.30 (2H, m), 4.02 (3H, s), 6.4.2 (1H, d, J = 5.4 Hz), 6.70 (1H, d, J = 3.6 Hz), 7·17 (1H, dd, J = 2.4 Hz, 8·8 Hz), 7·50 (1H, s) ,7·51 (1H,d,J=2.4 Hz), 7.72 (1H, br s)5 7.84 (1H, br s), 7.91 (1H5 d5 J=3.6 Hz), 8.26 (lH,t,J=5.6 Hz), 8·33 (1H, d, J = 8.8 Hz), 8.61 (1H, d, J = 5.4 Hz), 8.72 (1H, s). Production Example 327-1 K-(3-Diethylaminopropyl) 赊 τ 酸 笨 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 The title compound (7.21 g, 28.80 mmol, m.p. 57.60%). h-NMR spectrum (CDC13) 5 (ppm): 1·〇6 (6H, t, J=7.0 Hz), 1.71 (2H, quintet, J=6.0 Hz), 2.49-2.57 (6H, m), 3.36 ( 2H,q,J=6 Hz),6·83 (1H,br s),7.12 (2H,t,J=7.6 Hz), 7.17 (1H,t, J=7.6 Hz),7·34 (2H, t, J = 7.6 Hz). Example 328 L-amine methyl hydrazinyl-7-methyl gas -4- Π-Π-methyl sulphide rain 1H-W 哚-5- an oxygen 1 mouth quinine using 6-amine carbaryl-4- ( 1H-indol-5-yloxy)-7-methoxyquinoline (280 mg, 0.8349 mmol), N-(3-methylthiopropyl)amino decanoic acid phenyl ester (2〇7 mg, 0.9184 The title compound (177 mg, 0.3810 mmo 45.64%) of the title compound (177 mg, 0.3810 mmo, 45.64%) ° -434 - The paper size is applicable to China. National Standard (CNS) A4 Specification (210X297 mm) 1304061 A7 B7 V. Description of Invention (429)

1H-NMR 光譜（DMSO-d6)5(ppm): 1.84 (2H，tt，J=6.8 Ηζ，6·8 Hz), 2.48 (3H, s), 2.55 (2H, t, J=6.8 Hz), 3.57 (2H, m), 4.02 (3H, s), 6.42 (1H, d, J=5.0 Hz), 6.70 (1H, d5 J=3.4 Hz), 7.18 (1H, d, J=8.8 Hz), 7.50 (1H, s)5 7.51 (1H, s), 7.72 (1H, s)5 7.85 (1H, s), 7,94 (1H, d, J=3.4 Hz), 8.27 (1H, br s), 8.34 (1H，d，J=8.8 Hz), 8·61 (1H，d，J=5.0 Hz)，8·72 (1H，s)。 製造例328-1 N-(3-甲硫基丙墓）胺基甲酸苯酯 Μ 使用3-甲硫基丙胺（5.5 ml，50 mmol)，進行與製造例 310-1同樣之反應，用矽凝膠管柱層析（己烷·乙酸乙酯系） 精製，得到為黃色油狀物之標題化合物（10.486 g，46.54 mmol，93.08%)。1H-NMR spectrum (DMSO-d6) 5 (ppm): 1.84 (2H, tt, J = 6.8 Ηζ, 6·8 Hz), 2.48 (3H, s), 2.55 (2H, t, J = 6.8 Hz), 3.57 (2H, m), 4.02 (3H, s), 6.42 (1H, d, J=5.0 Hz), 6.70 (1H, d5 J=3.4 Hz), 7.18 (1H, d, J=8.8 Hz), 7.50 (1H, s)5 7.51 (1H, s), 7.72 (1H, s)5 7.85 (1H, s), 7,94 (1H, d, J=3.4 Hz), 8.27 (1H, br s), 8.34 (1H, d, J = 8.8 Hz), 8·61 (1H, d, J = 5.0 Hz), 8.72 (1H, s). Production Example 328.1 N-(3-Methylthio-propyl) phenyl carbamate oxime The same reaction as in Production Example 310-1 was carried out using 3-methylthiopropylamine (5.5 ml, 50 mmol). The title compound (10.486 g, 46.54 mmol, 93.08%) was obtained as a yellow oil.

iH-NMR 光譜（CDC13) 5 (ppm): 1·89 (2H，quintet，J=6.8 Hz)， 2·12 (3H，s)，2·58 (2H，t，J=6.8 Hz)，3·38 (2H，q，J=6.8 Hz)， 5.21 (1H，br s)，7·12 (2H，t，J=7.6 Hz)，7.19 (1H，t，J=7.6 Hz)，7·35 (2H，t，J=7.6 Hz)。 實施例329 6- 胺甲醯某-4-Γ 1-(2-氩乙基胺甲醯基1H-钊哚-5-某查.1- 7- 甲氣某4嗾 使用6-胺甲醯基-4-( 1H-啕哚-5-基氧）-7-甲氧基喹啉（280 mg，0.8349 mmol)，N-(2-氯乙基）胺基甲酸苯酯（184 mg , 0.9 1 84 mmol)及氫化 #j(37 mg，0.9184 mmol)，藉由與實施 例3 10同樣之方法，得到為淡黃色結晶之標題化合物（3 6 mg ’ 0.0820 mmo卜 9.82%)。 -435 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 B7 五、發明説明（430 ) iH-NMR光譜（DMSO-d6)5(ppm): 4,02 (3H，s)，4·03 (2H，t， J=9.2 Hz), .4.59 (2H, t, J—9.2 Hz), 6.44 (1H, d, J=5.6 Hz), 6.75 (1H, d, J=3.6 Hz), 7.24 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.51(1H，s)，7·57 (1H，d，J=2.4 Hz)，7·72 (1H，br s)，7.76 (1H，d， J=3.6 Hz), 7.85 (1H5 br s), 8.38 (1H3 d, J=8.8 Hz), 8.62 (1H3 d5 J=5'6 Hz)，8·72 (1H，s) 〇 製造例329-1 N-(2-氯乙基）胺基甲酸苯酯 使用2-氯乙胺鹽酸鹽（5·8 g ’ 50 mmol)，進行與製造例 310-1同樣之反應，用矽凝膠管柱層析（己烷·乙酸乙醋系） 精製，將得到之結晶懸浮於乙趟·己燒中，遽取結晶，用 己烷稀釋，藉由吸引乾燥，得到為無色結晶之標題化合物 (6.088 g，30-49 mmol，60.99%) °iH-NMR 光譜（DMSO-d6)5(ppm): 3.38 (2H，q，J=6.0 Hz)， 3·66 (2H，t，J=6.0 Hz)，7·09 (2H，t，J=7.6 Hz)，7.19 (1H，t， J=7.6 Hz)，7.36 (2H，t，J=7.6 Hz)，8·01 (1H，t，J=6.0 Hz)。 實施例330 4-Π-(2,4-二氣笨基胺甲醯基1H-吲哚-5-基氣1-6,7-二甲 氧基TT奎TT株 4-(1Η-啕哚-5-基氧）-6,7-二甲氧基喹啉（4〇 mg，0.1249 mmo卜在w〇 9717329中記載者）溶於N，N_二甲基甲醯胺 (0.7 ml)中，加入氫化鈉（10 mg)，並於室溫授掉15分鐘。 在其中加入-異氰酸2,4-二氟苯酯（〇.〇 18 ml，0.1561 mmol) » 並於室溫攪拌2小時。在反應溶液中加入水，用乙酸乙酯萃 -436 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐）iH-NMR spectrum (CDC13) 5 (ppm): 1·89 (2H, quintet, J=6.8 Hz), 2·12 (3H, s), 2·58 (2H, t, J = 6.8 Hz), 3 · 38 (2H, q, J = 6.8 Hz), 5.21 (1H, br s), 7·12 (2H, t, J = 7.6 Hz), 7.19 (1H, t, J = 7.6 Hz), 7.35 (2H, t, J = 7.6 Hz). Example 329 6-Aminomethyl hydrazine Γ 4-Γ 1-(2-Argethylethylamine hydrazinyl 1H-indole-5- some s. 1- 7-methyl sulphur 4 嗾 6-amine formazan 4-(1H-indol-5-yloxy)-7-methoxyquinoline (280 mg, 0.8349 mmol), phenyl N-(2-chloroethyl)carbamate (184 mg, 0.9 The title compound (3 6 mg '0.0820 mmo, 9.82%) was obtained as pale yellow crystals. This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 B7 V. Description of invention (430) iH-NMR spectrum (DMSO-d6) 5 (ppm): 4,02 (3H, s), 4·03 (2H, t, J=9.2 Hz), .4.59 (2H, t, J-9.2 Hz), 6.44 (1H, d, J=5.6 Hz), 6.75 (1H, d, J=3.6 Hz) , 7.24 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.51(1H,s),7·57 (1H,d,J=2.4 Hz),7·72 (1H,br s),7.76 (1H , d, J=3.6 Hz), 7.85 (1H5 br s), 8.38 (1H3 d, J=8.8 Hz), 8.62 (1H3 d5 J=5'6 Hz), 8·72 (1H, s) 〇 Manufacturing example 329-1 N-(2-chloroethyl) carbamic acid phenyl ester was prepared using 2-chloroethylamine hydrochloride (5·8 g '50 mmol) The same reaction as in Example 310-1 was carried out by hydrazine gel column chromatography (hexane·acetic acid ethyl acetate), and the obtained crystals were suspended in acetonitrile·hexane, and crystals were taken and diluted with hexane. The title compound (6.088 g, 30-49 mmol, 60.99%) was obtained as a colorless crystals (yield: </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 3·66 (2H, t, J=6.0 Hz), 7·09 (2H, t, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.36 (2H, t, J=7.6 Hz) ), 8·01 (1H, t, J = 6.0 Hz). Example 330 4-Π-(2,4-dioxaaminocarbamyl 1H-indole-5-based gas 1-6,7 -Dimethoxy TT TT strain 4-(1Η-啕哚-5-yloxy)-6,7-dimethoxyquinoline (4 〇 mg, 0.1249 mmo b as described in w〇9717329) Sodium hydride (10 mg) was added to N,N-dimethylformamide (0.7 ml) and allowed to stand at room temperature for 15 min. 2,4-Difluorophenyl isocyanate (〇.〇 18 ml, 0.1561 mmol) was added thereto and stirred at room temperature for 2 hours. Add water to the reaction solution and extract with ethyl acetate -436 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

寒 韓 1304061 A7 B7 五、發明説明（431 ) 取，用飽和食鹽水洗淨，用無水硫酸鎂乾燥，及將濾液減 壓蒸餾。將得到之結晶懸浮於乙醚：乙醇=1 0 : 1中，將其 用己烷稀釋後濾取結晶，將結晶用乙醚：乙醇=1 0 : 1洗 淨，吸引乾燥後’得到為供色結晶之標題化合物（3 5 mg， 0.0736 mmol，58.94%) 0 W-NMR 光譜（CDCl3)5(ppm): 4·06 (3H，s)5 4·07 (3H，s)， 6·44 (1Η，J，J=5.2 Ηζ)，6·75 (1Η，d，J=4.0 Ηζ)，6.94-7.20 (2Η， m)，7·23 (1H，dd，J=2.4，8·8 Hz)，7.42-7.48 (3H，m)，7·63 (1H, s), 8.14-8.22 (1H, m), 8.29(1H, d, J=8.8 Hz), 8.47 (1H, d，J=5.2 Hz)。 實施例331-1 笨基胺甲醯基1H-吲哚-5-基氣1-6,7-二曱氣基4啉 使用4-(1H-啕哚-5-基氧）-6,7-二甲氧基喹啉（25 mg， 0.0780 mmol)及異氰酸苯 S旨（0.013 ml，0.117 mmol)進行與 實施例330同樣之反應，將得到之結晶懸浮於乙醚：乙醇 =10 : 1中，濾取結晶，將結晶用乙醚洗淨及吸引乾燥後， 得到為無色結晶之標題化合物（11 mg，0.0250 mmol， 32.09%) ° ipi-NMR 光譜（CDCl3)5(ppm): 4.03 (3H，s)，4.12 (3H，s)， 6.45 (1H, m), 6.73 (1H, m), 7.16-7.27 (2H, m), 7.38-7.43 (3H, m), 7.65-7.69 (3H, m), 7.97 (2H, m), 8.08 (1H, m), 8.43 (1H，br s)，8·38 (1H, d, J=8.8 Hz) 〇 實施例331-2 4-「1-( 2-4唑基胺甲醯基VIH-叫丨哚-5-基氣1-6,7-二甲氫某 -437 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 裝 訂 線 1304061 A7 B7 五、發明説明（432 ) 口奎淋 將4-(1Η-啕哚-5-基氧）-6,7-二甲氧基喹啉（25 mg， 0.0780 mmol)溶於N，N-二甲基甲醯胺（〇·4 ml)中，加入氫化 鈉（6 mg)並於室溫攪拌15分鐘。在其中加入N-(2〇塞唑基） 胺基甲酸苯醋（30 mg，〇· 13 62 mmol)並於80 °C攪拌2小時。 在反應液中加入水，用乙酸乙酯萃取，用飽和食鹽水洗 淨，用無水硫酸鎂乾燥並將濾液減壓蒸餾。將殘餘物付諸 於碎凝等管柱層析（己垸·乙酸乙酯.乙醇系），將得到之 結晶懸浮於乙醇，將其用己烷稀釋後濾取結晶，將結晶用 己燒洗分及吸引乾後’仔到為淡黃色結晶之標題化合物 (23 mg，0.0515 mmol，66.04%) 〇 h-NMR 光譜（CDCl3)5 (ppm): 3·94 (6H，s)，6.42 (1H，d， J=5.2 Hz), 6.68 (1H3 d, J=3.4 Hz), 7.08 (1H, d, J=4.0 Hz), 7.17 (1H，d，J=8.8 Hz)，7·38 (1H，s)，7·46-7·48 (2H，m)，7.56 (1H, s)5 8.07 (1H, d, J=3.4 Hz), 8.43 (1H, d, J=5.2 Hz), 8.65 (1H，d，J=8.8 Hz)，13.13 (1H，br s)。 實施例3 3 2 4-Π-環丙基胺曱醯某-1H-吲哚-5-基氣）-6,7-二甲氣某邊毗 使用丨嗓-5-基乳）-6,7-二曱乳基峻琳（5 0 mg， 0.1560 mmol)，氫化納（8 mg，0.1873 mmol)及 N-環丙基胺 基甲酸苯酯（30 mg，0.1716 mmol)進行與實施例3 10同樣之 反應，得到為淡紅色結晶之標題化合物（30 mg，0.0744 mmol * 47.6*4%) ° W-NMR 光譜（DMS〇-d6)(5(ppm): 0·71 (2H，m)，0.94 (2H，m)， -438 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂Han Han 1304061 A7 B7 V. Inventive Note (431) Take, wash with saturated brine, dry with anhydrous magnesium sulfate, and distill the filtrate under reduced pressure. The obtained crystal was suspended in diethyl ether: ethanol = 10:1, diluted with hexane, and the crystals were collected by filtration, and the crystals were washed with diethyl ether:ethanol = 1 : 1 : The title compound (3 5 mg, 0.0736 mmol, 58.94%) 0 W-NMR spectrum (CDCl3) 5 (ppm): 4·06 (3H, s)5 4·07 (3H, s), 6·44 (1Η , J, J=5.2 Ηζ), 6.75 (1Η, d, J=4.0 Ηζ), 6.94-7.20 (2Η, m), 7·23 (1H, dd, J=2.4, 8·8 Hz), 7.42-7.48 (3H,m),7·63 (1H, s), 8.14-8.22 (1H, m), 8.29 (1H, d, J=8.8 Hz), 8.47 (1H, d, J=5.2 Hz) . Example 331-1 Strepylamine-methyl indenyl 1H-indole-5-based gas 1-6,7-diindole-based 4 phenyl using 4-(1H-indol-5-yloxy)-6,7 -Dimethoxyquinoline (25 mg, 0.0780 mmol) and benzene sulfonate (0.013 ml, 0.117 mmol) were reacted in the same manner as in Example 330, and the obtained crystals were suspended in diethyl ether: ethanol = 10:1 The crystals were filtered, and the crystals were washed with diethyl ether and evaporated to give the title compound (11 mg, 0.0250 mmol, 32.09%) as a colorless crystals. ipi-NMR spectrum (CDCl3) 5 (ppm): 4.03 (3H) ,s), 4.12 (3H, s), 6.45 (1H, m), 6.73 (1H, m), 7.16-7.27 (2H, m), 7.38-7.43 (3H, m), 7.65-7.69 (3H, m ), 7.97 (2H, m), 8.08 (1H, m), 8.43 (1H, br s), 8.38 (1H, d, J = 8.8 Hz) 〇 Example 331-2 4-"1-( 2 -4oxazolylcarbamyl VIH-called 丨哚-5-based gas 1-6,7-dimethylhydrogen-437 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Gutter 1304061 A7 B7 V. Description of the invention (432) Methyl quinine dissolves 4-(1Η-啕哚-5-yloxy)-6,7-dimethoxyquinoline (25 mg, 0.0780 mmol) in N , N-dimethylformamide (〇·4 ml) Add sodium hydride (6 mg) and stir at room temperature for 15 minutes, add N-(2 oxazolyl) phenyl hydroxyacetate (30 mg, 〇 13 62 mmol) and stir at 80 °C 2 Water was added to the reaction mixture, and the mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc. Ethyl acetate, ethanol, and the obtained crystals are suspended in ethanol, and the crystals are diluted with hexane, and the crystals are filtered, and the crystals are washed with hexane and then dried to give the title compound as a pale yellow crystal. 23 mg, 0.0515 mmol, 66.04%) 〇h-NMR spectrum (CDCl3) 5 (ppm): 3·94 (6H, s), 6.42 (1H, d, J = 5.2 Hz), 6.68 (1H3 d, J= 3.4 Hz), 7.08 (1H, d, J=4.0 Hz), 7.17 (1H, d, J=8.8 Hz), 7·38 (1H, s), 7·46-7·48 (2H, m), 7.56 (1H, s)5 8.07 (1H, d, J=3.4 Hz), 8.43 (1H, d, J=5.2 Hz), 8.65 (1H, d, J=8.8 Hz), 13.13 (1H, br s) . Example 3 3 2 4-Π-cyclopropylamine 曱醯-1H-吲哚-5-based gas)-6,7-dimethyl gas is adjacent to 丨嗓-5-based milk -6, 7-Diterpenoids (50 mg, 0.1560 mmol), sodium hydride (8 mg, 0.1873 mmol) and phenyl N-cyclopropylcarbamate (30 mg, 0.1716 mmol) were carried out with Example 3 10 The title compound (30 mg, 0.0744 mmol * 47.6*4%) was obtained as a pale red crystal. mp NMR spectrum (DMS 〇-d6) (5 (ppm): 0·71 (2H, m), 0.94 (2H,m), -438 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding

線 !304061Line !304061

2.91 (1H，m)，4·06 (3H，s)，4·07 (3H，s)，5·79 (1H，br s)，6 41 (1H，d，J=5.2 Hz)，6.63 (1H，d，J=3.2 Hz)，7·16 (1H dd J=2.4 Hz，8.8 Hz)，7.26 (1H，s)，7.39-7.43 (2H，m)，7 63 (1H 0, 8.26 (1H，d，J=8.8 Hz)，8·45 (1H，d，J=5.2 Hz)。 ’fife 例 333 i^LidL?·二氟乙茱胺甲醯基）-1H-吲哚-5-某氫1 - 6.L -田-苴 :奎味 使用4-(1Η-吲哚-5-基氧）-6,7-二甲氧基喹啉（75 mg，0.3122 mmol)，氫化鈉（π mg，〇·3278 mmc)1)及 Ν·(2•氟乙 基）胺基曱紅豕酉旨（45 mg，0.3278 mmol)進行與實施例3 1 Ο 同樣之反應，用乙酸乙酯及四氫呋喃萃取，用飽和食鹽水 洗淨’用無水硫酸鎂乾燥並減壓餾去溶媒。使殘餘物吸著 於矽凝膠，然後付諸於矽凝膠管柱層析（己烷·乙酸乙酯 系）’得到為無色結晶之標題化合物（24 mg，0.0586 _〇1，18.78%)。 W-NMR 光譜（DMSO-d6)5(ppm): 3.56 (1H，q，J=5.0 Hz)， 3.63 (1H，q，J=5.0 Hz)，3·92 (3H，s)，3·96 (3H，s)，4·53 (1H， t，J=5.0 Hz)，4.65 (1H，t，J=5.0 Hz)，6·39 (1H，d，J二5.0 Hz)， 6.71 (1H, d, J=3.8 Hz), 7.17 (1H, dd3 J=2.0 Hz, 8.8 Hz), 7.40 (1H，s)，7·49 (1H，d，J=2.0 Hz)，7·55 (1H，s)，7·96 (1H，d， J=3.8 Hz), 8.34 (1H, d3 J=8.8 Hz), 8.42 (1H, d, J=5.0 Hz), 8.48 (1H，t，J=5.0 Hz)。實施例334 - 二甲氩基-4-(5-(1-(4-氯苽諾某）-峭哚）夤杳啉 -439 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）2.91 (1H,m),4·06 (3H,s),4·07 (3H,s),5·79 (1H,br s),6 41 (1H,d,J=5.2 Hz), 6.63 ( 1H,d,J=3.2 Hz),7·16 (1H dd J=2.4 Hz, 8.8 Hz), 7.26 (1H, s), 7.39-7.43 (2H, m), 7 63 (1H 0, 8.26 (1H) ,d,J=8.8 Hz),8·45 (1H,d,J=5.2 Hz). 'fife Example 333 i^LidL?·Difluoroacetamidylmercapto)-1H-吲哚-5- Hydrogen 1 - 6.L-Tian-苴: Querwei using 4-(1Η-吲哚-5-yloxy)-6,7-dimethoxyquinoline (75 mg, 0.3122 mmol), sodium hydride (π) Mg, 〇·3278 mmc) 1) and Ν·(2•fluoroethyl)amine-based ruthenium (45 mg, 0.3278 mmol) were reacted in the same manner as in Example 3 1 , using ethyl acetate and tetrahydrofuran. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate and evaporated. The residue was sorbed on a hydrazine gel, and then applied to a chrome column chromatography (hexanes ethyl acetate) to give the title compound (24 mg, 0.0586 _ 〇1, 18.78%) as colorless crystals. . W-NMR spectrum (DMSO-d6) 5 (ppm): 3.56 (1H, q, J = 5.0 Hz), 3.63 (1H, q, J = 5.0 Hz), 3.92 (3H, s), 3.96 (3H, s), 4·53 (1H, t, J=5.0 Hz), 4.65 (1H, t, J=5.0 Hz), 6.39 (1H, d, J 2 5.0 Hz), 6.71 (1H, d, J=3.8 Hz), 7.17 (1H, dd3 J=2.0 Hz, 8.8 Hz), 7.40 (1H, s), 7·49 (1H, d, J=2.0 Hz), 7·55 (1H, s ),7·96 (1H,d, J=3.8 Hz), 8.34 (1H, d3 J=8.8 Hz), 8.42 (1H, d, J=5.0 Hz), 8.48 (1H, t, J=5.0 Hz) . Example 334 - Dimethyl arsyl-4-(5-(1-(4-chloroindolyl)-thirsty) porphyrin-439 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂Binding

線 1304061 〜 、 A7 _______B7 五、發明説明（434 ) 將6,7-二甲氧基-4-(5-啕哚氧）喹啉（25 mg，0.0780 mmol ,記載於W0 9717329 , ρ·52)溶解於甲苯（1 6瓜丨），加 入異氰酸4-氟私醋（22 ml，0.1951 mmol，2.5 eqM)，並於 氮I氣下加熱回流5小時30分鐘。放冷後將反應液用乙酸乙 醋稀釋’用飽和食鹽水洗淨，用無水硫酸鎂乾燥並減壓餾 去溶媒’然後藉由矽凝膠管柱層析（己烷-乙酸乙酯系）精 製。將得到之結晶懸浮於乙醇中，將其用己烷稀釋，濾取 結晶，用己烷洗淨及吸引乾燥，得到為無色結晶之標題化 合物（18 mg，0.0393 mmol，50.44%)。 iH-NMR 光譜（CDCl3)5(ppm): 4·05 (3H，s)，4·07 (3H，s)， 6.43 (1Η, d, J=5.6 Hz), 6.72 (1H, d, J=3.4 Hz), 7.12 (2H, t, J=8.8 Hz)，7.22 (1H，dd，J=2.0, 8·8 Hz)，7·43 (3H，m)，7.53 (2H，m)，7·62 (1H，d，J=3.6 Hz)，7.63 (1H，s)，8·29 (1H，d， J=8.8 Hz)，8·46 (1H，d，J=5.6 Hz)。 實施例335 6,7-二甲氧基-4-「5-Π-(4-氣茉胺甲醯某吲哚）氣h套啉 藉由使用6,7-二甲氧基-4-(5-啕哚啉氧）喹啉（20 mg， 0.0620 mmol)進行與實施例334同樣之反應，得到為淡黃色 結晶之標題化合物（1 8 mg，0.0392 mmol，63 · 19% )。 1H-NMR 光譜（CDCl3)(5(ppm): 3.30 (2H，t，J=8.4 Hz)，4.05 (3H，s)，4.06 (3H，s)，4.12 (2H，t，J=8,4 Hz)，6.45 (1H，d， J=5.2 Hz)，6.47 (1H，br s)，7.01-7.07 (4H，m)，7·42 (2H，dd， J=9.2，13:2 Hz·)，7·43 (1H，s)，7·57 (1H，s)，8.04 (1H，d， J=8.8 Hz)，8·48 (1H，d，J=5.2 Hz)。 -440 - 本紙張尺度適财國@家標準(CNS) A4規格(210x 297公；f) 1304061 A7 B7 五、發明説明（435 ) 如下述合成中間體。 製造例335-t 6?7-二氣羞二吲哚淋氧、啐沘 將6,7-二甲氧基-4-(5-啕哚氧）喹啉（3〇邮，〇 〇78〇 mmol ’#己載於 w〇 9717329，Ρ·52)溶於三氟乙酸（0.9 ml)， 於冰冷下加入三乙矽烷（45 m卜0·2808 mmol，3.0 eqiM)， 並於氣蒙氣及室溫下攪掉4小時3〇分鐘。放冷後，將反應液 用乙酸乙醋稀釋，用飽和碳酸氫鏑水溶液中和，用乙酸乙 醋萃取’用飽和食鹽水洗淨，用無水硫酸鎂乾燥並減壓餾 去溶媒。將殘餘物用矽凝膠管柱層析（乙酸乙酯-乙醇系）精 製’得到為淡黃色結晶之標題化合物（2〇 mg，0.0620 mmol，66.28%)。 H-NMR光 if(CDCl3)5(ppm): 3.08 (2H，t，J=8.4 Hz)，3.65 (2H，t，J=8.4 Hz)，4·06 (6H，s)，6.48 (1H，d，J=5.4 Hz)，6.69 (1H，d，J=8.4 Hz)，6·84 (1H，dd，J=1.6, 8.4 Hz)，6.95 (1H，d， J=1.6 Hz)，7·49 (1H，s)，7.60 (1H，s)，8·48 (1H，d，J=5.4 Hz)。 實施例336 ϋ二(4-( 6-氰某- 7-Γ 2-曱氳乙氫基）-4-4啉某）氣笨某）-N’-(3-甲硫丙某 藉由與實施例11同樣之手法，從N-(4-(6-氰基-7-(2-甲氧 乙氧基）-4-喹啉基）氧苯基）胺基甲酸苯酯（40 mg，0.088 mmol)及3-(甲硫基）丙胺得到為白色結晶之標題化合物 (35.7 mg，0.077 mmol，87.1%) 〇 -441 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂 線 A7 B7 1304061 五、發明説明（436 ) iH-NMR 光譜（DMSO-d6)5(ppm): 1.68 (2H，m)，2·〇4 (3H s) 3·16 (2H，m)，3.18-3.35 (2H，m)，3.36 (3H，s)，3.76J.79 (2H m)，4.40-4.42 (2H，m)，6.23 (1H，t，J=5.6 Hz)，6.48 (1H d J=5.2 Hz)，7.16 (2H，d，J=9.2 Hz), 7·52 (2H，d，j=9.2 Hz)Line 1304061 ~, A7 _______B7 V. Description of the invention (434) 6,7-Dimethoxy-4-(5-oxime)quinoline (25 mg, 0.0780 mmol, described in W0 9717329, ρ·52) Dissolved in toluene (1 6 guanidine), added 4-fluoroacetic acid vinegar (22 ml, 0.1951 mmol, 2.5 eqM), and heated to reflux under nitrogen for 1 hour and 30 minutes. After cooling, the reaction mixture was diluted with ethyl acetate (washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove solvent) and then purified by gel column chromatography (hexane-ethyl acetate) refined. The obtained crystals were suspended in ethanol, and the crystals were crystallised eluted eluted eluted elute iH-NMR spectrum (CDCl3) 5 (ppm): 4·05 (3H, s), 4·07 (3H, s), 6.43 (1Η, d, J=5.6 Hz), 6.72 (1H, d, J= 3.4 Hz), 7.12 (2H, t, J=8.8 Hz), 7.22 (1H, dd, J=2.0, 8·8 Hz), 7·43 (3H, m), 7.53 (2H, m), 7· 62 (1H, d, J = 3.6 Hz), 7.63 (1H, s), 8.29 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 5.6 Hz). Example 335 6,7-Dimethoxy-4-"5-indole-(4-methane amide) oxime gas by using 6,7-dimethoxy-4-( The title compound (1 8 mg, 0.0392 mmol, 63 · 19%) was obtained as pale yellow crystals. Spectrum (CDCl3) (5 (ppm): 3.30 (2H, t, J = 8.4 Hz), 4.05 (3H, s), 4.06 (3H, s), 4.12 (2H, t, J = 8, 4 Hz), 6.45 (1H,d, J=5.2 Hz), 6.47 (1H, br s), 7.01-7.07 (4H, m), 7.42 (2H, dd, J=9.2, 13:2 Hz·), 7· 43 (1H, s), 7·57 (1H, s), 8.04 (1H, d, J = 8.8 Hz), 8.48 (1H, d, J = 5.2 Hz) -440 - The paper scale is suitable Country @家标准(CNS) A4 specification (210x 297 public; f) 1304061 A7 B7 V. Description of invention (435) Synthetic intermediates as described below. Manufacturing example 335-t 6?7-two sneezes, oxygen, 66,7-Dimethoxy-4-(5-oxime)quinoline (3〇 mail, 〇〇78〇mmol '#included on w〇9717329, Ρ·52) was dissolved in trifluoro Acetic acid (0.9 ml), added triethyl decane (45 m Bu 0·2808 mmol, 3.0 eqiM) under ice cooling And the mixture was stirred for 4 hours and 3 minutes at room temperature. After cooling, the reaction solution was diluted with ethyl acetate, neutralized with saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The mixture was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ , 66.28%) H-NMR light if (CDCl3) 5 (ppm): 3.08 (2H, t, J = 8.4 Hz), 3.65 (2H, t, J = 8.4 Hz), 4·06 (6H, s) , 6.48 (1H, d, J = 5.4 Hz), 6.69 (1H, d, J = 8.4 Hz), 6.84 (1H, dd, J = 1.6, 8.4 Hz), 6.95 (1H, d, J = 1.6 Hz), 7·49 (1H, s), 7.60 (1H, s), 8.48 (1H, d, J = 5.4 Hz). Example 336 ϋ (4-( 6-cyanyl- 7-Γ) 2-N-(4-(6-cyanide)-N-(3-methylthiopropanol) by the same method as in Example 11, from N-(4-(6-cyanide) Phenyl 7-(2-methoxyethoxy)-4-quinolinyloxyphenyl)carbamate (40 mg, 0.088 mmol) and 3-(methylthio)propylamine are obtained as white crystals. Title Compound (35.7 mg 0.077 mmol, 87.1%) 〇-441 - This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) Gutter A7 B7 1304061 V. Description of invention (436) iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.68 (2H, m), 2·〇4 (3H s) 3·16 (2H, m), 3.18-3.35 (2H, m), 3.36 (3H, s), 3.76J.79 ( 2H m), 4.40-4.42 (2H, m), 6.23 (1H, t, J = 5.6 Hz), 6.48 (1H d J=5.2 Hz), 7.16 (2H, d, J=9.2 Hz), 7·52 (2H,d,j=9.2 Hz)

7.61 (1H，s)，8·59 (1H，s)，8.70 (1H，d，J=4.〇 HZ)，8·75 (1H s)。-音施例337 Π-甲碏醯基丙基）脲 藉由與實施例11同樣之手法，從N-(4-(6-氰基甲氧 乙氧基）-4-喹啉）氧苯基）胺基甲酸苯酯（50 mg，〇丨丨mm()1) 及3-(甲磺醯基）丙胺得到為白色結晶之標題化合物（32·4 mg，0.065 mmol，59.2%) 〇 iH-NMR 光譜（DMS〇-d6)5(ppm): 1·85 (2H，m)，2.97 (3H，s)， 3.11 (2H，m)，3·21 (2H，m)，3.36 (3H，s)，3.77 (2H，m)，4.41 (2H，m)，6.30 (1H，m)，6·48 (1H，d，J=5.6 Hz)，7.16 (2H，d， J=8.8 Hz)，7·53 (2H，d，J=8.8 Hz)，7.61 (1H，s)，8.67 (1H，s)， 8.70 (1H，d，J=5.2 Hz)，8.75 (1H，s卜 f施例33 8 N-(4-(6-氰基- 7-(2-甲氧乙氧基套g林基）氫笨基 Γ甲磺醯基）脲 於氮蒙氣下，將氫化鈉（11 mg，0.275 mmol)懸浮於四氫 呋喃（8 ml)·中’於冰水冷卻下加入甲磺醯胺（3 1.4 mg， 0.330 mmol)後，於室溫授拌10分鐘。加入N-(4-(6-氰基- -442 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） 裝 訂7.61 (1H, s), 8.59 (1H, s), 8.70 (1H, d, J = 4. 〇 HZ), 8.75 (1H s). - Example 337 Π-Mercaptopropyl)urea from N-(4-(6-cyanomethoxyethoxy)-4-quinoline)oxybenzene by the same procedure as in Example 11. Phenyl phenyl carbamate (50 mg, 〇丨丨mm (1)) and 3-(methylsulfonyl) propylamine gave the title compound as white crystals (32·4 mg, 0.065 mmol, 59.2%) 〇iH -NMR spectroscopy (DMS 〇-d6) 5 (ppm): 1·85 (2H, m), 2.97 (3H, s), 3.11 (2H, m), 3·21 (2H, m), 3.36 (3H, s), 3.77 (2H, m), 4.41 (2H, m), 6.30 (1H, m), 6.48 (1H, d, J = 5.6 Hz), 7.16 (2H, d, J = 8.8 Hz), 7·53 (2H, d, J=8.8 Hz), 7.61 (1H, s), 8.67 (1H, s), 8.70 (1H, d, J = 5.2 Hz), 8.75 (1H, sb f Example 33 8 N-(4-(6-Cyano- 7-(2-methoxyethoxy)g-based)hydrogenated sodium sulfonate), sodium hydride (11 mg, 0.275 mmol) was suspended in tetrahydrofuran (8 ml)·························· Cyano--442 - This paper size applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) Binding

線 A7 B7 1304061 五、發明説明（437 ) 7-(2-甲氧乙氧基）-4-喹啉）氧苯基）胺基甲酸苯酯（50 mg , 0.110 mmol)並於60°C擴:拌1小時。濾去不溶物及減壓濃縮 後，加入四氫呋喃-己烷（1 : 2)使之結晶化，得到為灰白色 結晶之標題化合物（37.6 mg，0.082 mmol，75.0%)。 iH-NMR 光譜（DMS〇-d6)5(ppm): 2·75 (3H，s)，3.36 (3H，s)， 3·77 (2H，m)，4·41 (2H，m)，6.47 (1H，d，J=5,2 Hz)，7.05 (1H， d，J=8.8 Hz)，7.61 (2H，d，J=8.8 Hz)，7·64 (1H，s)5 8.44 (1H， s)，8·69 (2H，d，J=5.2 Hz)，8·75 (1H，s) 〇 實施例339 4-(4-(((4-氟表胺基）談基）胺基）笨氳基）-7-甲氣某- 6-4成 羧酸甲酯 &quot; 藉由與實施例10同樣之手法，從4-(4-胺基苯氧基）-7-曱 氧基-6-甲氧羰基喹淋（486 mg，1.5 mmol)及異氰酸4-氟苯 酉旨’得到為淡褐色結晶之標題化合物（600 mg，1.3 mmol , 86·80/〇)。 iH-NMR 光譜（DMSO-d6)5(ppm): 3.85 (3Η，s)，3·96 (3Η，s)， 6.46 (1H，d，J=5.2 Hz)，7·12 (2H，m)，7.23 (2H，d，J=8.8 Hz)， 7.46 (2H，m)，7.51 (1H，s)，7·58 (2H，d，J=8.8 Hz)，8.59 (1H， s)，8·67 (1H，d，J=5.2 Hz)，8·73 (1H，s)，8.82 (1H，s)。 藉由下述方法合成起始物質。 製造例339- 1 7-甲氧基-6-[氧幾基-4-(上硝基苽氧基奎啉 從WO 0Ό50405記載之4-氯甲氧基-6_甲氧羰基喹啉鹽 酸鹽（5.19g，18.0 mmol)，藉由與製造例丨丨同樣之手法得到 _______- 443 - 本成張尺度適用中國國私標準(CNS) A4規格(210 X 297公爱·） l3〇4〇6i五、發明説明（ A7 B7Line A7 B7 1304061 V. Description of the Invention (437) 7-(2-Methoxyethoxy)-4-quinolinyloxyphenyl)carbamic acid phenyl ester (50 mg, 0.110 mmol) and expanded at 60 ° C : Mix for 1 hour. The insoluble material was filtered, and the residue was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj iH-NMR spectrum (DMS〇-d6) 5 (ppm): 2·75 (3H, s), 3.36 (3H, s), 3·77 (2H, m), 4·41 (2H, m), 6.47 (1H,d,J=5,2 Hz), 7.05 (1H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 7·64 (1H, s)5 8.44 (1H, s), 8.69 (2H, d, J = 5.2 Hz), 8·75 (1H, s) 〇 Example 339 4-(4-(((4-)-fluoro-amino))) Alkyl group - 7-methyl gas - 6-4 alkyl carboxylate &quot; By the same procedure as in Example 10, from 4-(4-aminophenoxy)-7-decyloxy- 6-Methoxycarbonylquinone (486 mg, 1.5 mmol) and 4-fluorophenyl isocyanate were obtained as the title compound (600 mg, 1.3 mmol, 86·80 /?). iH-NMR spectrum (DMSO-d6) 5 (ppm): 3.85 (3Η, s), 3.96 (3Η, s), 6.46 (1H, d, J = 5.2 Hz), 7·12 (2H, m) , 7.23 (2H, d, J = 8.8 Hz), 7.46 (2H, m), 7.51 (1H, s), 7·58 (2H, d, J = 8.8 Hz), 8.59 (1H, s), 8· 67 (1H,d,J=5.2 Hz), 8.73 (1H, s), 8.82 (1H, s). The starting material was synthesized by the following method. Production Example 339- 1 7-Methoxy-6-[oxoyl-4-(4-nitromethoxyoxyquinoline) 4-chloromethoxy-6-methoxycarbonylquinoline hydrochloride as described in WO 0Ό50405 Salt (5.19g, 18.0 mmol), obtained by the same method as the manufacturing example _______- 443 - This is a standard for the Chinese National Private Standard (CNS) A4 specification (210 X 297 public love) l3〇4 〇6i 5, invention description (A7 B7

438 為淡褐色結晶之標題化合物（1.743 g，， 27.2%) 〇 iH-NMR 光譜（CDCl3)5(ppm): 3·97 (3Η，s)5 4.07 (3Η，s)， 6.62 (1H，d，J=5.2 Hz)，7·32 (2H，d，J=：9.2 Hz)，7·55 (1H，s)， 8·36 (2H，d, J=9.2 Hz)，8.69 (1H，s)，8·76 (1H，d，J=5.2438 is the title compound of light brown crystals (1.743 g, 27.2%) 〇iH-NMR spectrum (CDCl3) 5 (ppm): 3·97 (3Η, s) 5 4.07 (3Η, s), 6.62 (1H, d , J=5.2 Hz), 7·32 (2H, d, J=: 9.2 Hz), 7·55 (1H, s), 8·36 (2H, d, J=9.2 Hz), 8.69 (1H, s ),8·76 (1H,d,J=5.2

Hz) 〇 -製造例339-2 胺基笨氣基7-甲氡基-6-甲主羰基邊淋 從與製造例10同樣之方法，從7-甲氧基-6-甲氧羰基-4-(4 -硝基苯氧基）峻淋（1·73 g ’ 4.88 mmol)，得到為淡褐色 結晶之標題化合物（1 ·053 g ’ 3 ·25 mmol，66.5%)。 W-NMR 光譜（CDCl3)5(Ppm): 3.97 (3H，s)，4·〇4 (3H，s)， 6.42 (1H，d，J=5.2 Hz), 6·76 (2H，m)，6·98 (2H，m)，7·48 (1H， s)，8.61 (1H，d，J=5.2 Hz)，8·83 (1H，s)。 t施例340 1- 甲氣某-4-(4-((Π，3-4唑-2-基胺基）羰基）胺基）笨氣基）-奎〃林藉酸曱酯 藉由與實施例131同樣之手法，從4-(4-胺基苯氧基）-7-曱 氧基-6-甲氧羰基喹啉（486 mg，1·5 mmol)及N-(l，3-噻唑- 2- 基）胺基甲酸苯酯，得到為淡褐色結晶之標題化合物（306 mg，0.68 mmol，45.3%)。 W-NMR 光譜（DMS〇-d6)5(PPm): 3·85 (3H，s)，3·97 (3H，s)， 6.47 (1Η, d, J=5.2 Hz), 7.11 (1H3 br), 7.27 (2H, d, 1=9.2 Hz), 7.37 (1H，br)，7.52 (1H，s)，7·61 (2H，d，J=9.2 Hz), 8·59 (1H， -444 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）Hz) 〇-manufacturing example 339-2 Amino-based strepyl 7-methyl fluorenyl-6-methyl carbonyl fluorene was obtained in the same manner as in Production Example 10 from 7-methoxy-6-methoxycarbonyl-4 -(4-Nitrophenoxy) sulphate (1·73 g ' 4.88 mmol) gave the title compound (1·053 g ' 3 · 25 mmol, 66.5%). W-NMR spectrum (CDCl3) 5 (Ppm): 3.97 (3H, s), 4·〇4 (3H, s), 6.42 (1H, d, J = 5.2 Hz), 6·76 (2H, m), 6·98 (2H, m), 7·48 (1H, s), 8.61 (1H, d, J = 5.2 Hz), 8.83 (1H, s). t Example 340 1-Methane a 4-(4-((Π,3-4-3-ylamino)carbonyl)amino)amino)aminophene-quineline by acid oxime by Example 131, in the same manner, from 4-(4-aminophenoxy)-7-decyloxy-6-methoxycarbonylquinoline (486 mg, 1.5 mmol) and N-(l,3- The title compound (306 mg, 0.68 mmol, 45.3%) was obtained as a pale brown crystal. W-NMR spectrum (DMS〇-d6)5(PPm): 3·85 (3H, s), 3.97 (3H, s), 6.47 (1Η, d, J=5.2 Hz), 7.11 (1H3 br) , 7.27 (2H, d, 1=9.2 Hz), 7.37 (1H, br), 7.52 (1H, s), 7.61 (2H, d, J = 9.2 Hz), 8·59 (1H, -444 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

裝 訂Binding

1304061 A7 B7 五、發明説明（439 s)，8·67 (1H，d，J=5.2 Ηζ)，9·11 (1H，br)，1〇·53 (1H，br)。 實施例341 氟苯胺茱）羱4)胺基）茉氧其）-7-甲氫某-6-4啉 羧酸 在4-(4-(((4-氟苯胺基）羰基）胺基）苯氧基卜7-甲氧基·6-喹啉羧酸甲酯（300 mg，〇·65 mmol)中加入甲醇（9 ml)及2當 量氫氧化勒水溶液（3 ml)，於室溫攪拌2小時及於60°C攪拌 20分鐘。將反應液放冷至室溫，加入1當量鹽酸及中和後， 加入甲醇（6 ml)及水（6 ml)並攪拌一夜，濾取析出之淡褐色 結晶及減壓乾燥，得到標題化合物（227 mg，〇 51 mm〇l， 78.0%) 〇 W-NMR 光譜（DMSO-d6)5(ppm): 3.97 (3H，s)，6·49 (1H，d， J=5.2 Hz), 7.11 (2H, m), 7.23 (2H, d, J=8.8 Hz), 7.46 (2H, m)，7·49 (1H，s)，7·58 (2H，d，J=8.8 Hz)，8.57 (1H，s)，8.67 (1H，d，J=5.2 Hz), 8·75 (1H，s)，8.84 (1H，s)。 ίϋΐΐϋΐ 基胺某某）胺某）笨氣基1304061 A7 B7 V. INSTRUCTIONS (439 s), 8.67 (1H, d, J=5.2 Ηζ), 9·11 (1H, br), 1〇·53 (1H, br). Example 341 Fluoroaniline oxime) 羱 4) Amino) methoxy oxy) -7-methylhydro-6-phenyl carboxylic acid in 4-(4-((4-fluoroanilino)carbonyl)amino) Methyl phenoxy bromide 7-methoxy-6-quinolinecarboxylate (300 mg, 〇·65 mmol) was added with methanol (9 ml) and 2 EtOAc (3 mL). After stirring for 2 hours at 60 ° C for 20 minutes, the reaction solution was allowed to cool to room temperature, 1N hydrochloric acid was added and neutralized, methanol (6 ml) and water (6 ml) were added and stirred overnight, and the mixture was filtered. The title compound (227 mg, 〇51 mm ,l, 78.0%) 〇W-NMR spectrum (DMSO-d6) 5 (ppm): 3.97 (3H, s), 6·49 (1H) ,d, J=5.2 Hz), 7.11 (2H, m), 7.23 (2H, d, J=8.8 Hz), 7.46 (2H, m), 7·49 (1H, s), 7·58 (2H, d, J = 8.8 Hz), 8.57 (1H, s), 8.67 (1H, d, J = 5.2 Hz), 8·75 (1H, s), 8.84 (1H, s). a) stupid base

Lzig林藉醴 藉由與實施例341同樣之手法，從7-甲氧基-4-(4-(((l，3-4唆-2-基胺基）羰基）胺基）苯氧基喹啉羧酸甲酯（263 mg ’ 〇·58 mmol)，得到為淡褐色結晶之標題化合物（243 mg ’ 0.56 mmol，95.4%)。 i-NMR 光譜（DMSO-d6)d(ppm): 4.00 (3H，s)，6·63 (1H，d， j==5.2 Hz), 7.10 (1H, d, J=3.6 Hz), 7.31 (2H, d, J=8.8 Hz), ^ —___- 445 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱.) 1304061 A7 B7 五、發明説明（440 ) 7.36 (1H, d, J=3.6 Hz), 7.57 (1H, s), 7.65 (2H, d, J=8.8 Hz),8.62 (1H，s)，8.78 (1H，d，J=5.2 Hz)，9.64 (1H，s)。 實施例343 4_(4-(((4二氟苯胺某）羰基）胺基）茉氫某甲氫某-6〇杏琳 #酸2-丙酯 將4-(4-(((4-氟苯胺基）羰基）胺基）苯氧基）_7-甲氧基-6-奎淋幾酸（84 mg，0.19 mmol)溶於二甲基甲酿胺（1 mi)後， 於冰冷攪拌下加入1-乙基-3-(3-二甲胺丙基）羧醯亞胺鹽酸 鹽（54 rag，0.28 mmol)，1-羥基-1H-苯并三唑1水和物（38 mg，0·28 mmol)，三乙胺（0.079 ml，0.56 mmol)及 2-丙醇 (0.15 ml)並於室溫攪拌一夜。將反應液本身付諸於矽凝膠 管柱層析（溶出液；乙酸乙酯），將包含目的物之溶出部分 濃縮，懸浮於乙酸乙酯中，將其用己烷稀釋及濾取結晶， 藉由通風乾燥，得到為白色結晶之標題化合物（15.0 mg , 0·03 mmol，16%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): 1·32 (6H，d，J=6.4 Hz)， 3·95 (3H，s)，5.15 (1H，m)，6.45 (1H，d，J=5.2 Hz)，7.11 (2H， m)，7.23 (2H，d，J=9.2 Hz)，7·46 (2H，m)，7.50 (1H，s)，7·58 (2H，d，J=9.2 Hz)，8·48 (1H，s)，8.66 (1H，d，J=5.2 Hz)，8·73 (1H，s)，8.82 (1H，s)。 f施例344 氣笨胺某）羰基）胺基）笨氣基7-甲氣基-6^^ 羧酸2-甲氫美乙酯將4-(4-(((4-氟苯胺基）羰基）胺基）苯氧基）-7-甲氧基-6、Lzig Lin borrowed from 7-methoxy-4-(4-(((1,3-4唆-2-ylamino))carbonyl)amino)phenoxy group by the same procedure as Example 341. The title compound (243 mg '0.56 mmol, 95.4%) was obtained as a pale brown crystal. m.p. NMR (DMSO-d6) d (ppm): 4.00 (3H,s),6·63 (1H,d, j==5.2 Hz), 7.10 (1H, d, J=3.6 Hz), 7.31 (2H, d, J=8.8 Hz), ^ —___- 445 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public.) 1304061 A7 B7 V. Invention description (440 ) 7.36 (1H, d, J=3.6 Hz), 7.57 (1H, s), 7.65 (2H, d, J = 8.8 Hz), 8.62 (1H, s), 8.78 (1H, d, J = 5.2 Hz), 9.64 (1H, s). Example 343 4_(4-(((4) Fluoroaniline, carbonyl)amino), hydrazine, hydrogen, methyl hydrazine, -6 〇 琳 琳 #################################################################### After _7-methoxy-6-quinolinic acid (84 mg, 0.19 mmol) was dissolved in dimethylamine (1 mi), 1-ethyl-3-(3-dimethyl) was added under ice-cooling stirring. Aminopropyl)carboxylimine hydrochloride (54 rag, 0.28 mmol), 1-hydroxy-1H-benzotriene 1 Water and (38 mg, 0·28 mmol), triethylamine (0.079 ml, 0.56 mmol) and 2-propanol (0.15 ml) were stirred overnight at room temperature. Column chromatography (eluent; ethyl acetate), the fractions containing the desired material were concentrated, suspended in ethyl acetate, diluted with hexanes and filtered and crystallised. The title compound (15.0 mg, 0·03 mmol, 16%) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 1·32 (6H, d, J = 6.4 Hz), 3·95 (3H, s ), 5.15 (1H, m), 6.45 (1H, d, J = 5.2 Hz), 7.11 (2H, m), 7.23 (2H, d, J = 9.2 Hz), 7.46 (2H, m), 7.50 (1H, s), 7·58 (2H, d, J = 9.2 Hz), 8·48 (1H, s), 8.66 (1H, d, J = 5.2 Hz), 8.73 (1H, s), 8.82 (1H, s). f Example 344 gas stupid amine) carbonyl) amine) stupid base 7-methyl group-6^^ carboxylic acid 2-methylhydrogen ethyl ester 4-(4-((4-fluoroanilinyl)) Carbonyl)amino)phenoxy)-7-methoxy-6,

裝 訂Binding

線 -446 - 本紙張尺度通用中國國家標準(CNS) A4規格(210 X 297公釐）Line -446 - This paper scales the common Chinese National Standard (CNS) A4 specification (210 X 297 mm)

1304061 A7 B7 五、發明説明（441) 喹啉羧酸（84 mg，0.19 mmol)溶於二甲基甲醯胺〇 ml)後， 於冰冷攪拌下加入1-乙基- 3-( 3-二甲胺丙基）羧醯亞胺鹽酸 鹽（54 mg，0.28 mmol)，1-羥基-1H-苯并三唑1水和物（38 mg，0.28 mmol)，三乙胺（〇·〇79 m卜 0.56 mmol)及2-甲氧 基乙醇（0· 15 ml)並於室溫授拌一夜。將反應液本身付諸於 矽凝膠管柱層析（溶出液；乙酸乙酯），將包含目的物之溶 出部分濃縮，懸浮於乙酸乙酯中，將其用己烷稀釋及濾取 結晶，藉由通風乾燥，得到為白色結晶之標題化合物（471 mg，0.093 mmol，49.6%)。 iH-NMR光譜（DMS〇-d6)5(ppm): 3.29 (3H，s)，3.65 (2H，m)， 3·96 (3H，s)，4·40 (2H，m)，6.46 (1H，d，J=5.2 Ηζ)，7·11 (2H， m), 7.24 (2H, d, J=8.8 Hz), 7.46 (2H, m), 7.51 (1H, s), 7.58 (2H, d, J=8.8 Hz), 8.56 (1H, s)3 8.67 (1H, d, J=5.2 Hz), 8.73 (1H，s)，8·81 (1H，s)。 實施例345 1:-甲氧基-々-(Ή」：!，]-嘍唑基胺基）羰某）胺某）茉氣基 6-4啉藉醴2-甲氧乙酯 將7-甲氧基-4-( 4-(((1，3-嘍唑-2-基胺基）羰基）胺基）苯氧 基）-6-4淋幾酸（87.3 mg，0.20 mmol)溶於二甲基甲醯胺（1 ml)後，於冰冷攪拌下加入1-乙基-3-(3-二甲胺丙基）幾醯 亞胺鹽酸鹽（58 mg，0.30 mmol)，1-經基-1H-苯并三唑1水 和物（41 mg，0·30 mmol)，三乙胺（〇·〇84 m卜 0·60 mmol) 及2-甲氧乙胺（0.052 ml，0·60 mmol)並於室溫攪拌5小時。 將反應液分溶於乙酸乙酯及水中，將有機層用水洗淨及用 -447 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 、 A7 _ B7 五、發明説明（442 ) 無水硫酸鍰乾燥。餾去溶媒後，接續加入乙酸乙酯及己烷 以使結晶析出，濾取及減壓乾燥，得到為白色結晶之標題 化合物（24.4 mg，0.049 mmol，24.7%)。 ili-NMR 光譜（DMS〇-d6)5(ppm): 3·29 (3H，s)，3.48 (4H，s)， 4.02 (3Η, s), 6.47 (1H, d, J=5.2 Hz), 7.11 (1H5 br), 7.26 (2H3 d, J=8-.8 Hz), 7.37 (1H, br), 7.51 (1H5 s), 7.61 (2H5 d5 J=8.81304061 A7 B7 V. INSTRUCTIONS (441) After quinolinecarboxylic acid (84 mg, 0.19 mmol) dissolved in dimethylformamide 〇ml), 1-ethyl-3-(3-di) was added with ice-cooling stirring. Methylaminopropyl)carboxylimine hydrochloride (54 mg, 0.28 mmol), 1-hydroxy-1H-benzotriazole 1 water and (38 mg, 0.28 mmol), triethylamine (〇·〇79 mBu 0.56 mmol) and 2-methoxyethanol (0.15 ml) were stirred overnight at room temperature. The reaction solution itself was applied to a gel column chromatography (eluent; ethyl acetate), and the fractions containing the desired material were concentrated, suspended in ethyl acetate, diluted with hexane and filtered to crystallize. The title compound (471 mg, 0.093 mmol, 49.6%) was obtained as white crystals. iH-NMR spectrum (DMS 〇-d6) 5 (ppm): 3.29 (3H, s), 3.65 (2H, m), 3·96 (3H, s), 4·40 (2H, m), 6.46 (1H) ,d,J=5.2 Ηζ),7·11 (2H, m), 7.24 (2H, d, J=8.8 Hz), 7.46 (2H, m), 7.51 (1H, s), 7.58 (2H, d, J=8.8 Hz), 8.56 (1H, s)3 8.67 (1H, d, J=5.2 Hz), 8.73 (1H, s), 8.81 (1H, s). Example 345: 1:-methoxy-oxime-(Ή): !,]-carbazolylamino)carbonyl)amine (m)methane-based 6-phenone-dosing 2-methoxyethyl ester 7- Methoxy-4-(4-(((1,3-oxazol-2-ylamino)carbonyl))amino)phenoxy)-6-4 leucoic acid (87.3 mg, 0.20 mmol) is soluble After dimethylformamide (1 ml), 1-ethyl-3-(3-dimethylaminopropyl) quinone imine hydrochloride (58 mg, 0.30 mmol), 1- Hydrazine-1H-benzotriazole 1 water and compound (41 mg, 0·30 mmol), triethylamine (〇·〇 84 m Bu 0·60 mmol) and 2-methoxyethylamine (0.052 ml, 0 • 60 mmol) and stirred at room temperature for 5 hours. The reaction solution is dissolved in ethyl acetate and water, and the organic layer is washed with water and used -447 - This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061, A7 _ B7 V. Invention Description (442) Anhydrous barium sulfate is dried. After distilling off the solvent, ethyl acetate and hexane were added to give crystals, which were crystallized, and dried under reduced pressure to give the title compound (24.4 mg, 0.049 mmol, 24.7%). Ili-NMR spectrum (DMS〇-d6) 5 (ppm): 3·29 (3H, s), 3.48 (4H, s), 4.02 (3Η, s), 6.47 (1H, d, J = 5.2 Hz), 7.11 (1H5 br), 7.26 (2H3 d, J=8-.8 Hz), 7.37 (1H, br), 7.51 (1H5 s), 7.61 (2H5 d5 J=8.8

Hz)，8.44 (1H，s)，8·62 (1H，s)，8.65 (1H，d，J=5.2 Hz)，9.11 (1H，s), 10.54 (1H，s) 〇 實施例346 U氧基-7-甲氣基-4-(4-(((l，3-嘍唑-2-基胺某）蕤某、fe 基）本·乳基）-6 -邊淋讀酿胺 藉由與實施例345同樣之手法，從7-曱氧基-4-(4-(((l，3-4峻-2-基胺基）羰基）胺基）苯氧基-6-喹啉羧酸（55 mg， 〇· 13 mmol)及甲氧胺鹽酸鹽，得到為淡黃色結晶之標題化 合物（36.1 mg，0.078 mmol，61.5%)。 iH-NMR 光譜（DMS〇-d6)(5(ppm): 3.73 (3H，s)，3.97 (3H，s)， 6.47 (1H, d, 1=5.2 Hz), 7.11 (1H, br), 7.25 (2H, d3 J=8.8 Hz), 7.37 (1H, br), 7.48 (1H, s), 7.62 (2H, d, J=8.8 Hz), 8.44 (1H, s)，8·65 (1H，d，J=5.2 Hz)，9.11 (1H，s)，11.44 (1H，s)。 實施例347 ir (4-( 2,4-二氟笨胺某）羰基）胺基苯氧基7-甲氣基-6〇杏 藉由與實施例10同樣之方法，從4-(4-胺基苯氧基）-7-甲 氧基-6 一奎淋幾酿胺（50 mg，0.16 mmol)及異氰酸2,4-二氟 -448 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7Hz), 8.44 (1H, s), 8.62 (1H, s), 8.65 (1H, d, J = 5.2 Hz), 9.11 (1H, s), 10.54 (1H, s) 〇 Example 346 U Oxygen Benzyl-7-methyl-l-yl-4-(4-(((l,3-oxazol-2-ylamine)), fe))··········· The same procedure as in Example 345, from 7-decyloxy-4-(4-(((1, 3-4-thin-2-ylamino)carbonyl)amino)phenoxy-6-quinolinecarboxylate The title compound (36.1 mg, 0.078 mmol, 61.5%) was obtained as pale-yellow crystals (yield: </ br> Ppm): 3.73 (3H, s), 3.97 (3H, s), 6.47 (1H, d, 1 = 5.2 Hz), 7.11 (1H, br), 7.25 (2H, d3 J=8.8 Hz), 7.37 (1H , br), 7.48 (1H, s), 7.62 (2H, d, J=8.8 Hz), 8.44 (1H, s), 8·65 (1H, d, J=5.2 Hz), 9.11 (1H, s) , 11.44 (1H, s). Example 347 ir (4-( 2,4-difluoromethaneamine)carbonyl)aminophenoxy 7-carbyl-6 anthracene was the same as in Example 10. Method, from 4-(4-aminophenoxy)-7-methoxy-6-quinidine-amine (50 mg, 0.16 mmol) and isocyanic acid 2,4-difluoro-448 - paper Scale applicable National Standards (CNS) A4 size (210 X 297 mm) 1304061 A7

未醋’仔到為淡黃色結晶之標題化合物（59.9 mg，q p mmol，79.8%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): 4,00 (3H，s)，6·4ό d J=5.2 Hz)，7.03 (1H，m)，7·23 (2H，d，J=8.8 Hz)，7.33 (1H m)，7.50 (1H，s)，7.58 (2H，d，J=8.8 Hz)，7·72 (1H，s)，7 (1H, s), 8.07 (1H, m), 8.52 (1H, s), 8.64 (1H, d, J=5.2 Hz) 8·67 (1H，s)，9·16 (1H，s)。 ’ 以下述方法合成起始物質。 製造例347- 1 胺基苯氧基）-7-甲氣基-6-4嘥淼sfefe 從製造例14記載之4-(4-胺基苯氧基）-6-氰基-7-甲氧基嗜 琳（4.76 g，11.6 mmol)，藉由與實施例112同樣之手法得到 為淡黃色結晶之標題化合物（1.56 g，5·0 mmol，43.4%)。 1H-NMR 光譜（DMSO-d6)5(ppm): 4·00 (3H，s)，5.15 (2H，m) 6.39 (1H, d, J=5.2 Hz), 6.65 (2H, d, J=8.8 Hz), 6.92 (2H, d &gt;8.8 Hz), 7·46 (1H，s)，7·70 (1H，s)，7·83 (1H，s)，8.60 (ih， d，J=5.2 Hz)，8·66 (1H，s)。 ’ t施例348 氣笨胺基）某V4-曱胺芄氫基）-7-曱氫甚 鼓醯胺 藉由與實施例10同樣之方法，從7-甲氧基- 4-(4-甲胺基苯 氧基）-6-峻淋致酿胺（288 mg，0.89 mmol)及異氰酸4-氟苯 醋，得到為白色結晶之標題化合物（265 mg，0.58 mmol， 64.6%) 〇 -449 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 x 297公釐)The title compound (59.9 mg, qp mmol, 79.8%) 未iH-NMR spectrum (DMSO-d6) 5 (ppm): 4,00 (3H, s), 6.4 ό d J=5.2 Hz), 7.03 (1H, m), 7·23 (2H, d, J=8.8 Hz), 7.33 (1H m), 7.50 (1H, s), 7.58 (2H, d, J=8.8 Hz) ),7·72 (1H, s), 7 (1H, s), 8.07 (1H, m), 8.52 (1H, s), 8.64 (1H, d, J=5.2 Hz) 8·67 (1H, s ), 9·16 (1H, s). The starting material was synthesized by the following method. Production Example 347-1 Aminophenoxy)-7-methylglycol-6-4嘥淼sfefe 4-(4-Aminophenoxy)-6-cyano-7-A described in Production Example 14. The title compound (1.56 g, 5·0 mmol, 43.4%) was obtained as pale yellow crystals. 1H-NMR spectrum (DMSO-d6) 5 (ppm): 4·00 (3H, s), 5.15 (2H, m) 6.39 (1H, d, J = 5.2 Hz), 6.65 (2H, d, J = 8.8 Hz), 6.92 (2H, d &gt; 8.8 Hz), 7·46 (1H, s), 7·70 (1H, s), 7·83 (1H, s), 8.60 (ih, d, J=5.2 Hz), 8.66 (1H, s). ' 例 Example 348 gas aminyl) a V4-Amidino hydrazino)-7-hydrazine hydrogen sulfoxime by the same method as in Example 10, from 7-methoxy-4-(4- Methylaminophenoxy)-6-anthracene (288 mg, 0.89 mmol) and 4-fluorobenzene acetoacetate afforded the title compound (265 mg, 0.58 mmol, 64.6%) -449 - This paper size is applicable to China National Standard (CNS) Α4 specification (210 x 297 mm)

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綠 1304061 A7 B7 五、發明説明（444 ) iH-NMR 光譜（DMSCUd6)(5(ppm): 3·29 (3H，s)，4·00 (3H，s)， 6·65 (1Η，d，J=5.2 Ηζ)，7·06 (2Η，m)，7·32 (2Η，d，J=8.8 Ηζ)， 7·41-7·48 (4H，m)5 7·51 (1H，s)，7.73 (1H，s)，7·85 (1H，s)， 8·23 (1H，s)，8·67 (1H，s)，8·69 (1H，d，J=5.2 Hz)。 如下述合成起始物質^ 製造例348-1 7-甲乳基-4-(4-甲胺基笨氧基）-6 -g杳说酿胺 將4-甲胺基酴（1·〇4 g，8·45 mmol)溶於二甲基亞鐵（1〇 ml) ’然後於室溫慢慢加入氫化麵（290 mg，8·45 mmol)並 攪拌20分鐘。加入製造例152-3得到之7-甲氧基-4_氯奎 啉羧醯胺（l.OOg，4.23 mmol)並於100。〇加熱攪拌3小時。冷 卻至室溫，將反應液分溶於乙酸乙酯及水中，將有機層用 水及飽和食鹽水洗淨及用無水硫酸鈉乾燥。餘去溶媒，然 後付諸於矽凝膠管拄層析（溶出液；乙酸乙g旨），將包本目 的物之溶出部分濃縮，懸浮於乙酸乙酯中，將其用己燒稀 釋及濾取結晶，藉由通風乾燥，得到為白色結晶之標題化 合物（815 mg，2.52 mmol，59.6%)。 H-NMR 光譜（CDCl3)(5(ppm): 2,88 (3H，s)，4·〇9-4·16 (4H m)，5.88 (1Η，br)，6·45 (1Η，d，J=5.6 Ηζ)，6.68 (2Η，m) 7 01 (2H，m), 7·51 (1H，s)，7.80 (1H，br)，8.61 (1H，d，6 Hz) 9·31(1Η，§)。 ， * 實施例349 L甲氣某-4“ 4-((2-4唑胺基）羰某H 啉羚醯脖 __ - 450 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)Green 1304061 A7 B7 V. Description of invention (444) iH-NMR spectrum (DMSCUd6) (5 (ppm): 3·29 (3H, s), 4·00 (3H, s), 6·65 (1Η, d, J=5.2 Ηζ),7·06 (2Η,m),7·32 (2Η,d,J=8.8 Ηζ), 7·41-7·48 (4H,m)5 7·51 (1H,s) , 7.73 (1H, s), 7.85 (1H, s), 8·23 (1H, s), 8.67 (1H, s), 8.69 (1H, d, J = 5.2 Hz). Synthetic starting material ^ Manufacturing Example 348-1 7-Methyllacyl-4-(4-methylaminophenyloxy)-6-g杳 said brewing amine 4-methylamino hydrazine (1·〇4 g , 8.45 mmol) was dissolved in dimethyl ferrous iron (1 〇 ml). Then, a hydrogenation surface (290 mg, 8.45 mmol) was slowly added at room temperature and stirred for 20 minutes. 7-methoxy-4_chloroquinoline carboxamide (1.0 g, 4.23 mmol) and stirred at 100 ° C for 3 hours. Cooled to room temperature, the reaction solution was dissolved in ethyl acetate and water, The organic layer is washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent is removed, and then applied to a gel column chromatography (eluate; acetic acid) to concentrate the dissolved portion of the target product. , suspended in ethyl acetate The title compound (815 mg, 2.52 mmol, 59.6%) was obtained as white crystals (H.sub.2) (5 (ppm): 2,88. (3H, s), 4·〇9-4·16 (4H m), 5.88 (1Η, br), 6·45 (1Η, d, J=5.6 Ηζ), 6.68 (2Η, m) 7 01 (2H , m), 7·51 (1H, s), 7.80 (1H, br), 8.61 (1H, d, 6 Hz) 9·31 (1Η, §). , * Example 349 L 甲甲-4 4-((2-4 oxazolamido)carbonyl carbonyl H 啉 醯 _ __ - 450 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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線 1304061 一 A7 _ B7 五、發明説明（445 ) 藉由與實施例13 1同樣之方法，從6-胺曱醯基-7·甲氧基· 4-(4-甲胺基苯氧基）喹啉（5〇 mg，0.16 mm〇1)及N-(1，3•噻 唆-2-基）胺基甲酸苯酯，得到為白色結晶之標題化合物 (33.0 mg，〇·〇73 mmol，47·5%)。 i：H-NMR 光譜（DMS〇-d6)(5(ppm): 3.37 (3H，s)，4.02 (3H，s)， 6.64 (1H, br), 7.02 (1H, br), 7.30-7.33 (3H, m), 7.47 (2H, d, J=8.8 Hz)，7·51 (1H，s)，7.72 (1H，s)，7·85 (1H，s)，8.67 (1H， s)，8·69 (1H，d，J=5.2 Hz)。 實施例350 環丙胺羰基胺基笨氣某）-7·甲轰甚违啉羧 醯胺 藉由與實施例11同樣之手法，從N-(4-(6-胺甲酿基-7-甲 氧基-4-喹啉基）氧苯基）-N-曱基胺基曱酸4-硝基苯酯（73 mg，0.15 mmol)及環丙胺，得到為白色結晶之標題化合物 (30.0 mg，0·073 mmol，49.4%)。 iH-NMR 光譜（DMSO-d6)5(ppm)·· 〇·4ΐ (2H，m)，0·54 (2H, m)， 2·50 (1Η，m)，3·16 (3Η，s)，4·〇3 (3Η，s)，6·27 (1Η，d，Line 1304061 - A7 _ B7 V. Description of the Invention (445) From the same procedure as in Example 13 1 , from 6-aminoindol-7-methoxy-4-(4-methylaminophenoxy) Quinoline (5 〇 mg, 0.16 mm 〇 1) and N-(1,3 thiazol-2-yl) phenyl carbamate, the title compound (33.0 mg, 〇·〇 73 mmol, 47.5%). i:H-NMR spectrum (DMS〇-d6) (5 (ppm): 3.37 (3H, s), 4.02 (3H, s), 6.64 (1H, br), 7.02 (1H, br), 7.30-7.33 ( 3H, m), 7.47 (2H, d, J=8.8 Hz), 7·51 (1H, s), 7.72 (1H, s), 7.85 (1H, s), 8.67 (1H, s), 8 · 69 (1H, d, J = 5.2 Hz). Example 350 Cyclopropylamine carbonylamine group stupid -7-methyl carbamide carboxy carbamide The same procedure as in Example 11 from N-( 4-(6-Aminomethyl-7-methoxy-4-quinolinyl)oxyphenyl)-N-decylamino decanoic acid 4-nitrophenyl ester (73 mg, 0.15 mmol) and ring The title compound (30.0 mg, 0. 073 mmol, 49.4%). iH-NMR spectrum (DMSO-d6) 5 (ppm)··〇·4ΐ (2H, m), 0·54 (2H, m), 2·50 (1Η, m), 3·16 (3Η, s) ,4·〇3 (3Η,s),6·27 (1Η,d,

Hz)，6.60 (1H，d，J=5.6 Hz)，7.27 (2H，m)，7.36 (2H，m)， 7·52 (1H，s)，7·73 (1H，s)，7·85 (1H，s)，8·66 (1H，s)，8·69 (1H，d，J=5.6 Hz)。 藉由下述方法合成起始物質。 製造例350- 1 〜（4-(6-胺甲痕羞，7-甲氧基-4-啐毗摹）氣笨某）_^甲羞^ 基甲酸4 -减基笨醋 • 451 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（446 ) 藉由與製造例17同樣之方法，從6-胺甲醯基_7_甲氧基_4-(心甲胺基苯氧基）喹啉（323 mg ,丨〇〇 mm〇1)及氯甲酸4·硝 基苯醋，得到為淡黃色結晶之標題化合物（373 mg, 〇〇76 mmol，76.4%)。 lH-NMR 光譜（CDCl3)5(ppm): 3·47 (3H，s)，4·15 (3H，s)， 5.89 (1Η, br), 6.56 (1H, d3 J=5.6 Hz), 7.23-7.45 (6H, m), 7·56 (1H，s)，7.82 (1H，s)，8·27 (2H，d，J=8.8 Hz)，8.69 (1H， d，J=5.6 Hz)，9.29 (1H，s)。 實施例351 氧基-4-(4-(( 3-曱硫基丙胺基）卷甚）_4·甲胺某笨氣 6-4淋#醯胺 藉由與實施例11同樣之手法，從Ν-(4-(6-胺曱酿基-7-甲 氧基-4-喹啉基）氧苯基）-Ν-甲基胺基甲酸4-硝基苯酯（73 mg，0.15 mmol)及3-(甲硫基）環丙胺，得到為白色結晶之 標題化合物（44.8 mg，0.099 mmol，65.9%)。 iH-NMR 光譜（DMS〇-d6)(5(ppm): 1.64 (2H，m)，2·01 (3H，s)， 2·42 (2H，m)，3.09 (2H，m)，3·16 (3H，s)，4·01 (3H，s)5 6·17 (1H, t, J=5.6 Hz), 6.59 (1H, d, J=5.2 Hz), 7.28 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=8.8 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H，s)，8·65 (1H，s)，8·67 (1H，d，J=5.2 Hz)。 實施例359 甲磺醯基丙胺基j羰基）-4-甲胺某笨氳某 羞..：6'4：淋#醯胺 藉由與實施例11同樣之手法，從N-(4-(6-胺甲醯基-7-甲 452 本畝張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 … A7 B7 五、發明説明（447 ) 氧基-4-喹啉基）氧苯基）-N-甲基胺基甲酸4-硝基苯酯（73 mg，0.15 mmol)及3-(甲磺醯基）丙胺，得到為白色結晶之 標題化合物（42.7 mg，0.088 mmol，58.7%)。 iH-NMR光譜（DMSO-d6)5(ppm): 1.81 (2H，m)，2·94 (3H，s)， 3.06 (2Η，m)，3·12 (2Η，m)，3.17 (3Η，s)，4.01 (3Η，s)，6·26 (1H, t5 J-5.6 Hz), 6.60 (1H, d, J=5.2 Hz), 7.28 (2H, d, J=8.8 Hz)，7·39 (2H，d，J=8.8 Hz)，7.51 (1H，s)，7·72 (1H，s)，7.84 (1H，s)，8·65 (1H，s)，8·68 (1H，d，J=5.2 Hz)。 f施例353 4-(3-氟= 4-((3-甲硫基丙胺基）羰基）胺某茉氲甚甲氣 某-6-4啉羧醯胺 藉由與實施例11同樣之手法，從N-(4-(6-胺甲醯基-7-甲 氧基-4-4°林基）氧-2-氟苯基）胺基甲酸4-苯酉旨（89.5 mg， 0·20 mmol)及3-(甲硫基）丙胺，得到為淡褐色結晶之標題 化合物（71·1 mg，0.155 mmol，77.5%)。 iH-NMR光 1f(DMSO-d6)5(ppm): ΐ·69 (2H，m)，2.04 (3ΙΊ，s)， 2.04-2.05 (2Η，m)，3·17 (2Η，m)，4·01 (3Η，s)，6·51 (1Η，d， J=5.2 Hz)，6·65 (1H，t，J=6.0 Hz)，7·05 (1H，d，J=9.6 Hz), 7.30 (1H，dd，J=2.8，11·6 Hz)，7.49 (1H，s)，7.71 (1H，s)， 7.83 (1H，s)，8·21 (1H，m)，8.33 (1H，s)，8.64-8.65 (2H，m)。 用下述方法合成起始物質。 製造例3 5 3 - 1Hz), 6.60 (1H, d, J = 5.6 Hz), 7.27 (2H, m), 7.36 (2H, m), 7·52 (1H, s), 7.73 (1H, s), 7.85 (1H, s), 8.66 (1H, s), 8.69 (1H, d, J = 5.6 Hz). The starting material was synthesized by the following method. Production Example 350-1~(4-(6-Amine Axie, 7-Methoxy-4-pyrene) Gas Stupid)_^甲羞^ Benzoic acid 4 - Substituted vinegar • 451 - Ben The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Inventive Note (446) By the same method as in Production Example 17, from 6-aminomercapto-7-methoxy _4-(cardiamine phenoxy)quinoline (323 mg, 丨〇〇mm〇1) and 4·nitrophenyl chloroformic acid, the title compound (373 mg, 〇〇 76 mmol, 76.4%). lH-NMR spectrum (CDCl3) 5 (ppm): 3·47 (3H, s), 4·15 (3H, s), 5.89 (1Η, br), 6.56 (1H, d3 J=5.6 Hz), 7.23- 7.45 (6H, m), 7·56 (1H, s), 7.82 (1H, s), 8.27 (2H, d, J = 8.8 Hz), 8.69 (1H, d, J = 5.6 Hz), 9.29 (1H, s). Example 351 oxy-4-(4-((3-indolethiopropylamino) ruthenium) _4. methylamine a stupid gas 6-4 leaching # 醯 amine by the same method as in Example 11, from Ν -(4-(6-Amine-branched-7-methoxy-4-quinolinyl)oxyphenyl)-indole-methylaminocarbamic acid 4-nitrophenyl ester (73 mg, 0.15 mmol) <RTIgt; , 2·01 (3H, s), 2·42 (2H, m), 3.09 (2H, m), 3·16 (3H, s), 4·01 (3H, s) 5 6·17 (1H, t, J=5.6 Hz), 6.59 (1H, d, J=5.2 Hz), 7.28 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=8.8 Hz), 7.50 (1H, s) , 7.72 (1H, s), 7.84 (1H, s), 8.65 (1H, s), 8.67 (1H, d, J = 5.2 Hz). Example 359 methanesulfonyl propylamine j carbonyl) -4-Methylamine is awkward and shy..:6'4: leaching #醯amine by the same method as in Example 11, from N-(4-(6-aminocarbamimid-7-methyl 452) The mu scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ... A7 B7 V. Description of Invention (447) Oxy-4-quinolinyl)oxyphenyl)-N- 4-Nitrophenyl carbazide (73 mg, 0.15 mmol) and 3-(methylsulfonyl) propylamine gave the title compound (42.7 mg, 0.088 mmol, 58.7%) as white crystals. (DMSO-d6) 5 (ppm): 1.81 (2H, m), 2·94 (3H, s), 3.06 (2Η, m), 3·12 (2Η, m), 3.17 (3Η, s), 4.01 (3Η, s), 6.26 (1H, t5 J-5.6 Hz), 6.60 (1H, d, J=5.2 Hz), 7.28 (2H, d, J=8.8 Hz), 7·39 (2H,d , J=8.8 Hz), 7.51 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 8·65 (1H, s), 8.68 (1H, d, J=5.2 Hz) f Example 353 4-(3-Fluoro= 4-((3-methylthiopropylamino)carbonyl)amine a certain jasmine, a gas, a -6-4 carboxy carboxamide, and Example 11 The same procedure, from N-(4-(6-aminocarbazyl-7-methoxy-4-4°-based)oxy-2-fluorophenyl)carbamic acid 4-benzoquinone (89.5 mg) The title compound (71·1 mg, 0.155 mmol, 77.5%) was obtained as pale brown crystals. iH-NMR light 1f (DMSO-d6) 5 (ppm): ΐ·69 (2H, m), 2.04 (3ΙΊ, s), 2.04-2.05 (2Η, m), 3·17 (2Η, m), 4 ·01 (3Η, s), 6·51 (1Η, d, J=5.2 Hz), 6.65 (1H, t, J=6.0 Hz), 7·05 (1H, d, J=9.6 Hz), 7.30 (1H, dd, J=2.8, 11·6 Hz), 7.49 (1H, s), 7.71 (1H, s), 7.83 (1H, s), 8. 21 (1H, m), 8.33 (1H, s), 8.64 - 8.65 (2H, m). The starting material was synthesized by the following method. Manufacturing Example 3 5 3 - 1

差甲酷基基-4-喹咪基）氣-2-氣茉某）胺基 甲酸苯IL _______ - 453 - 本紙張尺度適用中國國家揉準(CNS) Α4規格(210X 297公穿) 1304061 A7 B7 五、發明説明（448 ) 藉由與製造例17同樣之方法，從6-胺甲醯基-7-甲氧基-4-(3 -氣-4-胺.基苯氧基）tr奎琳（752 mg，2.30 mmol)，得到為淡 κ色結晶之標題化合物（39 1.5 mg，0.875 mmol，38· 1 %)。 iH-NMR 光譜（CDCl3)5(ppm): 4.14 (3H，s)，5·92 (1H，s)， 6·52 (1Η，d，J=5.6 Ηζ)，7.02 (2Η，m)，7.21-7.31 (4Η，m)， 7·43 (2H，m)，7.55 (1H，s)，7.81 (1H，s)，8.23 (1H，b〇, 8.68 (1H，d，J=5,6 Hz)，9·27 (1H，s)。 實施例3.54 甲碚8產基丙胺基）羰基）胺甚1氣基甲蒼 基二林淼Sfe 藉由與實施例11同樣之手法，從N-(4-(6-胺甲醯基-7-甲 氧基-4-喹淋基）氧-2-氟苯基）胺基甲酸4-苯酯（89.5 mg , 〇·20 mm〇l)及3-(甲磺醯基）丙胺，得到為白色結晶之標題 化合物（41.3 mg，0.084 mmol，42.1%)。 1H-NMR 光譜（DMSO-d6)5(ppm): 1.85 (2H，m)，2.97 (3H，s)， 3·12 (2H，m)，3.21 (2H，m)，4·01 (3H，s)，6·51 (1H，d，J=5.2差甲基基基-4-Quinimiyl) gas-2-气茉) Amino benzoic acid benzene IL _______ - 453 - This paper scale is applicable to China National Standard (CNS) Α4 specification (210X 297 public wear) 1304061 A7 B7 V. Inventive Note (448) From the same method as in Production Example 17, from 6-aminomethylmethyl-7-methoxy-4-(3-air-4-amine-phenoxy)tr. The title compound (39 1.5 mg, 0.875 mmol, 38. 1%) was obtained as pale crystals. iH-NMR spectrum (CDCl3) 5 (ppm): 4.14 (3H, s), 5.92 (1H, s), 6·52 (1Η, d, J=5.6 Ηζ), 7.02 (2Η, m), 7.21. -7.31 (4Η,m), 7·43 (2H,m),7.55 (1H,s),7.81 (1H,s),8.23 (1H,b〇, 8.68 (1H,d,J=5,6 Hz ), 9·27 (1H, s). Example 3.54 formazan-8-based propylamino)carbonyl)amine 1 gas-methyl-cylylene hydrazine Sfe By the same procedure as in Example 11, from N-( 4-(6-Aminomethylamido-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)carbamic acid 4-phenyl ester (89.5 mg, 〇·20 mm〇l) and 3 - (Methanesulfonyl) propylamine gave the title compound (41.3 mg, 0.084 mmol, 421. 1H-NMR spectrum (DMSO-d6) 5 (ppm): 1.85 (2H, m), 2.97 (3H, s), 3·12 (2H, m), 3.21 (2H, m), 4·01 (3H, s),6·51 (1H,d,J=5.2

Hz), 6.73 (1H, t, J=5.6 Hz), 7.05 (1H, d, J=9.6 Hz), 7.31 (1H, dd，J=2.8, 11.6 Hz)，7.50 (1H，s)，7·72 (1H，s)，7·83 (1H，s)， 8.20 (1H，m)，8.40 (1H，s)，8.64-8.66 (2H，m)。 實施例3 5 5 -乱-4- ((2,2,2-三氟乙胺基）羰基）胺某笨氣基）_7_甲争| 基-6-4琳#醯胺 藉由與貪施例11同樣之手法，從N-( 4-(6-胺甲醯基.7·甲 氧基-4-嗜淋基）乳-2-氟苯基）胺基甲酸苯g§ (67 mg，0.15 -454 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)Hz), 6.73 (1H, t, J=5.6 Hz), 7.05 (1H, d, J=9.6 Hz), 7.31 (1H, dd, J=2.8, 11.6 Hz), 7.50 (1H, s), 7· 72 (1H, s), 7·83 (1H, s), 8.20 (1H, m), 8.40 (1H, s), 8.64-8.66 (2H, m). Example 3 5 5 - chaotic-4-((2,2,2-trifluoroethylamino)carbonyl)amine a stupid base)_7_甲争 | 基-6-4琳#醯胺用与贪Example 11 is the same procedure as N-(4-(6-Aminomethyl-7-methoxy-4-indolyl) lacto-2-fluorophenyl)carbamic acid benzene g§ (67 mg , 0.15 -454 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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線 1304061 A7 B7 五、發明説明（449 ) mmol)及2,2,2-三氟乙胺，得到為淡褐色結晶之標題化合物 (47.4 mg，·〇·1〇5 mmol，69.9%) 〇 WNMR 光譜（DMS〇-d6)(5(ppm): 3·96 (2H，m)，4·〇2 (3H，s)， 6.53 (1Η，d，J=5.2 Ηζ)，7.09 (1Η，d，J=8.8 Ηζ)，7.17 (1Η，t， J=6.4 Hz), 7.35 (1H, dd, J=2.85 11.6 Hz)3 7.50 (1H, s), 7.72 (1H，7·84 (1H，s)，8.16 (1H，m)，8.51 (ih，s)，8.64-8.67 (2H，m)。 ，， 實施例3.56 ir.d ((_3·-乙乳基丙胺卷)羰基）胺基_3·牟』笨氧甚甲氧 基林卷醯胺 藉由與貫施例11同樣之手法，從N-( 4-(6-胺甲醯基-7-甲 氧基-4-喳啉基）氧-2-氟苯基）胺基甲酸苯酯（67 mg , 〇15 mmol)及3-乙氧基丙胺，得到為淡褐色結晶之標題化合物 (45.2 mg ’ 0.099 mmol，66.0%)。 H-NMR 光譜（DMSO-dJ (5 (ppm): 1.10 (3H，t，J=7.2 Hz)， 1.65 (2H，m)，3·14 (2H，q，J=7.2 Hz)，3.35-3.44 (4H，m)， 4.01 (3H，s)，6·52 (1H，d，J=5.2 Hz)，6·61 (1H，m)，7.05 (1H， d5 J=8.8 Hz), 7.31 (1H, dd, J=2.8, 11.6 Hz), 7.50 (1H, s), 7.72(1H，s)，7.84(1H，s)，8.22(1H，s)，8.35(1H，s)，8.64-8·67 (2H，m) 〇 實施例357 1·.(3-氟-4-(( 2-氣乙胺某）諾某）胺某笨氣基）-7-甲氫某-6-v奎淋教酿胺 藉由與實施例11同樣之手法，從N-(4-(6 -胺甲酿基-7·甲 -455 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）Line 1304061 A7 B7 V. Inventive Description (449) mmol) and 2,2,2-Trifluoroethylamine, the title compound (47.4 mg,············· Spectrum (DMS〇-d6) (5 (ppm): 3·96 (2H, m), 4·〇2 (3H, s), 6.53 (1Η, d, J=5.2 Ηζ), 7.09 (1Η, d, J=8.8 Ηζ), 7.17 (1Η, t, J=6.4 Hz), 7.35 (1H, dd, J=2.85 11.6 Hz)3 7.50 (1H, s), 7.72 (1H,7·84 (1H, s) , 8.16 (1H, m), 8.51 (ih, s), 8.64 - 8.67 (2H, m).,, Example 3.56 ir.d ((_3·-ethyllacyl propylamine) carbonyl)amine _3·牟 笨 笨 甚 methoxy methoxy oxime oxime amide by the same method as in Example 11, from N-(4-(6-aminocarbamido-7-methoxy-4-indolyl)oxy Benzyl-2-fluorophenyl)carbamate (67 mg, 〇15 mmol) and 3-ethoxypropylamine afforded the title compound (45.2 mg &lt; Spectrum (DMSO-dJ (5 (ppm): 1.10 (3H, t, J = 7.2 Hz), 1.65 (2H, m), 3·14 (2H, q, J = 7.2 Hz), 3.35-3.44 (4H, m), 4.01 (3H, s), 6.52 (1H, d, J = 5.2 Hz), 6.61 (1H, m), 7.05 (1H D5 J=8.8 Hz), 7.31 (1H, dd, J=2.8, 11.6 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 8.22 (1H, s), 8.35 (1H, s), 8.64-8·67 (2H, m) 〇 Example 357 1·. (3-Fluoro-4-((2-ethylethylamine)) a certain amine base)-7 -Methylhydro-6-v quinone-branched amine was applied in the same manner as in Example 11 from N-(4-(6-aminoglycol-7-methyl-455) paper scale applicable to China Standard (CNS) A4 size (210 X 297 mm)

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線 1304061 、 ' ' A7 B7 五、發明説明（450 ) — 氧基-4-p奎淋基）氧-2-#L麥基）胺基甲酸苯g旨（33 mg，0.074 mmol)及2-氟乙胺鹽酸鹽’得到為淡褐色結晶之標題化合物 (23.9 mg，0.057 mmol，77.8%)。 ^-NMR 光請（DMSO-d6)5(ppm): 3.08 (2H，m)，4·02 (3H，s)， 4.40 (1Η，t，J=5.2 Ηζ)，4.52 (1Η，t，J=5.2 Ηζ)，6·55 (1Η，d， J-5.2 Hz), 6.88 (1H, m)3 7.08 (1H, d, J=9.2 Hz), 7.33 (1H, dd，J=2.8, 11.6 Hz)，7.51 (1H，s)，7.74 (1H，s)，7.85 (1H，s)， 8·21 (1H，m)，8.51 (1H，s)，8.65 (1H，s)，8.67 (1H，d，J=5.2Line 1304061, ' ' A7 B7 V, invention description (450 ) - oxy-4-p quinolyl) oxy-2-#L methicyl) carbamic acid benzene g (33 mg, 0.074 mmol) and 2- The title compound (23.9 mg, 0.057 mmol, 77.8%) was obtained as pale brown crystals. ^-NMR light (DMSO-d6) 5 (ppm): 3.08 (2H, m), 4·02 (3H, s), 4.40 (1Η, t, J = 5.2 Ηζ), 4.52 (1Η, t, J =5.2 Ηζ),6·55 (1Η,d, J-5.2 Hz), 6.88 (1H, m)3 7.08 (1H, d, J=9.2 Hz), 7.33 (1H, dd, J=2.8, 11.6 Hz ), 7.51 (1H, s), 7.74 (1H, s), 7.85 (1H, s), 8·21 (1H, m), 8.51 (1H, s), 8.65 (1H, s), 8.67 (1H, d, J=5.2

Hz)。 _實施例358 氯丙胺基）羰基）胺基-3-氣茉夤.某17-曱 邊啉燊醯胺 藉由與實施例11同樣之手法，從N-(4-(6-胺甲酿基-7-甲 氧基-4-喹啉基）氧-2-氟苯基）胺基甲酸苯酯（33 mg , 0.074 mmol)及3-氯丙胺，得到為淡黃色結晶之標題化合物（22.〇 mg，0.049 mmol，66.8%)。 光譜（DMS〇-d6)S (PPm): 1.89 (2H，m)，3.22 (2H，m)， 3.68 (2H，m)，4.01 (3H，s)，6.52 (1H，d，J = 5.2 Hz)，6·71 (1H， m), 7.06 (1H, d5 J=8.8 Hz), 7.31 (1H, dd, J=2.85 11.6 Hz), 7·50 (1H，s)，7.72 (1H，s)，7.84 (1H，s)，8.20 (1H，m)，8·37 (1H，s)，8·64-8·66 (2H，m)。 t施例3 59 -氣丙胺某）羰某）胺基茇蓋甲 !^林羧醯胺 _____ - 456 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 1304061 A7 —____B7__ 五、發明説明（451 ) 藉由與實施例11同樣之手法，從N-(4-(6-胺甲醯基-7- f 氧基-4-喹啉基）氧-2-氟苯基）胺基甲酸苯酯（67 mg，〇.15 mmol)及3-氟丙胺鹽酸鹽，得到為淡黃色結晶之標題化合物 (7.9 mg，0.018 mmo卜 12.2%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): 1.82 (2H，m)，3.20 (2H，m)， 4.01 (3H，s)，4·44 (1H，t，J=6.0 Hz)，4·55 (1H，t，J=6.〇 Hz)， 6.52 (1H，d，J=5.2 Hz)，6.69 (1H，m)，7,06 (1H，d，J=8.8 Hz)， 7·31 (1H，dd，J=2.8，11·6 Hz)，7.50 (1H, s)，7·72 (1H，s)， 7·84 (1H，s)，8·21 (1H，m)，8·38 (1H，s)，8·64-8·66 (2H，m)。 實施例360 2^_-甲氧乙氧某）-4“4-(〇-甲氧基丙胺基）羰基）胺甚苯氧 基）-6-4g林#醢脖 藉由與實施例11同樣之手法，從^^(4-(6-胺甲醯基-7-(2-甲氧乙氧基）-4-喹啉基）氧苯基）胺基甲酸苯酯（5〇 mg， 0.106 mmol)及3-甲氧丙胺，得到為白色結晶之標題化合物 (35·2 mg，0.075 mmol，71.1%)。 H-NMR 光 if(DMSO-d6)5(ppm): 1.66 (2H，m)，3·13 (2H，m)， 3.23 (3H，s)，3·28-3·34 (2H，m)，3·36 (3H，s)，3·79 (2H，m)， 4.40 (2H，m)，6.16 (1H，m)，6.43 (1H，d，J=5.6 Hz)，7.15 (2H， d，J=8.8 Hz)，7·51 (2H，d，J=8.8 Hz)，7·54 (1H，s)，7.79 (1H， s)，7.81 (1H，s)，8.60 (1H，s)，8·63 (1H，d，J=5.6 Hz)，8.77 (1H，s)。 用下述方法合成起始物質。 製造例360- 1 ____- 457 - I紙張尺度適用中國國家標準(CNS) A4規格（21〇 X 297公爱） 1304061 A7 _— __— —B7 五、發明説明（452 ) 苯氧基乙氡某m-μ㈣脖 ,藉由與實施例112相同之手法，從製造例10記載之4-(4-胺基苯氧基）·6·氰基·7~(2·甲氧基乙氧基）如林（3·448 g , 9.67 mm〇1)得到為褐色結晶之標題化合物（i 3〇3 g)。將其 直接用於下述反應。 製造例360-2 胺甲臨崦啉某芙美）脖 基曱酸4_苯酯 藉由與製造例17相同之手法，從4-胺基苯氧基卜7_(2_ 曱氧基乙氧基）-6-喹啉羧醯胺（13〇3 g , 3·69 mm〇1)得到為 淡黃色結晶之標題化合物（1·462 g , 3 〇9 mm〇1 , 83 7%)。 iH-NMR 光譜（CDCl3)5(ppm): 3·48 (3H，S)，3.89 (2H，m)， 4.44 (2H，m)，5·87 (1H，s)5 6·50 (1H，d，J=5.6 Hz)，7.16-7.29 (7H，m)，7.42 (2H，m)，7.58 (1H，s)，7.60 (1H，s)，8·10 (1H， s)，8·64 (1H，d，J=5.6 Hz)，9.31 (1H，s)。 實施例3 6 1 1^11^.((2-氟乙胺基）羰基&gt;)胺基茉氣基）-7-(2-甲氣乙氫某）_ 奎淋教醯胺 藉由與實施例11同樣之手法，從N-(4-(6-胺甲醯基-7-(2-、曱氧乙氧基）-4-喳啉基）氧苯基）胺基甲酸苯酯（47.3 mg， 0.10 mmol)及2-氟乙胺鹽酸鹽，得到為淡褐色結晶之標題 化合物（33.1 mg，0.075 mmol，74.8%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 3·26-3·38 (5H，m)，3.79 (2H，m)，4·38-4·41 (3H，m)，4·51 (1H，t，J=5.2 Hz)，6.39 (1H， -458 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（453 ) m), 6.43 (1H5 d5 J=5.2 Hz), 7.17 (2H, d5 J=8.8 Hz), 7.50-7.54 (3H，m)，7.79 (1H，s)，7.81 (1H，s)，8·63 (1H，d，J=5.2 Hz)， 8·71 (1H，s)，8.77 (1H，s) 〇 實施例362 4-(4-((3-氟丙胺基）羰基）胺基笨氣基）-7-(2-甲氣乙氣基）-6〃套啉羧醯胺 藉由與實施例11同樣之手法，從N-(4-(6-胺甲醯基-7-(2-甲氧乙氧基）-4-喹啉基）氧苯基）胺基甲酸苯酯（47.3 mg， 0.10 mmol)及3-氟丙胺鹽酸鹽，得到為淡黃色結晶之標題 化合物（8.0 mg，0.018 mmol，17.5%)。 iH-NMR 光譜（DMS〇-d6) 5 (ppm)·· 1.76-1.87 (2H，m)，3·17 (2H，m)，3·36 (3H，s)，3·79 (2H，m)，4·38-4·45 (3H，m)，4.55 (1H，m)，6·24 (1H，m)，6·43 (1H，d，J=5.2 Hz)，7.16 (2H，d， J=8.8 Hz)，7.51 (2H，d，J=8.8 Hz)，7.53 (1H，s)，7.79 (1H，s)， 7.81 (1H，s)，8.62-8.64 (2H，m)，8·77 (1H，s)。 實施例363 4-(3-氣-4-((3-甲氣丙胺基）羰基）胺基笨氣基）-7-(2-甲氣 乙氧基）-4 口林致酿胺 藉由與實施例11同樣之手法，從Ν-(4-(6-胺甲醯基-7-(2-甲氧乙氧基）-4-喹啉基）氧-2-氟苯基）胺基甲酸苯酯（50 mg，0.102 mmol)及3 -甲氧基丙胺，得到為白色結晶之標題 化合物（37.2 mg，0.076 mmol，75.2%)。 iH-NMR 光譜（DMSO-d6)5(Ppm): 1·66 (2H, m)，3.16 (2H，m)， 3·23 (3H，s)，3·28-3·34 (2H，m)，3.36 (3H，s)，3·79 (2H, m)， 459 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 裝 訂 1304061 A7 B7 五、發明説明（454 ) 4.40 (2H，m)，6.52 (1H，d，J=5.6 Hz)，6.62 (1H，m)，7.06 (1H， d, J=11.2 Hz), 7.31 (iH) dd, J=2.8, 11.6 Hz), 7.55 (1H, s), 7.80 (1H? s), 7.81 (in, s)? 8.22 (1H, m), 8.36 (1H5 s)5 8.65 (1H，d，J=5.6 Hz)，8·75 〇H，s)。 如下述合成起始物質。 寧邊例3 6 3 - 1 甲氫某乙氫基）-6-4啉# si 默 藉由與實施例112相同之手法，從製造例12記載之4-(4-胺基-3-氟苯氧基）-6-氰基_7_(2-甲氧基乙氧基）喹啉（6 368 g，18·0 mmol)得到為淡黃色結晶之標題化合物（991㈤幻。 將其直接用於下述反應。 Μ造例363-2 Ν-(4-(卜胺甲酿某-2^甲氧乙氣基杳嗾基）氣· m 基）胺基甲酸笨酉旨Hz). Example 358 chloropropylamino)carbonyl)amino-3-carboquinone. A 17-mercapto-linamide amine was synthesized from N-(4-(6-amine) by the same procedure as in Example 11. Phenyl 7-methoxy-4-quinolinyl)oxy-2-fluorophenyl)carbamate (33 mg, 0.074 mmol) eluted elute .〇mg, 0.049 mmol, 66.8%). Spectrum (DMS〇-d6)S (PPm): 1.89 (2H,m), 3.22 (2H,m), 3.68 (2H,m),4.01 (3H,s),6.52 (1H,d,J = 5.2 Hz ),6·71 (1H, m), 7.06 (1H, d5 J=8.8 Hz), 7.31 (1H, dd, J=2.85 11.6 Hz), 7·50 (1H, s), 7.72 (1H, s) , 7.84 (1H, s), 8.20 (1H, m), 8.37 (1H, s), 8·64-8·66 (2H, m). tExample 3 59 - amphetamine carbonyl) amine 茇 茇 ^ ^ ^ carboxy carbamide _____ - 456 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 —____B7__ V. DESCRIPTION OF THE INVENTION (451) By the same procedure as in Example 11, N-(4-(6-aminocarbamimid-7-f-oxy-4-quinolinyl)oxy-2-fluoro Phenyl) phenyl carbamate (67 mg, 〇. 15 mmol) and 3-fluoropropylamine hydrochloride afforded the title compound (yield: 7.9 mg, 0.018 mmo, 12.2%) yiH-NMR spectrum DMSO-d6)5 (ppm): 1.82 (2H, m), 3.20 (2H, m), 4.01 (3H, s), 4·44 (1H, t, J = 6.0 Hz), 4·55 (1H, t, J=6.〇Hz), 6.52 (1H,d,J=5.2 Hz), 6.69 (1H,m),7,06 (1H,d,J=8.8 Hz), 7·31 (1H,dd , J=2.8,11·6 Hz), 7.50 (1H, s), 7·72 (1H, s), 7·84 (1H, s), 8·21 (1H, m), 8·38 (1H , s), 8·64-8·66 (2H, m). Example 360 2^--methoxyethoxy(oxy)oxy-4"4-(indolyl-methoxypropylamino)carbonyl)amine-phenoxy)-6-4 g Lin# The same necking as in Example 11 The method, from ^^(4-(6-aminocarbamido-7-(2-methoxyethoxy)-4-quinolinyl)oxyphenyl)carbamic acid phenyl ester (5〇mg, 0.106) The title compound (35. 2 mg, 0.075 mmol, 71.1%) was obtained as white crystals. H-NMR light if (DMSO-d6) 5 (ppm): 1.66 (2H, m) ,3·13 (2H,m), 3.23 (3H,s),3·28-3·34 (2H,m),3·36 (3H,s),3·79 (2H,m), 4.40 ( 2H,m), 6.16 (1H,m), 6.43 (1H,d,J=5.6 Hz), 7.15 (2H, d,J=8.8 Hz), 7·51 (2H,d,J=8.8 Hz), 7·54 (1H, s), 7.79 (1H, s), 7.81 (1H, s), 8.60 (1H, s), 8.63 (1H, d, J = 5.6 Hz), 8.77 (1H, s) The starting material was synthesized by the following method. Manufacturing Example 360- 1 ____- 457 - I Paper scale applicable to China National Standard (CNS) A4 specification (21〇X 297 public) 1304061 A7 _— __———B7 V. Invention Description (452) A m-μ (four) neck of phenoxyacetamidine, manufactured by the same method as in Example 112 4-(4-Aminophenoxy)·6·cyano·7~(2·methoxyethoxy) as described in 10, which is obtained as a brown crystal of (3·448 g, 9.67 mm〇1). The title compound (i 3 〇 3 g) was directly used in the following reaction. Production Example 360-2 Aminomethyl porphyrin, a phenanthroline, 4-phenyl ester, the same method as in Production Example 17, The title compound (1) is obtained as pale yellow crystals from 4-aminophenoxyb 7-(2-methoxyethoxy)-6-quinolinecarboxamide (13 〇3 g, 3·69 mm 〇1) · 462 g , 3 〇 9 mm 〇 1 , 83 7%). iH-NMR spectrum (CDCl3) 5 (ppm): 3·48 (3H, S), 3.89 (2H, m), 4.44 (2H, m) ,5·87 (1H,s)5 6·50 (1H,d,J=5.6 Hz), 7.16-7.29 (7H,m), 7.42 (2H,m),7.58 (1H,s), 7.60 (1H , s), 8·10 (1H, s), 8.64 (1H, d, J = 5.6 Hz), 9.31 (1H, s). Example 3 6 1 1^11^.((2-Fluoroethylamino)carbonyl&gt;) Amino-Mosyl)-7-(2-Methyl Ethyl)_ 奎淋教胺胺 By Example 11 was the same procedure as the phenyl N-(4-(6-aminocarbamido-7-(2-, methoxyethoxy)-4-indolyl)oxyphenyl)carbamate ( The title compound (33.1 mg, 0.075 mmol, 74.8%) was obtained as pale brown crystals. iH-NMR spectrum (DMSO-d6) 5 (ppm): 3·26-3·38 (5H, m), 3.79 (2H, m), 4·38-4·41 (3H, m), 4.51 (1H,t,J=5.2 Hz),6.39 (1H, -458 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (453) m), 6.43 (1H5 d5 J=5.2 Hz), 7.17 (2H, d5 J=8.8 Hz), 7.50-7.54 (3H,m), 7.79 (1H,s), 7.81 (1H,s),8·63 (1H, d, J = 5.2 Hz), 8·71 (1H, s), 8.77 (1H, s) 〇 Example 362 4-(4-((3-fluoropropylamino)carbonyl)amino) stupid)-7 -(2-methylethane-ethane group)-6-indole-carboxycarboxamide was used in the same manner as in Example 11 from N-(4-(6-aminocarbazinyl-7-(2-methoxy) Phenyloxy)-4-quinolinyl)oxyphenyl)carbamate (47.3 mg, 0.10 mmol) eluted elute 17.5%). iH-NMR spectrum (DMS〇-d6) 5 (ppm)··1.76-1.87 (2H,m),3·17 (2H,m),3·36 (3H,s),3·79 (2H,m ),4·38-4·45 (3H,m),4.55 (1H,m),6·24 (1H,m),6·43 (1H,d,J=5.2 Hz), 7.16 (2H,d , J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz), 7.53 (1H, s), 7.79 (1H, s), 7.81 (1H, s), 8.62-8.64 (2H, m), 8 · 77 (1H, s). Example 363 4-(3-Gas-4-((3-methylapropylamino)carbonyl)amino) stupid)-7-(2-methylethoxy)-4-branched amine The same procedure as in Example 11 was carried out from Ν-(4-(6-aminocarbamido-7-(2-methoxyethoxy)-4-quinolinyl)oxy-2-fluorophenyl)amino group. The title compound (37.2 mg, 0.076 mmol, 75.2%) was obtained as white crystals. iH-NMR spectrum (DMSO-d6) 5 (Ppm): 1.66 (2H, m), 3.16 (2H, m), 3·23 (3H, s), 3·28-3·34 (2H, m ), 3.36 (3H, s), 3·79 (2H, m), 459 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) Binding 1304061 A7 B7 V. Description of invention (454) 4.40 (2H,m), 6.52 (1H,d,J=5.6 Hz), 6.62 (1H,m),7.06 (1H, d, J=11.2 Hz), 7.31 (iH) dd, J=2.8, 11.6 Hz ), 7.55 (1H, s), 7.80 (1H? s), 7.81 (in, s)? 8.22 (1H, m), 8.36 (1H5 s)5 8.65 (1H,d,J=5.6 Hz),8· 75 〇H, s). The starting materials were synthesized as described below. Ningbian Example 3 6 3 - 1 methylhydrogenylamino)-6-4 oxane # si The same procedure as in Example 112, the 4-(4-amino-3-fluoro group described in Production Example 12 Phenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (6 368 g, 18·0 mmol) gave the title compound as a pale-yellow crystal. The following reaction is carried out. Μ 363 363-2 Ν-(4-(b-aminoglycol -2^methoxyethyl fluorenyl) gas · m group) carbamic acid formic acid

藉由與製造例17相同之手法，從4-(4-胺基-3-氟苯氧基）-7-(2-甲氧基乙氧基）-6-4淋幾醯胺（991 mg，2·67 mmol)得 到為淡褐色結晶之標題化合物（1.〇74 g，2.19 mmo 1， 81·9%” 1H-NMR 光譜（CDCl3)5(ppm): 3·48 (3Η，s)，3·90 (2Η，m)， 4.46 (2H，m)，5.88 (1H，s)，6·58 (1H，d，J=5.2 Hz)，7.02-7.06 (2H，m)，7.21-7.30 (4H，m)，7·43 (2H，m)，7·71 (1H，s)，8·08 (1H，s)，8.27 (1H，br)，8·68 (1H，d，J=5.2 Hz)，9.29 (1H，s)。 實施例364 -460 - 本紙張尺度通用中國國家標準(CNS) A4規格（210 x 297公釐） 1304061 〜 ' · A7 _______— B7 五、發明説明（455 ) 1304061 -、 A7 厂—____ B7 五、發明説明（456 ) J=5.2 Hz)，8.75 (1H，s)。 實施例366 K3-氣-4-ί(4-氣茉胺基）羰基）胺基茉氣某17-甲氣基-6· 查琳致醯胺 藉由與實施例10同樣之方法，從4-(4-胺基-3-氯苯氧基）-7-曱氧基-6-喹啉羧醯胺（50 mg，0.145 mmol)及異氰酸4-氟 私酉旨’得到為淡褐色結晶之標題化合物（53.6 mg，0.111 mmc^，76.9%) 〇 1H-NMR 光譜（DMSO-d6)5(ppm): 4·01 (3H，s)，6,55 (1H，d， J=5.2 Hz)，7·14 (2H，m)，7.28 (1H，dd，J=2.4, 9.2 Hz)，7.47 (2H，m)，7.51 (1H，s)，7·55 (1H，d，J=2.4 Hz)，7·73 (1H，s)， 7.85 (1H，s)，8·25 (1H，d，J=9.2 Hz)，8.38 (1H，s)，8·65 (1H， s)5 8.67 (1H，d，J=5.2 Hz)，9.43 (1H，s)。 用下述方法合成起始物質。 製造例366-1 U4-胺基二3-氯苯氧基）-7-甲氣某-6^套呲激酸胺 將4-胺基-3-氯酚（1·2 13 g，8.45 mmol)溶於二甲基亞颯 (10 ml) ’於室溫下慢慢加入氫化鏑（290 mg，8·45 mmoi)並 攪拌30分鐘。加入製造例152-3得到之7-甲氧基氯喳啉_ 6-羧醯胺（l.〇〇g，4.23 mmol)，並於i〇〇°C加熱授拌2小時。 放冷至室溫，將反應液分溶於乙酸乙酯及水中，將有機層 用水及飽和食鹽水洗淨及用無水硫酸鈉乾燥。餘去溶媒， 然後付諸於碎凝膠管柱層析（溶出液；乙酸乙酯/甲: 1)，將包含目的物之溶出部分濃縮，懸浮於四氣唉喃中， -462 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公爱 1 ----—-_ 1304061 A7 B7 五、發明説明（457 ) 將其用己燒稀釋及)慮取結晶’藉由通風乾燥，得到為淡褐 色結晶之標題化合物（1.216 g ’ j.54 mmol，83 7%)。 iH-NMR 光譜（CDCl3)6(PPm): 4.10 (2H，s)，4.13 (3H，s)， 5·90 (1H，br)，6.46 (1H，d，J=5.6 Hz)，6.86 (1H，m)，6.93 (1H， dd, J=2.4, 8.4 Hz), 7.13 (1H, d, J=2.4 Hz), 7.53 (1H, s), 7.80 (1H，br)，8·64 (1H，d，J=5.6 Hz)，9·27 (1H，s)。 t施例367 K3 -氣.-4-((2 -g篆咬胺基）羰基）胺基笨氧基甲氣基- 6_ 邊啉羧醯胺 藉由與實施例131同樣之方法，從4-(4-胺基-3-氯苯氧 基）-7-甲氧基-6-喳琳幾醯胺（50 mg，〇·ΐ45 mmol)及N-(1，3-嘍唑-2-基）胺基甲酸苯酯，得到為淡褐色結晶之標題 化合物（38.3 mg，0.082 mmol，56·2%)。 光譜（DMS〇-d6)5(ppm): 4.02 (3H，s)，ό·5ό (1Η，d， J-5,2 Hz)，7.15 (1H，s)，7.31 (1H，d，J=8.0 Hz)，7.40 (1H，s)， 7·51 (1H，s)，7·59 (1H，s)，7·73 (1H，s)，7·85 (1H，s)，8.27 (1H，d，J=8.0 Hz)，8.65 (1H，s)，8.67 (1H，d，J=5.2 Hz)， 11·19 (1H，s) 〇 實施例368 U 3-氣-4-(環丙胺羰某）胺某茉氣某）-7-甲氣某-6〃杳啉藉 醯胺 藉由與實施例11同樣之方法，從N-(4-(6-胺甲醯基-7-甲 氧基-4-4 17林基）氧-2-氯苯基）胺基甲酸苯g旨（7〇 mg，〇. 1 5 mmol)及環丙胺，得到為白色結晶之標題化合物（22.4 mg， -463 - 本纸張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 裝 訂 線 1304061 、 ' - A7 ____ B7 五、發明説明（~~) ~ 0.052 mmol，34.8%)。 ^H-NMR 光譜（DMSO-d6)5(ppm): 0.41 (2H，m)，0·66 (2H，m)， 2·56 (1H，m)，4·01 (3H，s)，6·51 (1H，d，J=5.6 Hz)，7.18 (1H， d，J=2.8 Hz)，7·23 (1H，dd，J=2.8，8·8 Hz)，7·48 (1H，d， J=2.8 Hz)，7.50 (1H，s)，7·72 (1H，s)，7·84 (1H，s)，7·97 (1H， s)，8·25 (1H，d，J=8.8 Hz)，8.64 (1H，s)，8.65 (1H，d，J=5.6 Hz) 〇 用下述方法合成起始物質。 製造例368-1 K心（6-胺甲蓋基-7H基· 4-,套啉基）氩-2_豪苽某）胺基 甲酸苯酯 藉由與製造例17相同之方法，從4-(4-胺基-3-氟苯氧基）-7-曱氧基-6-喹啉羧醯胺（600 mg，1.745 mmol)得到為淡褐 色結晶之標題化合物（708 mg，1.526 mmol，87.4%)。 iH-NMR 光譜（CDCl3)6(ppm): 4·Η (3H，s)，5.89 (1H，br)， 6.50 (1H, d, J=5.6 Hz), 7.16 (2H, dd5 J=2.4, 8.8 Hz), 7.22- 7.30 (4H，m)，7·44 (2H，m)，7·55 (1H，s)，7.81 (1H，br)，8.31 (1H，d，J=8.8 Hz)，8·68 (1H，d，J=5.6 Hz)，9·27 (1H，s)。 實施例369 -氯-4- (2-氟乙胺羰基）胺基笨氣基）-hjp氣基_ 4琳 複酷胺 藉由與實施例11同樣之方法，從N-(4-(6-胺甲醯基-7-曱 氧基-4-喹啉基·）氧-2-氣苯基）胺基甲酸笨酯（2〇〇 mg , 0.431 mmol)及2-氟乙胺鹽酸鹽，得到為淡褐色結晶之標題 _^_______- 464 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 〜· A7 __ B7____ 五、發明説明（459 ) 化合物（95·8 mg，0.221 mmol，51.3%)。 j-NMR 光譜（DMS〇-d6)5(ppm): 3.98 (1H，m)，3.46 (1H，m)， 4.02 (3H, s), 4.42 (1H, t, J=4.8 Hz), 4.53 (1H, dd, J=4.8, 5.6 Hz)5 6.52 (1H, d, J=5.2 Hz), 7.23 (1H, d, J=2.4, 8.8 Hz), 7·29 (1H，m)，7·48 (1H，d，J=2.4 Hz)，7·50 (1H，s)，7·72 (1H， s)，7.84 (1H，s)，8·22·8·25 (2H，m)，8·64·8·66 (2H，m)。 實施例370 7-芊氧基-4- (4-(環丙胺羰某）胺某-3-氟笨氣基V 6- 4啉羧 醯胺 藉由與實施例11同樣之方法，從N-(4-(7-芊氧基-6-胺甲 醯基-4-喳啉基）氧-2-氟苯基）胺基甲酸苯酯（760 mg， 1.452 mmol)及環丙胺，得到為淡黃色結晶之標題化合物 (663 mg，1.363 mmol，93.9〇/〇)。 H-NMR光 if (DMS〇-d6) (5 (ppm): 0·41 (2H，m)，0·65 (2H，m)， 2.56 (1H，m)，5·44 (2H，s)，6·54 (1H，d，J=5.6 Hz)，6.82 (1H， d, J=2.8 Hz), 7.08 (1H, m), 7.33 (1H, dd, J=2.8, 12.0 Hz), 7.38 (1H, d, J=7.2 Hz), 7.44 (2H, m), 7.58 (2H, d, J=7.2 Hz), 7.61 (1H, s), 7.75 (1H, s), 7.84 (1H, s), 8.20-8.24 (2H3 m), 8.63 (1H，s)，8.66 (1H，d，Hz)。 藉由下述方法合成起始物質。 製造例370- 1 1^11^联基-氟苯氧幕）-芊氧某V 6啉# fe 藉由與實施例1 12相同之手法，從製造例8記載之4-(心胺 基-3-氟苯氧基）-7-芊氧基-氰基α奎淋（2·27 g , 5·89 mm〇i) _____ ' 465 - 本紙張尺度適用中國國家標準(CNS) A4規格（2l〇x^i^釐) &quot; -—- 1304061 〜 、· A7 ________B7 __ 五、發明説明（46〇) 可得到淡褐色結晶（752 mg，1.86 mmol，3 1.6%)。 iH-NMR 光譜（CDCl3)5(ppm): 3·77 (2H，s)，5.34 (2H，s)， 5·78 (1H，br)，6.47 (1H，d，J=5.2 Ηζ)，6·79-6·91 (3H，m)， 7.41- 7.54 (5H，m)，7·62 (1H，s)，7·81 (1H，br)，8.65 (1H，d， &gt;5·2 Hz)，9.31 (1H, s)。 製造例370-2 N-(4-(7-芊氧基-6-胺曱醯基-4-4啉基）惫.-2-蠢.茇某）胺基 甲酸笨酯 藉由與製造例17相同之方法，從4-(4-胺基-3-氟苯氧基）-7-(芊氧基）-6-4啉羧醯胺（752 mg，1.864 mmol)得到為淡 黃色結晶之標題化合物（760 mg，1.452 mmol，77.9%)。 iH-NMR 光譜（CDCl3)c5(ppm): 5·35 (2H，s)，5·80 (1H，br)， 6·52 (1H，d，J=5.2 Hz)，7·03 (2H，m)，7.22-7.30 (4H，m)， 7.41- 7.49 (5H, m), 7.53 (2H, d, J=6.8 Hz), 7.64 (1H, s), 7.82 (1H，br)，8·24 (1H，br)，8·69 (1H，d，J=5.2 Hz)，9.30 (1H， 實施例371 (4-(%丙胺幾基）胺基-3- 笨氧基）-7-¾基-6-林幾酿 藉由與實施例83同樣之手法，從7-芊氧基-4-(4-(環丙胺 致基）胺基-3-氣冬氧基）-6-p奎°林幾酿胺（640 mg，1.316 mmol)，得到為淡黃色結晶之標題化合物（498 mg，1 256 mmol，95.5%) 〇 iH-NMR 光譜（DMS〇-d6)c5(ppm): 0.41 (2H，m)，0·6ό (2H，m)， _ ·__- 466 -___ 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061By the same procedure as in Production Example 17, decylamine (991 mg) was eluted from 4-(4-amino-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-4. , 2.67 mmol) of the title compound (1. 〇 74 g, 2.19 mm, 1, 81.9%) 1H-NMR spectrum (CDCl3) 5 (ppm): 3·48 (3Η, s) ,3·90 (2Η,m), 4.46 (2H,m),5.88 (1H,s),6·58 (1H,d,J=5.2 Hz), 7.02-7.06 (2H,m), 7.21-7.30 (4H,m),7·43 (2H,m),7·71 (1H,s),8·08 (1H,s), 8.27 (1H,br),8·68 (1H,d,J= 5.2 Hz), 9.29 (1H, s). Examples 364 - 460 - General paper size (CNS) A4 size (210 x 297 mm) 1304061 ~ ' · A7 _______ — B7 5. Description of invention (455 1304061 -, A7 Plant - ____ B7 V. Description of the Invention (456) J = 5.2 Hz), 8.75 (1H, s) Example 366 K3-Gas-4-ί(4-Gamosyl)carbonyl)amine A methyl 17-methyl group-6·charine-induced guanamine was obtained from 4-(4-amino-3-chlorophenoxy)-7-decyloxy group by the same method as in Example 10. 6-quinoline carboxamide (50 mg, 0.145 mmol) and isocyanate 4-fluoro private The title compound (53.6 mg, 0.111 mmc^, 76.9%) 淡1H-NMR spectrum (DMSO-d6) 5 (ppm): 4·01 (3H, s), 6, 55 (1H, d, J =5.2 Hz),7·14 (2H,m), 7.28 (1H,dd,J=2.4, 9.2 Hz), 7.47 (2H,m),7.51 (1H,s),7·55 (1H,d, J=2.4 Hz),7·73 (1H,s), 7.85 (1H,s),8·25 (1H,d,J=9.2 Hz), 8.38 (1H,s),8·65 (1H, s 5 8.67 (1H, d, J = 5.2 Hz), 9.43 (1H, s). The starting material was synthesized by the following method. Production Example 366-1 U4-Aminodi-3-chlorophenoxy)-7- Methane -6^ sets of chloramines 4-amino-3-chlorophenol (1·2 13 g, 8.45 mmol) dissolved in dimethyl hydrazine (10 ml) ' slowly added at room temperature Hydrogenated hydrazine (290 mg, 8.45 mm oi) and stirred for 30 minutes. 7-Methoxy chlorinated porphyrin-6-carboxyguanamine (1. g, 4.23 mmol) obtained in Preparation 152-3 was added, and the mixture was stirred and heated at i ° C for 2 hours. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine. The solvent was removed, and then applied to a broken gel column chromatography (eluent; ethyl acetate/methyl: 1), and the dissolved fraction containing the target substance was concentrated and suspended in a gas mixture, -462 - paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public love 1 ------_ 1304061 A7 B7 5, invention description (457) diluted with hexane and) crystallized 'by drying The title compound (1.216 g ' j. 54 mmol, 83 7%) was obtained as pale brown crystals. iH-NMR spectrum (CDCl3) 6 (PPm): 4.10 (2H, s), 4.13 (3H, s), 5·90 (1H, br), 6.46 (1H, d, J = 5.6 Hz), 6.86 (1H , m), 6.93 (1H, dd, J=2.4, 8.4 Hz), 7.13 (1H, d, J=2.4 Hz), 7.53 (1H, s), 7.80 (1H, br), 8·64 (1H, d, J = 5.6 Hz), 9·27 (1H, s). t Example 367 K3 - gas. -4-((2 - g 篆 amino) carbonyl) amine phenyloxycarbazyl-6 porphyrin carboxamide The same procedure as in Example 131, from 4 -(4-Amino-3-chlorophenoxy)-7-methoxy-6-indolylamine (50 mg, 〇·ΐ45 mmol) and N-(1,3-carbazole-2- The title compound (38.3 mg, 0.082 mmol, 56.2%) was obtained as pale brown crystals. Spectrum (DMS〇-d6) 5 (ppm): 4.02 (3H, s), ό·5ό (1Η, d, J-5, 2 Hz), 7.15 (1H, s), 7.31 (1H, d, J= 8.0 Hz), 7.40 (1H, s), 7·51 (1H, s), 7·59 (1H, s), 7.73 (1H, s), 7.85 (1H, s), 8.27 (1H , d, J = 8.0 Hz), 8.65 (1H, s), 8.67 (1H, d, J = 5.2 Hz), 11·19 (1H, s) 〇 Example 368 U 3-Gas-4-(cyclopropylamine) A carbonyl group, an amine, a certain gas, a -7-methyl gas, a -6 porphyrin, and a guanamine, by the same method as in Example 11, from N-(4-(6-aminocarbazinyl-7-) Oxy-4-4 17-phenyl)oxy-2-chlorophenyl) carbamic acid phenyl g (7 mg, mp. -463 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) gutter 1304061, '- A7 ____ B7 5. Invention description (~~) ~ 0.052 mmol, 34.8%). ^H-NMR spectrum (DMSO-d6) 5 (ppm): 0.41 (2H, m), 0·66 (2H, m), 2·56 (1H, m), 4·01 (3H, s), 6 · 51 (1H, d, J = 5.6 Hz), 7.18 (1H, d, J = 2.8 Hz), 7·23 (1H, dd, J=2.8, 8·8 Hz), 7·48 (1H, d , J=2.8 Hz), 7.50 (1H, s), 7·72 (1H, s), 7.84 (1H, s), 7·97 (1H, s), 8·25 (1H, d, J = 8.8 Hz), 8.64 (1H, s), 8.65 (1H, d, J = 5.6 Hz) 起始 The starting material was synthesized by the following method. Production Example 368-1 K-heart (6-Aminomethyl-Glycol-7H-yl-4-yl, phenyl-organyl) argon-2 _ 苽 )) phenyl carbamate by the same method as in Production Example 17, from 4 -(4-Amino-3-fluorophenoxy)-7-decyloxy-6-quinolinecarboxamide (600 mg, 1.745 mmol). 87.4%). iH-NMR spectrum (CDCl3) 6 (ppm): 4·Η (3H, s), 5.89 (1H, br), 6.50 (1H, d, J = 5.6 Hz), 7.16 (2H, dd5 J=2.4, 8.8 Hz), 7.22- 7.30 (4H,m),7·44 (2H,m),7·55 (1H,s),7.81 (1H,br),8.31 (1H,d,J=8.8 Hz),8 · 68 (1H, d, J = 5.6 Hz), 9·27 (1H, s). Example 369 -Chloro-4-(2-fluoroethylamine carbonyl)amine-based stupid base)-hjp gas group _ 4 linalocarbamide in the same manner as in Example 11, from N-(4-(6) -Aminomethylmercapto-7-methoxy-4-quinolinyl)oxy-2-phenylphenylcarbamate (2 mg, 0.431 mmol) and 2-fluoroethylamine hydrochloride , get the title of light brown crystal _^_______- 464 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ~· A7 __ B7____ V. Description of invention (459) Compound (95· 8 mg, 0.221 mmol, 51.3%). j-NMR spectrum (DMS 〇-d6) 5 (ppm): 3.98 (1H, m), 3.46 (1H, m), 4.02 (3H, s), 4.42 (1H, t, J = 4.8 Hz), 4.53 ( 1H, dd, J=4.8, 5.6 Hz)5 6.52 (1H, d, J=5.2 Hz), 7.23 (1H, d, J=2.4, 8.8 Hz), 7·29 (1H, m), 7·48 (1H,d,J=2.4 Hz), 7·50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 8·22·8·25 (2H, m), 8 · 64·8·66 (2H, m). Example 370 7-Methoxy-4-(4-(cyclopropylaminecarbonyl)amine Some -3-fluoroindolyl V 6 - 4 -carboxycarboxamide The same procedure as in Example 11 from N- (4-(7-decyloxy-6-amine-mercapto-4-indolyl)oxy-2-fluorophenyl)carbamic acid phenyl ester (760 mg, 1.452 mmol) and cyclopropylamine The title compound (663 mg, 1.363 mmol, 93.9 〇/〇) of the yellow crystals. H-NMR light if (DMS 〇-d6) (5 (ppm): 0·41 (2H, m), 0·65 (2H, m), 2.56 (1H,m),5·44 (2H,s),6·54 (1H,d,J=5.6 Hz), 6.82 (1H, d, J=2.8 Hz), 7.08 (1H, m ), 7.33 (1H, dd, J=2.8, 12.0 Hz), 7.38 (1H, d, J=7.2 Hz), 7.44 (2H, m), 7.58 (2H, d, J=7.2 Hz), 7.61 (1H , s), 7.75 (1H, s), 7.84 (1H, s), 8.20-8.24 (2H3 m), 8.63 (1H, s), 8.66 (1H, d, Hz). Production Example 370 - 1 1 ^ 11 ^ hydrazine - fluorophenoxy oxymethane) - oxime a V 6 porphyrin # fe By the same procedure as in Example 12, the 4-(amine) described in Production Example 8 3-fluorophenoxy)-7-methoxy-cyano alpha quinine (2·27 g , 5·89 mm〇i) _____ ' 465 - This paper scale applies to Chinese national standard Quasi (CNS) A4 specification (2l〇x^i^PCT) &quot; --- 1304061 ~ , · A7 ________B7 __ V. Description of invention (46〇) Available in light brown crystals (752 mg, 1.86 mmol, 3 1.6%) iH-NMR spectrum (CDCl3) 5 (ppm): 3·77 (2H, s), 5.34 (2H, s), 5·78 (1H, br), 6.47 (1H, d, J = 5.2 Ηζ) ,6·79-6·91 (3H,m), 7.41- 7.54 (5H,m),7·62 (1H,s),7·81 (1H,br),8.65 (1H,d, &gt;5 · 2 Hz), 9.31 (1H, s). Production Example 370-2 N-(4-(7-decyloxy-6-aminoindol-4-yl)phenyl. a) carbamic acid benzoate from 4-(4-amino-3-fluorophenoxy)-7-(decyloxy)-6-4 carboxycarboxamide in the same manner as in Production Example 17 The title compound (760 mg, 1.452 mmol, 77.9%). iH-NMR spectrum (CDCl3) c5 (ppm): 5·35 (2H, s), 5·80 (1H, br), 6·52 (1H, d, J = 5.2 Hz), 7·03 (2H, m), 7.22-7.30 (4H, m), 7.41- 7.49 (5H, m), 7.53 (2H, d, J=6.8 Hz), 7.64 (1H, s), 7.82 (1H, br), 8.24 (1H, br), 8.69 (1H, d, J = 5.2 Hz), 9.30 (1H, Example 371 (4-(% propylamino)amino-3-phenyloxy)-7-3⁄4 -6-Lin was brewed in the same manner as in Example 83 from 7-methoxy-4-(4-(cyclopropylamine)amino-3-oxaxyloxy-6-p-quino. The title compound (498 mg, 1 256 mmol, 95.5%) was obtained as a pale yellow crystal. 〇iH-NMR spectrum (DMS 〇-d6) c5 (ppm): 0.41 (2H) ,m),0·6ό (2H,m), _ ·__- 466 -___ This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1304061

2.57 (1H，m)，6·42 (1H，d，J=5.2 HZ)，6.83 (1H，s)，7.31 (1H， d, J=9.2 Hz), 7.30 (1H, s), 7.34 (1H, dd, J=2.8, 11.6 Hz), 8.08 (1H，s)，8.21-8.26 (2H，m)，8·61 (1H，d，j=5 2 Hz) 8 91 (1H，br)，8·96 (1H，s)。 實施例372 1114· (1環丙胺胺基-3-氣苯氣某）-7-Π-丄么N-二乙胺基） 否氧基）-6- 4说途碼_ 藉由與實施例7同樣之手法，從4-(4-(環丙胺羰基）胺基_ 3-氟苯氧基）_7-羥基-6-喹啉羧醯胺（50 mg，〇·126 mmol)及 N-(3-氯丙基）·ν，Ν-二乙胺鹽酸鹽，得到為淡黃色結晶之標 題化合物（34·2 mg，〇·〇67 mmol，53.2%)。 W-NMR 光譜（DMSO-d6)5(PPm): 0·41 (2H，m)，〇·65 (2H，m)， 〇·95 (6Η，t，J=7.2 Ηζ)，1·96 (2Η，m)，2.44-2.49 (4Η，m)， 2.57-2.59 (3H，m)，4·30 (2H，m)，6·52 (1H，d，J=5.2 Hz)， 6.70 (1H，s)，7.09 (1H，d，J=10.8 Hz)，7·32 (1H，m)，7.50 (1H， s)，7·79 (1H，s)，7·91 (1H，s)，8·19-8·22 (2H，m)，8.66 (1H，d， J=5.2 Hz)，8.69 (1H，s) o 實施例373 環丙胺羰基）胺某-3-氣笨氣某二乙胺基） 乙氧基）-6- 4琳藏酿胺 藉由與實施例7同樣之手法，從4-(4-(環丙胺羰基）胺基-3-氟苯氧基）-7-#呈基-6“奎淋叛酿胺（50 mg，0.126 mmol)及 N-(2-溴乙基）-·Ν，Ν-二乙胺氫溴酸鹽，得到為淡黃色結晶之 標題化合物（20.6 mg，0.042 mmol，33.0%)。 -467 - 本畝張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 、 A7 ' ' * B7 五、發明説明（~^ iH-NMR 光譜（DMS〇-d6)5(ppm): 0·41 (2H，m)，〇 65 (2H，m)， 0.97 (6H，t，J=7.2 Hz)，2·50-2·58 (5H，m)，2·85 (2H，m)，4.36 (2H，m)，6·52 (1H，d，J=5.2 Hz)，6.81 (ih，s)，7.09 (1H，d， J=6.8 Hz)，7·34 (1H，d，J=11.6 Hz)，7 57 (1H，s)，7 81 (1H， s)，8.19-8.22 (2H，m)，8.31 (1H，s)，8.67 (1H，d，J=5.2 Hz)， 8.80 (1H，s) 〇 實施例374 4-(4-(環_.丙一驗幾棊）胺基苯氢噁福啉基） 丙氧基）-6〃奎淋藉gj胺 藉由與實施例7同樣之手法，從4-(4-(環丙胺羰基）胺基· 3- 氟苯氧基）-7-¾基-6-喹淋致酿胺（5〇 mg，0.126 mmol)及 N-(3-氯丙基）嗎福啉，得到為黃色結晶之標題化合物（35.〇 mg，0.067 mmol，53·0ο/〇)。 iH-NMR 光譜（DMS〇-d6)5(ppm): 0·41 (2Η，m)，0·65 (2Η，m)， 2·01 (2Η，m)，2·39 (4Η，br)，2.46-2.50 (2Η，m)，2·56 (lH，m)， 3·59 (4Η，m)，4·31 (2Η，m)，6·52 (1Η，d，J=5.2 Hz), 6.82 (1Η， s)，7.08 (1H，d，J=8.4 Hz)，7.31 (1H，m)，7·52 (1H，s)，7.78 (2H，s)，8.19-8.24 (2H，m)，8.65-8.67 (2H，m)。 實施例375 4- (4-(環丙胺羰某）胺基-3 -氣笨氣某l 74 2- (4-嗎福啉某） 乙氧基）-6〃奎琳藉醯胺 藉由與實施例7同樣之手法，從4-(4-(環丙胺羰基）胺基-3-氟苯氧基）-7-羥基-6-喹啉羧醯胺（50 mg，0.126 mmol)及 N-(2-氯乙基）嗎福啉鹽酸鹽，得到為黃色結晶之標題化合 _ 468 -____ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 〜 '一 B7_ 五、發明説明（463) 物（35.1 mg，〇·〇69 mmol，54.6%)。 lH-NMR 光譜（DMS〇-d6)5(ppm): 0·41 (2H，m)，0·65 (2H，m)， 2·50-2·56 (5H，m)，2.79 (2H，m)，3.60 (4H，br)，4.41 (2H，m)， 6.53 (1H5 d, J=5.2 Hz), 6.81 (1H, s), 7.08 (1H, d, J=9.6 Hz), 7.33 (1H，d，J=12.8 Hz), 7·58 (1H，s)3 7·87 (1H，s)，8.19-8.23 (2H，m)，8·39 (1H，s)，8·67 (1H，d，J=5.2 Hz)，8,82 (1H，s)。 實施例376 4-(4-(環丙胺凝基）胺基-3 -乱苯乳基比症基）甲乳 基）-6 -ρ奎琳裁酿胺 藉由與實施例7同樣之手法，從4-(4-(環丙胺羰基）胺基- 3- 氟苯氧基）-7-經基-6-峻琳幾酿胺（50 mg，0.126 mmol)及 2- 氯甲基吡啶鹽酸鹽，得到為淡褐色結晶之標題化合物 (20.2 mg，0.041 mmol，32.8%)。 1H-NMR 光譜（DMSO-d6)5(ppm): 0·41 (2H，m)，0·65 (2H，m)， 2.56 (1H，m)，5·53 (2H，s)，6.54 (1H，d，J=5.2 Hz)，6.80 (1H， s)，7.08 (1H，d，J=10.4 Hz)，7.30-7.40 (2H，m)，7.59 (1H，s)， 7·62 (1H，d，J=8.0 Hz)，7.79 (1H，s)，7·86 (1H，dd，J=2.0, 7.6 Hz)，8.19-8.23 (3H，m)，8.61-8.68 (3H，m)。 實施例377 4- (4-(環丙胺羰基）胺基-3-氟笨氧基朴卜咬基）甲氧 基）-6_ 口奎淋被酿胺 藉由與實施例7同樣之手法，從4-(4-(環丙胺羰基）胺基· 3- 乱冬乳基）-7-¾基-6-峻琳竣酿胺（50 mg，〇 126 mmol)及 3-氣甲基吡啶鹽酸鹽，得到為淡黃色結晶之標題化合物 -469 - I紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） '~~—---- A7 B7 1304061 五、發明説明（464) (20.2 mg，0.041 mmol，32·8〇/〇) 〇 1H-NMR 光譜（DMSO-d6)5(ppm): 0·41 (2Η，m)，0.65 (2Η，m)， 2.56 (1H, m), 5.47 (2H, s), 6.55 (1H, d, J=5.2 Hz), 6.81 (iHj s)，7.08 (1H，d，J=10.0 Hz)，7.32 (1H，d，J=12.4 Hz)，7·45 (1H，m)，7.64 (1H，s)，7·73 (1H，s)，7·83 (1H，s)，7.98 (iH， m)，8·23 (2H，br)，8·57 (2H，br)，8.66 (1H，d，J=5.2 Hz)，8·8〇 (1H，s) 〇 t施例378 i二(4-(環丙胺基）胺基-3-氣苯氣基）-7-“4-吡啶基） 基）-6-4g林#龜胺 藉由與實施例7同樣之手法，從4-(4-(環丙胺羰基）胺基-3-氟苯氧基）·7-經基-6-〃奎淋幾酿胺（50 mg，0.126 mmol)及 ‘氯甲基吡啶鹽酸鹽，得到為淡黃色結晶之標題化合物 (29.8 mg，0.061 mmol，4 8.5%) 〇 1H-NMR光譜（DMS〇-d6)5(ppm): 0·41 (2H，m)，0·65 (2H，m)， 2.56 (1H，m)，5.50 (2H，s)，6.54 (1H，d，J=5.2 Hz)，6·80 (1H， s)，7.07(lH，d，J=8.0Hz)，7.32(lH，d，J=11.6Hz)，7.53- 7.55 (3H，m)，7·76 (1H，s)，7.92 (1H，s)，8.19-8.22 (2H, m)， 8.55 (1H，s)，8·60-8·66 (3H，m)。 f施例379 氧基-4“3-氯-4-(環丙胺羰基）胺基笨氣某）-6-峰啉羧 座胺 藉由與實施例.11同樣之手法，從N-(4-(7-苄氧基-6-胺甲 酿基-4-喳啉基）氧-2-氯苯基）胺基甲酸苯酯（2.97 g，5.50 ___- 470 -__ 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）2.57 (1H,m),6·42 (1H,d,J=5.2 HZ), 6.83 (1H,s), 7.31 (1H, d, J=9.2 Hz), 7.30 (1H, s), 7.34 (1H , dd, J=2.8, 11.6 Hz), 8.08 (1H, s), 8.21-8.26 (2H, m), 8.61 (1H, d, j=5 2 Hz) 8 91 (1H, br), 8 · 96 (1H, s). Example 372 1114·(1cyclopropylaminomethyl-3-benzenebenzene)-7-Π-丄N-diethylamino)NO-oxy)-6- 4-way code_ by way of example 7 In the same manner, 4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-hydroxy-6-quinolinecarboxamide (50 mg, 〇·126 mmol) and N-( The title compound (34. 2 mg, 〇·〇 67 mmol, 53.2%) was obtained as pale yellow crystals. W-NMR spectrum (DMSO-d6) 5 (PPm): 0·41 (2H, m), 〇·65 (2H, m), 〇·95 (6Η, t, J=7.2 Ηζ), 1.96 ( 2Η,m),2.44-2.49 (4Η,m), 2.57-2.59 (3H,m),4·30 (2H,m),6·52 (1H,d,J=5.2 Hz), 6.70 (1H, s), 7.09 (1H, d, J = 10.8 Hz), 7.32 (1H, m), 7.50 (1H, s), 7·79 (1H, s), 7·91 (1H, s), 8 · 19-8·22 (2H, m), 8.66 (1H, d, J = 5.2 Hz), 8.69 (1H, s) o Example 373 cyclopropylamine carbonyl)amine some-3-gas stupid certain diethylamine Ethyloxy)-6- 4 linalylamine was obtained from 4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-# by the same procedure as in Example 7. Base-6 "Queron Resin (50 mg, 0.126 mmol) and N-(2-bromoethyl)--indole, hydrazine-diethylamine hydrobromide, the title compound (20.6) Mg, 0.042 mmol, 33.0%) -467 - The Chinese standard (CNS) A4 size (210 X 297 mm) is applied to the per mu scale. 1304061, A7 ' ' * B7 V. Invention description (~^ iH-NMR spectrum (DMS〇-d6)5(ppm): 0·41 (2H,m), 〇65 (2H,m), 0.97 (6H,t,J=7.2 Hz), 2·50-2·58 (5 H,m),2·85 (2H,m), 4.36 (2H,m),6·52 (1H,d,J=5.2 Hz), 6.81 (ih,s),7.09 (1H,d, J= 6.8 Hz), 7·34 (1H, d, J = 11.6 Hz), 7 57 (1H, s), 7 81 (1H, s), 8.19-8.22 (2H, m), 8.31 (1H, s), 8.67 (1H, d, J = 5.2 Hz), 8.80 (1H, s) 〇 Example 374 4-(4-(cyclo-.C.A.) Aminophenylhydroquinolyl) Propyloxy) -6〃奎〃 by gj amine by the same method as in Example 7, from 4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-3⁄4yl-6-quino The title compound (35. 〇mg, 0.067 mmol, 5·0ο / 〇) was obtained as a yellow crystal. Spectrum (DMS〇-d6) 5 (ppm): 0·41 (2Η, m), 0·65 (2Η, m), 2·01 (2Η, m), 2·39 (4Η, br), 2.46- 2.50 (2Η,m),2·56 (lH,m), 3·59 (4Η,m),4·31 (2Η,m),6·52 (1Η,d,J=5.2 Hz), 6.82 ( 1Η, s), 7.08 (1H, d, J=8.4 Hz), 7.31 (1H, m), 7.52 (1H, s), 7.78 (2H, s), 8.19-8.24 (2H, m), 8.65 -8.67 (2H, m). Example 375 4-(4-(cyclopropylaminecarbonyl)amino-3-gas stupid l 74 2-(4-morpholine) ethoxy)-6〃 琳 醯 醯 醯 藉Example 7 in the same manner as 4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-hydroxy-6-quinolinecarboxamide (50 mg, 0.126 mmol) and N- (2-Chloroethyl) porphyrin hydrochloride, obtained as the title compound of yellow crystal _ 468 -____ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 ~ 'One B7_ V. Description of the invention (463) (35.1 mg, 〇·〇 69 mmol, 54.6%). lH-NMR spectrum (DMS〇-d6) 5 (ppm): 0·41 (2H, m), 0·65 (2H, m), 2·50-2·56 (5H, m), 2.79 (2H, m), 3.60 (4H, br), 4.41 (2H, m), 6.53 (1H5 d, J = 5.2 Hz), 6.81 (1H, s), 7.08 (1H, d, J = 9.6 Hz), 7.33 (1H ,d,J=12.8 Hz), 7·58 (1H,s)3 7·87 (1H,s),8.19-8.23 (2H,m),8·39 (1H,s),8·67 (1H , d, J = 5.2 Hz), 8, 82 (1H, s). Example 376 4-(4-(cyclopropylamine)amino-3(indolinyl)-based methylamino)-6-ρ-quinelined amine by the same method as in Example 7, From 4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-ylamino-6-junolin (50 mg, 0.126 mmol) and 2-chloromethylpyridine hydrochloride The title compound (20.2 mg, 0.041 mmol, 32.8%). 1H-NMR spectrum (DMSO-d6) 5 (ppm): 0·41 (2H, m), 0·65 (2H, m), 2.56 (1H, m), 5·53 (2H, s), 6.54 ( 1H,d,J=5.2 Hz), 6.80 (1H, s), 7.08 (1H,d,J=10.4 Hz), 7.30-7.40 (2H,m),7.59 (1H,s), 7·62 (1H , d, J = 8.0 Hz), 7.79 (1H, s), 7·86 (1H, dd, J = 2.0, 7.6 Hz), 8.19-8.23 (3H, m), 8.61 - 8.68 (3H, m). Example 377 4-(4-(Cyclopropylaminocarbonyl)amino-3-fluoropropionyloxy)methoxy)-6_ hydroxyquinone-brown amine was obtained by the same procedure as in Example 7. 4-(4-(Cyclopropylaminocarbonyl)amino] 3-converted milk base)-7-3⁄4yl-6-Junlin anthraquinone (50 mg, 〇126 mmol) and 3-gasmethylpyridine hydrochloride Salt, the title compound obtained as pale yellow crystal - 469 - I paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) '~~—---- A7 B7 1304061 V. Description of invention (464) (20.2 mg, 0.041 mmol, 32·8 〇/〇) 〇1H-NMR spectrum (DMSO-d6) 5 (ppm): 0·41 (2Η, m), 0.65 (2Η, m), 2.56 (1H, m ), 5.47 (2H, s), 6.55 (1H, d, J=5.2 Hz), 6.81 (iHj s), 7.08 (1H, d, J = 10.0 Hz), 7.32 (1H, d, J = 12.4 Hz) ,7·45 (1H,m), 7.64 (1H,s),7·73 (1H,s),7·83 (1H,s),7.98 (iH, m),8·23 (2H,br) ,8·57 (2H,br),8.66 (1H,d,J=5.2 Hz),8·8〇(1H,s) 〇texample 378 i bis(4-(cyclopropylamino)amino-3 - Benzene gas group) - 7 - "4-pyridyl) group) - 6-4 g Lin # turtle amine by the same method as in Example 7, from 4-(4-(Cyclopropylaminocarbonyl)amino-3-fluorophenoxy)·7-carbyl-6-quinone-brown amine (50 mg, 0.126 mmol) and 'chloromethylpyridine hydrochloride The title compound (29.8 mg, 0.061 mmol, 4 8.5%) was obtained as pale yellow crystals. 〇1H-NMR spectrum (DMS 〇-d6) 5 (ppm): 0·41 (2H, m), 0·65 (2H) ,m), 2.56 (1H,m), 5.50 (2H,s), 6.54 (1H,d,J=5.2 Hz),6·80 (1H, s),7.07 (lH,d,J=8.0Hz) , 7.32 (lH, d, J = 11.6 Hz), 7.53 - 7.55 (3H, m), 7.76 (1H, s), 7.92 (1H, s), 8.19-8.22 (2H, m), 8.55 (1H , s), 8·60-8·66 (3H, m) f Example 379 oxy-4 "3-chloro-4-(cyclopropylaminecarbonyl)amine-based stupid)-6-peak carboxylic acid Amine from N-(4-(7-benzyloxy-6-amine-mercapto-4-indolyl)oxy-2-chlorophenyl)carbamic acid benzene by the same procedure as in Example 11. Ester (2.97 g, 5.50 ___- 470 -__ This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)

訂Order

線 1304061 A7 B7Line 1304061 A7 B7

晶之標題化合物（2.433 mmol)及環丙胺，得到為淡黃色結晶之 g，4.84 mmol，87.9%) 〇 ，m)，〇·65 (2H，m)，The title compound (2.433 mmol) and cyclopropylamine gave g as pale yellow crystals, 4.84 mmol, 87.9%) 〇, m), 〇·65 (2H, m),

j-NMR光 if(DMSO-d6) 5 (ppm): 〇 41 (2H， 2·56 (1H，m)，5·41 (2H，s)，6.51 (1H，d， (1H，s)，7·82 (1H，s)，7·97 (1H，s)，8.25 (1H，d，J=9.2 Hz)3 8.60 (1H，s)，8.64 (1H，d，J=5.6 Hz)。 用下述方法合成起始物質。 製造例379-1 4二(土胺基-3-氣苯氧^-7-芊氫某_6•袤其 將4-胺基-3-氣紛（10.77 g，75·0 mmol)溶於二甲基亞石風 (150 ml)，然後於室溫慢慢加入氫化鈉（3 〇〇 g , 75 〇 mm〇1) 及攪拌30分鐘。加入用公知方法合成之7_芊氧基氯-&amp; 氰基喹淋（ 14.737 g，50.0 mmol)，並於1〇〇。〇加熱授拌2小 時。放冷至室溫’將反應液分溶於乙酸乙g旨及水中，將有 機層用水及飽和食鹽水洗淨及用無水硫酸鈉乾燥。餘去溶 媒，然後付諸於矽凝膠管柱層析（溶出液；乙酸乙酯），將 包含目的物之溶出部分濃縮，懸浮於乙酸乙酯中，將其用 己烷稀釋及濾取結晶，藉由通風乾燥，得到為淡褐色結晶 之標題化合物（11.777 g，29·3 mmol，5 8.6%)。 【H-NMR 光譜（CDCl3)5(ppm): 4.13 (2H，s)，5·35 (2H，s)， 6.47 (lH，d: J=5.2 Hz)，6.85 (1H，d，J=8.8 Hz)，6.92 (1H，dd， J=2.4, 9.2 Hz), 7.13 (1H, d, J=2.4 Hz), 7.36 (1H, d, J = 7.6 本紙張尺度適用中國國家標準(CNS) A4規格（210X297公釐） 1304061 A7 B7 五、發明説明（466 )j-NMR light if (DMSO-d6) 5 (ppm): 〇41 (2H, 2·56 (1H, m), 5·41 (2H, s), 6.51 (1H, d, (1H, s), 7·82 (1H, s), 7.97 (1H, s), 8.25 (1H, d, J = 9.2 Hz) 3 8.60 (1H, s), 8.64 (1H, d, J = 5.6 Hz). The starting material was synthesized by the following method. Production Example 377-1 4 II (Amino-amino-3-phenophenoxy^-7-hydrazine hydrogen _6• 袤 将 4-amino-3- Cyclone (10.77 g , 75·0 mmol) dissolved in dimethyl sulphur (150 ml), then slowly add sodium hydride (3 〇〇g, 75 〇mm〇1) at room temperature and stir for 30 minutes. Add by a known method. 7_芊oxychloro-&amp; cyanoquinone (14737 g, 50.0 mmol), and at 1 Torr. Heated for 2 hours. Allow to cool to room temperature. Dissolve the reaction solution in ethyl acetate. In the water, the organic layer is washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent is removed, and then applied to a gel column chromatography (eluent; ethyl acetate) to contain the desired product. The dissolved fraction was concentrated, suspended in ethyl acetate, diluted with hexanes and filtered and crystallised, dried by air to give the title of pale brown crystals. Compound (11.777 g, 29.3 mmol, 5 8.6%) [H-NMR spectrum (CDCl3) 5 (ppm): 4.13 (2H, s), 5·35 (2H, s), 6.47 (lH, d : J=5.2 Hz), 6.85 (1H, d, J=8.8 Hz), 6.92 (1H, dd, J=2.4, 9.2 Hz), 7.13 (1H, d, J=2.4 Hz), 7.36 (1H, d , J = 7.6 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 B7 V. Invention description (466)

Hz), 7.42 (2H, m), 7.51-7.55 (3H, m)5 8.65 (1 H, d, J=5.2 Hz), 8·69 (1H，s) 〇 f造例379-2 £-(4-胺基-3-氟茉氫某）-7-(芊i基）-6- +呲淼醯賒 藉由與實施例112相同之手法，從4-(4-胺基-3-氯笨氧 基）-7:芊氧基-6-氰基喹啉（14.55 g，36.2 mmol)得到淡褐色 之標題化合物（5.74 g，13.7 mmol，37·8%)結晶。 j-NMR 光譜（CDCl3)5(ppm): 4·10 (2H，s)，5·34 (2H，s)， 5.78 (1Η, br), 6.47 (1H, d, J=5.2 Hz), 6.85 (1H, d, J=8.4 Hz), 6.92 (1H, dd, J=2.4, 8.4 Hz), 7.13 (1H, d, J=2.4 Hz), 7.38-7.53 (4H，m), 7·62 (1H，s)，7·82 (1H，br)，8·62 (1H，s)，8·64 (1H，d，J=5.2 Hz)，9·30 (1H，s)。 製造例379-3 Ν· (4- ( 7-芊氣基-6-胺甲醯基-4- 4嗾某）氣-2-氯苯基）胺某 甲酸笨酯 藉由與製造例17同樣之方法，從4-(4-胺基-3-氯苯氧基）-7-(芊氧基）-6-4：琳羧醯胺（4.20 g，10.0 mmol)，得到為淡 褐色結晶之標題化合物（2.97 g，5.50 mmol，55.0%)。 iH-NMR 光譜（CDCl3)5(ppm): 5.35 (2H，s)，5.81 (1H，br)， 6.51 (1H, d, J=5.2 Hz), 7.16 (1H, dd, J=2.8, 8.8 Hz), 7.22-7.30 (4H, m), 7.41-7.54 (8H, m), 7.64 (1H, s), 7.81 (1H, br), 8.32 (1H, d, 1=9.2 Hz), 8.69 (1H, d, J-5.2 Hz), 9.30 (1H, s)。 · · 實施例380 -472 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱） 裝 訂 線 1304061 、 A7 ' ^_B7 五明(—~) ^ 〜' -— (環丙胺羰基）胺基苯里•羥某杏毗 藉由與實施例83同樣之手法’從7_苄氧基-4_(3_氯(環 丙胺羰基）胺基苯氧基）-6-喹啉羧醯胺（1 〇16 g , 2 = mmol),得到為黃色結晶之標題化合物（697 , 1 mmo卜 83.6%)。 WNMR光譜（DMSO-d6)5(ppm): 0.43 (2H，m)，0·68 (2H, m) 2·58 (1H，m)，6.56 (1H，d，J=5.6 Hz)，7.23 (1H，s)，7·3〇 (1H，’ m)5 7.36 (1H, s), 7.55 (1H, d, J=2.4 Hz), 8.01 (1H, s), 8.19 (1H，s)，8.33 (1H，d，J=9.2 Hz)，8·72 (1H，d，J=5.6 Hz)，8.89 (1H，s)，9·01 (1H，s) 〇 實施例3 8 1 iiil：—氯-心（環丙胺羰基）胺基笨氣某甲氧λ 藉由與實施例7同樣之手法，從4-(3-氯-4-(環丙胺羰基） 胺基苯氧基）-7-經基-6-4淋複醯胺（50 mg，0.121 mmol)及 2-甲氧基乙基溴化物，得到為淡黃色結晶之標題化合物 (29.9 mg，0.063 mmol，52.4%)。 h-NMR 光譜（DMSO-d6)5(ppm): 0.41 (2H，m)，0.65 (2H，m)， 2.57 (1H，m)，3·36 (3H，s)，3.81 (2H，m)，4·41 (2H，m)，6.53 (1H，d，J=5.2 Hz)，7,20 (1H，d，J=2.8 Hz)，7·25 (1H，dd， J=2.8，9·2 Hz)，7.41 (1H，d，J=2.8 Hz)，7.57 (1H，s)，7·82 (1H，s)，7·83 (1H，s)，7·99 (1H，s)，8.28 (1H，d，J = 9.2 Hz)， 8·68 (1H，d，J=5.2 Hz)，8.77 (1H，s)。 -473 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（468) 實施例382 1:(.3-氣-4:(環丙胺羰基）胺某苯氳某）-7_门^4_嗎福啉基） 丙氧基）-6-，奎啦藉醯脖 藉由與實施例7同樣之手法，從4-(3-氯-4-(環丙胺羰基） 胺基苯氧基）-7-羥基-6-喹啉羧醯胺（5〇 mg，0.121 mmol)及 N- (3-鼠丙基）嗎福淋’得到為淡黃色結晶之標題化合物 (30.5 mg，0.056 mmol，46.6%)。 iH-NMR光譜（DMSO-d6)5(ppm): 0·41 (2H，m)，0·65 (2H，m)， 2·02 (2H’ m)，2·39 (4H，br)，2·46·2·59 (3H，m)，3·59 (4H，m)， 4.31 (2H, m), 6.53 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz) 7·25 (1H，dd，J=2.8, 9.2 Hz)，7.49 (1H，d，J=2.8 Hz)，7.52 (1H, s)3 7.78 (2H, s), 7.98 (1H, s), 8.28 (1H, d, J-9.2 Hz), 8·65 (1H，s)，8·66 (1H，d，J=5.2 Hz)。 ’ 實施例383 胺幾基）胺棊苯氧茱嗎福啉某） 厶氧基）-6- 4淋#醯胺 .藉由與實施例7同樣之手法，從4_(3·氯_4_(環丙胺叛基） 胺基本氧基）-7-¾基-6-p奎琳幾醯胺（50 mg，〇 ” 7 6 υ·121 mm〇i)及 N-(2-氯乙基）嗎福啉鹽酸鹽，得到為淡黃色 &amp;〜日曰 &lt; 標題化 合物（29.8 mg，0.057 mmol，46.8%)。 iH-NMR 光譜（DMSO-d6)6(ppm): 0·41 (2H，m)，〇 65 (2H ㈤） 2.50-2.56 (5H，m)，2.80 (2H，m)，3·60 (4H，br)5 4 41 (2H m) ’ 6.53 (1H，d; J=5.2 Hz)，7.20 (1H，d，J=2.8 H2) 7 …1TT’」」’ a /·25 (1H，dd， J=2.8, 8.8 Hz)，7.50 (1H，d，J=2.8 Hz)，7.58 (1H $) ? g? __________- 474 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 1304061 Λ7 A 7 ~ ~_____ Β7 五、發明説明（~~^ (1Η，s)，7·99 (1Η，s)，8·27 (1Η，d，J=8 8 Ηζ)，8·38 (1Η，s)， 8.67 (1Η, d，J=5.2 Ηζ)，8.82 (1Η，s)。 實施例384 K 3 -氣-4 -(環丙胺規基）胺基笔急^ ) · 7 _ π · n -六氤吡啶基） 玲乳基）-6_g套g林致酿胺 藉由與實施例7同樣之手法，從4_(3_氯(環丙胺羰基） 胺基苯氧基）-7-羥基-6-喹啉羧醯胺（5〇 mg , 〇 121 mm〇i)及 1 ·(氯丙基）六氫吡啶鹽酸鹽，得到為淡黃色結晶之標題化 合物（27·3 mg，0.051 mmol，41.9%)。 iH-NMR 光譜（DMS〇-d6)&lt;5(ppm): 0.42 (2ϋ，m)，0.65 (211，m)， 1·36 (2H，m)，1.47 (4H，m)，1.99 (2H，m)，2.33 (4H，br)，2.42 (2H，m)，2.56 (1H，m)，4·27 (2H，m)，6·50 (1H，d，J=5.2 Hz)， 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.47 (1H，d，J=2.8 Hz)，7.49 (1H，s)，7·76 (2H，br)，7.96 (1H，s)， 8.25 (1H, d, J=8.8 Hz), 8.64 (1H, d, J=5.2 Hz), 8.65 (1H5 s) 0 實施例385 3 -氣-4-(環丙胺羰基）胺基笨最某）_7_( 2“丨-吡咯啶）乙 氧基）-6-4琳#醯胺 藉由與實施例7同樣之手法，從4-(3-氯-4-(環丙胺羰基） 胺基表氧基）-7-輕基-6-峻淋幾酿胺（50 mg，0.121 mmol)及 1 -(氯乙基）吡咯啶鹽酸鹽，得到為淡黃色結晶之標題化合 物（24.6 mg·，〇'〇48 mmol，39.8%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 0.41 (2H，m)，0.65 (2H，m)， __- 475 - 本畝張尺度適用中國國家標準(CNS) A4規格(210X297公¢) 1304061 A7 B7 五、發明説明（47〇) 1·67 (4H，br)，2.49-2.58 (5H，m)，2.89 (2H，m)，4.38 (2H m) 6·51 (1H，d，J=5.2 Hz)，7.18 (1H，d，J=2.8 Hz)，7.23 (1H dd J=2.8，9·2 Hz)，7.48 (1H，d，J=2.8 Hz)，7.56 (ih s) 7 72 (1H，s)，7.96 (1H，s)，8·25 (1H，d，J=9.2 Hz)，8·33 (1H s)， 8.65 (1H，d，J=5.2 Hz)，8·76 (1H，s)。 ’ ’ 實施桐386 4-(3 -氣- 4- (環丙胺談基）胺基笨氣基）-7-(2 - &gt;»·基） 6〃奎淋教酿胺 藉由與實施例7同樣之手法，從4-(3 -氯- 4-(環丙胺談基） 胺基冬乳基）-7-¾基-6-0奎^林叛酿胺（206 mg，〇·499 mmol) 及2-溴乙醇，得到為淡黃色結晶之標題化合物（7 mg , 0.139 mmol，27·9%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): 0.41 (2H，m)，0.65 (2H，m)， 2·56 (1H，m)，3·84 (2H，m)，4·30 (2H，m)，5.12 (1H，t，J=5.2 Hz)，6·51 (1H，d，J=5.2 Hz)，7·19 (1H，d，J=2.8 Hz)，7.24 (1H， dd，J=2.8, 8.8 Hz)，7·49 (1H，d，J=2.8 Hz)，7.54 (1H，s)，7.82 (1H，s)，7·94 (1H，s)，7·97 (1H，s)，8.26 (1H，d，J=8.8 Hz)， 8·66 (1H，d，J=5.2 Hz)，8·80 (1H，s)。 實施例387 4-(3-氣-4-(瑷丙胺羰基）胺基茉氫某）-7-(3-羥某丙氣基）-6-。套淋羧醯胺 藉由與實施例7同樣之手法，從4-(3-氯-4-(環丙胺羰基） 胺基苯氧1)-7-經基-6-喹啉羧醯胺（206 mg，0.499 mmol) 及3-溴丙醇，得到為淡黃色結晶之標題化合物（67·〇 mg ’ -476 -____ 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 裝 訂Hz), 7.42 (2H, m), 7.51-7.55 (3H, m)5 8.65 (1 H, d, J=5.2 Hz), 8·69 (1H, s) 〇f Example 379-2 £-( 4-amino-3-fluoromethane hydrogen)-7-(芊iyl)-6- + oxime by the same procedure as in Example 112, from 4-(4-amino-3-chloro Hydroxy)-7-methoxy-6-cyanoquinoline (14.55 g, 36.2 mmol j-NMR spectrum (CDCl3) 5 (ppm): 4·10 (2H, s), 5·34 (2H, s), 5.78 (1Η, br), 6.47 (1H, d, J=5.2 Hz), 6.85 (1H, d, J=8.4 Hz), 6.92 (1H, dd, J=2.4, 8.4 Hz), 7.13 (1H, d, J=2.4 Hz), 7.38-7.53 (4H,m), 7·62 ( 1H, s), 7·82 (1H, br), 8.62 (1H, s), 8.64 (1H, d, J = 5.2 Hz), 9·30 (1H, s). Production Example 379-3 Ν·(4-(7-fluorenyl-6-amine-carbamoyl-4- 4 oxime) gas-2-chlorophenyl)amine A certain acid cumyl ester was obtained in the same manner as in Production Example 17. The method was obtained from 4-(4-amino-3-chlorophenoxy)-7-(decyloxy)-6-4: carbarylamine (4.20 g, 10.0 mmol). The title compound (2.97 g, 5.50 mmol, 55.0%). iH-NMR spectrum (CDCl3) 5 (ppm): 5.35 (2H, s), 5.81 (1H, br), 6.51 (1H, d, J = 5.2 Hz), 7.16 (1H, dd, J=2.8, 8.8 Hz ), 7.22-7.30 (4H, m), 7.41-7.54 (8H, m), 7.64 (1H, s), 7.81 (1H, br), 8.32 (1H, d, 1 = 9.2 Hz), 8.69 (1H, d, J-5.2 Hz), 9.30 (1H, s). · · Example 380 -472 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) Gutter 1304061, A7 ' ^_B7 Wu Ming (-~) ^ ~' - (Cyclopropylamine carbonyl Aminophenyl hydroxy-apricot was obtained by the same procedure as in Example 83 from 7-benzyloxy-4(3-chloro(cyclopropylaminocarbonyl)aminophenoxy)-6-quinolinecarboxylate The title compound (697, 1 mmo, 83.6%) was obtained as yellow crystals. WNMR spectrum (DMSO-d6) 5 (ppm): 0.43 (2H, m), 0·68 (2H, m) 2·58 (1H, m), 6.56 (1H, d, J = 5.6 Hz), 7.23 ( 1H, s), 7·3〇(1H,' m)5 7.36 (1H, s), 7.55 (1H, d, J=2.4 Hz), 8.01 (1H, s), 8.19 (1H, s), 8.33 (1H, d, J = 9.2 Hz), 8.72 (1H, d, J = 5.6 Hz), 8.89 (1H, s), 9·01 (1H, s) 〇 Example 3 8 1 iiil: - Chlorine -Hetal (cyclopropylamine carbonyl)amine group, a certain methoxy λ, by the same procedure as in Example 7, from 4-(3-chloro-4-(cyclopropylaminecarbonyl)aminophenoxy)-7- The title compound (29.9 mg, 0.063 mmol, 52.4%) was obtained as pale yellow crystals. H-NMR spectrum (DMSO-d6) 5 (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.57 (1H, m), 3·36 (3H, s), 3.81 (2H, m) , 4·41 (2H, m), 6.53 (1H, d, J = 5.2 Hz), 7, 20 (1H, d, J = 2.8 Hz), 7·25 (1H, dd, J=2.8, 9· 2 Hz), 7.41 (1H, d, J = 2.8 Hz), 7.57 (1H, s), 7·82 (1H, s), 7·83 (1H, s), 7·99 (1H, s), 8.28 (1H,d,J = 9.2 Hz), 8·68 (1H,d,J=5.2 Hz), 8.77 (1H, s). -473 - This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of invention (468) Example 382 1: (3-gas-4: (cyclopropylamine carbonyl) Amine benzoquinone)-7_[^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ -(cyclopropylaminecarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide (5 mg, 0.121 mmol) and N-(3-murlypropyl)moffine The title compound was crystallized (30.5 mg, 0.056 mmol, 46.6%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 0·41 (2H, m), 0·65 (2H, m), 2·02 (2H' m), 2·39 (4H, br), 2·46·2·59 (3H,m),3·59 (4H,m), 4.31 (2H, m), 6.53 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz) 7·25 (1H, dd, J=2.8, 9.2 Hz), 7.49 (1H, d, J=2.8 Hz), 7.52 (1H, s)3 7.78 (2H, s), 7.98 (1H, s) , 8.28 (1H, d, J-9.2 Hz), 8·65 (1H, s), 8.66 (1H, d, J = 5.2 Hz). 'Example 383 Amino acid group> Aminium phenoxyphene phenanthroline a) Alkoxy)-6- 4 lining #醯胺. By the same method as in Example 7, from 4_(3·氯_4_(( Cyclopropylamine tracing) Amine basic oxy)-7-3⁄4 -6-p quinalin (50 mg, 〇" 7 6 υ · 121 mm 〇i) and N-(2-chloroethyl)? For example, the title compound (29.8 mg, 0.057 mmol, 46.8%). iH-NMR spectrum (DMSO-d6) 6 (ppm): 0·41 (2H, m), 〇65 (2H (five)) 2.50-2.56 (5H, m), 2.80 (2H, m), 3·60 (4H, br) 5 4 41 (2H m) ' 6.53 (1H, d; J=5.2 Hz), 7.20 (1H, d, J = 2.8 H2) 7 ... 1TT'""' a / · 25 (1H, dd, J = 2.8, 8.8 Hz), 7.50 (1H, d, J = 2.8 Hz), 7.58 (1H $) ? g? __________- 474 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 Λ7 A 7 ~ ~_____ Β7 V. Invention description (~~^ (1Η, s),7·99 (1Η,s),8·27 (1Η,d,J=8 8 Ηζ),8·38 (1Η,s), 8.67 (1Η, d,J=5.2 Ηζ), 8.82 ( 1Η, s) Example 384 K 3 -Gas-4 -(cyclopropylamine)amino-based pen urgent ^) · 7 _ π · n - hexamidine pyridyl) lingeryl)-6_g sets of g-induced amine by the same method as in Example 7, from 4_(3-chloro(cyclopropylaminecarbonyl)aminophenoxy 7-Hydroxy-6-quinolinecarboxamide (5 mg, 〇121 mm〇i) and 1 · (chloropropyl) hexahydropyridine hydrochloride to give the title compound as pale yellow crystals (27· 3 mg, 0.051 mmol, 41.9%). iH-NMR spectrum (DMS 〇-d6) &lt; 5 (ppm): 0.42 (2 ϋ, m), 0.65 (211, m), 1·36 (2H, m), 1.47 (4H, m), 1.99 (2H) , m), 2.33 (4H, br), 2.42 (2H, m), 2.56 (1H, m), 4·27 (2H, m), 6.50 (1H, d, J = 5.2 Hz), 7.18 ( 1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.47 (1H,d,J=2.8 Hz), 7.49 (1H,s),7·76 (2H,br ), 7.96 (1H, s), 8.25 (1H, d, J = 8.8 Hz), 8.64 (1H, d, J = 5.2 Hz), 8.65 (1H5 s) 0 Example 385 3 - gas -4- (ring Propylamine carbonyl)amino group stupid) _7_( 2 "丨-pyrrolidine) ethoxy)-6-4 lin #醯 amine by the same method as in Example 7, from 4-(3-chloro-4- (cyclopropylaminecarbonyl)aminophenoxy)-7-light-6-anthracene (50 mg, 0.121 mmol) and 1-(chloroethyl)pyrrolidine hydrochloride afforded pale yellow crystals The title compound (24.6 mg·, 〇'〇 48 mmol, 39.8%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.41 (2H, m), 0.65 (2H, m), __- 475 - This mu-scale is applicable to China National Standard (CNS) A4 specification (210X297 public) 1304061 A7 B7 V. Invention description (47〇) 1·67 (4H, br), 2.49-2.58 (5H,m), 2.89 (2H,m), 4.38 (2H m) 6·51 (1H,d,J=5.2 Hz), 7.18 (1H,d,J=2.8 Hz), 7.23 (1H dd J= 2.8,9·2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.56 (ih s) 7 72 (1H, s), 7.96 (1H, s), 8·25 (1H, d, J= 9.2 Hz), 8·33 (1H s), 8.65 (1H, d, J=5.2 Hz), 8·76 (1H, s). ' ' Implementation of Tong 386 4-(3 - gas - 4- (cyclopropylamine)基基)amino-based stupid base)-7-(2 ->&gt;»-based) 6〃 淋 教 教 酿 酿 藉 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 Propylamine amide) Amino-based yamyl)-7-3⁄4yl-6-0 quinolin (206 mg, 499·499 mmol) and 2-bromoethanol gave the title compound as light yellow crystals (7) Mg, 0.139 mmol, 27.9%) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.41 (2H, m), 0.65 (2H, m), 2·56 (1H, m), 3· 84 (2H,m),4·30 (2H,m), 5.12 (1H,t,J=5.2 Hz),6·51 (1H,d,J=5.2 Hz),7·19 (1H,d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 8.8 Hz), 7·49 (1H, d, J=2.8 Hz), 7.54 (1H, s), 7.82 (1H, s), 7· 94 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J = 8.8 Hz), 8·6 6 (1H, d, J = 5.2 Hz), 8·80 (1H, s). Example 387 4-(3-Gas-4-(indolyl carbonyl)aminomethane hydrogen)-7-(3-hydroxylpropyl)-6-. Carbarylamine was used in the same manner as in Example 7 from 4-(3-chloro-4-(cyclopropylaminecarbonyl)aminophenoxy 1)-7-yl-6-quinolinecarboxamide ( 206 mg, 0.499 mmol) and 3-bromopropanol give the title compound as pale yellow crystals (67·〇mg ' -476 -____ This paper scale applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) Binding

線 1304061 A7 ~ ·___ B7 __ 五、發明説明（471) 0.142 mmol，28.5%)。 lH-NMR 光譜（DMSO-d6)5(ppm): 〇·4ΐ (2H，m)，0.65 (2H，m)， 1.98 (2H，m)，2·56 (1H，m)，3.62 (2H，m)，4·32 (2H，m)，4.69 (1H, m), 6.50 (1H, d, J=5.2 Hz), 7.18-7.24 (2H, m), 7.48- 7.50 (2H，m)，7·73 (1H，s)，7·86 (1H，s)，7·97 (1H，s)，8·26 (1H，d，J=8.4 Hz)，8.64 (1H，d，J=5.2 Hz)，8.67 (1H，s)。 實施例388 氣-4-(環丙胺羰公胺某苽氫某V7_((4R)_2,2·二甲 1，3-二氧戍.環-4-碁丄n基）·6_崦啉義醯胺 藉由與實施例7同樣之手法，從氯(環丙胺羰基） 胺基苯氧基）-7-經基ϋ琳幾醯胺（413 mg，1.00 mmol)及 4-甲苯磺酸（（4R)-2,2-二甲基-丨，％二氧戊環_4-基）甲酯， 仔到為淡男色結晶之標題化合物（234.4 mg，0.445 mmol ’ 44.5%) lH-NMR 光譜（DMSO-d6)5(ppm): 0.41 (2H，m)，0·65 (2H，m)， 1·33 (3H，s)，1.40 (3H，s)，2·56 (1H，m)，3.99 (1H，m)，4·14 (1H，m)，4·27 (1H，m)，4.41 (1H，m)，4·58 (1H，m)，6·51 (1H， d，J=5.2 Hz)，7.20 (1H，d，J=2.8 Hz)，7·25 (1H，dd，J=2.8, 8.8 Hz)，7.49 (1H，d，J=2.8 Hz)，7.57 (1H，s)，7.84 (2H，br)， 7.99 (1H，s)，8.28 (1H，d，J=8.8 Hz)，8.67 (1H，d，J=5.2 Hz)， 8.80 (1H，s) 〇 實施例389 41丄3-氯-4-(環丙胺羰基）胺棊笨氣基）_7_((43)_2,2_二甲基-1，3 -二乳戍環-4-基）甲氧某）-6 -4 g林幾酿胺 _ - 477 -___ 本紙張尺度適用中國國家標準(CNS) A4規格（210X297公釐） 1304061 A7 B7 五、發明説明（472) 藉由與實施例7同樣之手法，從4-(3-氯-4-(環丙胺羰基） 胺基私氧基）-7-經基-6-4，林幾酿胺（413 mg，1.00 mmol)及 4-甲苯磺酸（（4S)-2,2-二甲基-1，3-二氧戊環-4-基）甲酯，得 到為淡黃色結晶之標題化合物（253 mg，0.480 mmol， 48·0%) 〇 實施例390 仑（3-氯-4-(環丙胺羰某）胺基苯氣基以2R)-2,3·二蕤某 丙基）氧-6 -邊淋幾酿胺 將4-(3-氯-4-(環丙胺羰基）胺基苯氧基）-7-((4R)-2,2-二 甲基-1，3-二氧戊環-4-基）甲氧基）-6-喹啉羧醯胺（2 19 mg , 0.416 mmol)於室溫溶於三氟乙酸（2 ml) -四氫吱喃（2 ml)-水（1 ml)後，攪拌1小時。將反應液用水（30 ml)稀釋，在其 中慢慢加入碳酸氫鈉（3 g)及中和後，用乙酸乙酯萃取，有 機層用飽和食鹽水洗淨及用無水繞酸鈉乾燥。餘去溶媒， 懸浮於四氫呋喃，濾取析出之結晶，用少量乙酸乙酯洗淨 及通風乾燥，得到為白色結晶之標題化合物（121.4 mg， 0.249 mmol，60.0%) 〇 W-NMR 光譜（DMSO-d6)5(ppm): 0.41 (2H，m)，0.65 (2H，m)， 2·56 (1H，m)，3·53 (2H，m)，3·94 (1H，m)，4·24 (1H，m)，4.33 (1H, m), 4.83 (1H, t, J=5.6 Hz), 5.26 (1H, d, J=5.6 Hz), 6.53 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.26 (1H3 dd, J=2.8, 9.2 Hz), 7.51 (1H, d, J=2.8 Hz), 7.54 (1H, s), 7.84 (1H，s)，7·9·9 (2H，br)，8·28 (1H，d，J=9.2 Hz)，8.67 (1H，d， J=5.2 Hz)，8·81 (1H，s)。 -478 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公*) 裝 訂Line 1304061 A7 ~ ·___ B7 __ V. Description of invention (471) 0.142 mmol, 28.5%). lH-NMR spectrum (DMSO-d6) 5 (ppm): 〇·4ΐ (2H, m), 0.65 (2H, m), 1.98 (2H, m), 2·56 (1H, m), 3.62 (2H, m),4·32 (2H,m),4.69 (1H, m), 6.50 (1H, d, J=5.2 Hz), 7.18-7.24 (2H, m), 7.48- 7.50 (2H,m),7 · 73 (1H, s), 7·86 (1H, s), 7·97 (1H, s), 8.26 (1H, d, J = 8.4 Hz), 8.64 (1H, d, J = 5.2 Hz ), 8.67 (1H, s). Example 388 gas-4-(cyclopropylamine carbonylamine) hydrazine hydrogen V7_((4R)_2,2·dimethyl 1,3-dioxan.cyclo-4-indolyl)·6_porphyrin Imidamide was used in the same manner as in Example 7 from chloro(cyclopropylaminecarbonyl)aminophenoxy)-7- via carbendazim (413 mg, 1.00 mmol) and 4-toluenesulfonic acid ( (4R)-2,2-Dimethyl-anthracene, % dioxolane-4-yl)methyl ester, the title compound (234.4 mg, 0.445 mmol ' 44.5%) as a pale male crystal. lH-NMR spectrum (DMSO-d6) 5 (ppm): 0.41 (2H, m), 0·65 (2H, m), 1·33 (3H, s), 1.40 (3H, s), 2·56 (1H, m) , 3.99 (1H, m), 4·14 (1H, m), 4·27 (1H, m), 4.41 (1H, m), 4·58 (1H, m), 6·51 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7·25 (1H, dd, J=2.8, 8.8 Hz), 7.49 (1H, d, J=2.8 Hz), 7.57 (1H, s), 7.84 (2H, br), 7.99 (1H, s), 8.28 (1H, d, J = 8.8 Hz), 8.67 (1H, d, J = 5.2 Hz), 8.80 (1H, s) 〇 Example 389 41丄3-chloro-4-(cyclopropylaminecarbonyl)amine 棊 stupid base)_7_((43)_2,2_dimethyl-1,3-di-indolecyclo-4-yl)methoxy() -6 -4 g forest a few amines _ - 477 -___ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 B7 V. Description of invention (472) By the same method as in Example 7, from 4-(3-chloro-4- (cyclopropylamine carbonyl) aminyl ethoxy)-7-ylamino-6-4, linalylamine (413 mg, 1.00 mmol) and 4-toluenesulfonic acid ((4S)-2,2-dimethyl - 1,3-dioxolan-4-yl)methyl ester gave the title compound (253 mg, 0.480 mmol, 48·0%) as pale yellow crystals. 4-(3-chloro-4-(cyclopropylaminecarbonyl)amine group of cyclopropylamine carbonyl)aminobenzylbenzene group with 2R)-2,3·diindole propyl)oxy-6-side Phenoxy)-7-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-quinolinecarboxamide (2 19 mg, 0.416 mmol) was dissolved in trifluoroacetic acid (2 ml)-tetrahydrofuran (2 ml)-water (1 ml) at room temperature and stirred for 1 hour. The reaction solution was diluted with water (30 ml), and then sodium hydrogen carbonate (3 g) was added and neutralized, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was crystallized eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted D6) 5 (ppm): 0.41 (2H, m), 0.65 (2H, m), 2·56 (1H, m), 3·53 (2H, m), 3·94 (1H, m), 4· 24 (1H,m), 4.33 (1H, m), 4.83 (1H, t, J=5.6 Hz), 5.26 (1H, d, J=5.6 Hz), 6.53 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.26 (1H3 dd, J=2.8, 9.2 Hz), 7.51 (1H, d, J=2.8 Hz), 7.54 (1H, s), 7.84 (1H, s) , 7·9·9 (2H, br), 8.28 (1H, d, J = 9.2 Hz), 8.67 (1H, d, J = 5.2 Hz), 8.81 (1H, s). -478 - This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 public*) binding

1304061 A7 B7 五、發明説明（473) 實施例391-1 心(._3二氩-4-(麗^胺羰某）胺某茉氫某）-7-((23)-2,%二鞀某 丙基).氧-6- 4g林券脸 將4-(3-氯-4-(環丙胺羰基）胺基苯氧基）-7-((4S)-2,2-二 甲基-1，3 - 一氧戊環-4-基）甲氧基）-6-p奎琳幾胺（236 mg， 0.448 mmol)於室溫溶於三氟乙酸（2 mi)-四氫呋喃（2 ml)-水（1 ml)後，並攪拌丨小時。將反應液用水（30 ml)稀釋，在 其中慢慢加入碳酸氫鈉（3 g)及中和後，用乙酸乙酯萃取， 將有機層用飽和食鹽水洗淨及用無水硫酸鈉乾燥。餾去溶 媒’懸浮於四氫呋喃中，濾取析出之結晶，用少量乙酸乙 酉旨洗淨及通風乾燥，得到為白色結晶之標題化合物（丨15 6 mg，0.237 mmol，53.0〇/〇) 實施例391-2 4-(3-氯-4-(環丙胺羰墓）胺某笨氣某）-7-Π，3_二氫戌環·2_ 基）甲氧基）-6- 4g林# gil脖 藉由與實施例7同樣之手法，從4-(3-氯-4-(環丙胺羰基） 胺基苯氧基）-7-¾基-6-P奎琳幾醯胺（310 mg，0.75 mmol)及 2-(溴甲基）-l，3-二氧戊環）得到為白色結晶之標題化合物 (71.2 mg，0.143 mmol，19.0%) 〇 iH-NMR 光譜（DMS〇-d6)3(ppm): 0.42 (2FI，m)，0.65 (2H，m)， 2.56 (1H，m)，3.92-4.02 (4H，m)，4·36 (2H，m), 5·36 (1H，m)， 6.53 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.26 (1H, dd, J=2.8, 8.8 Hz), 7.51 (1H, d, J=2.8 Hz), 7.58 (1H, s), 7.81 (1H，s)，7·83 (1H，s)，7.99 (1H，s)，8.28 (1H，d，J=8.8 Hz)， -479 - 本紙張尺度適用中國國家標準(CNS) A4規格（210X297公釐)1304061 A7 B7 V. INSTRUCTIONS INSTRUCTION (473) EXAMPLE 391-1 Heart (._3 Di-argon-4-(L-amine carbonyl) amine A certain hydrogen hydrogen)-7-((23)-2,% diterpene a propyl). Oxygen-6-4g vouchers face 4-(3-chloro-4-(cyclopropylaminecarbonyl)aminophenoxy)-7-((4S)-2,2-dimethyl- 1,3 -monooxypentan-4-yl)methoxy)-6-p-quineline (236 mg, 0.448 mmol) dissolved in trifluoroacetic acid (2 mi)-tetrahydrofuran (2 ml) at room temperature - After water (1 ml), stir for 丨 hours. The reaction mixture was diluted with water (30 ml), and then sodium hydrogen carbonate (3 g) was added and the mixture was evaporated. The solvent was distilled off in tetrahydrofuran, and the crystals were crystallized. -2 4-(3-chloro-4-(cyclopropylamine carbonyl tomb) amine some stupid)-7-Π,3_dihydroindole ring·2_yl)methoxy)-6- 4g林# gil neck By the same procedure as in Example 7, 4-(3-chloro-4-(cyclopropylaminecarbonyl)aminophenoxy)-7-3⁄4yl-6-P-quineinamine (310 mg, 0.75) The title compound (71.2 mg, 0.143 mmol, 19.0%) was obtained as white crystals (m.p.). Ppm): 0.42 (2FI, m), 0.65 (2H, m), 2.56 (1H, m), 3.92-4.02 (4H, m), 4·36 (2H, m), 5·36 (1H, m) , 6.53 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.26 (1H, dd, J=2.8, 8.8 Hz), 7.51 (1H, d, J=2.8 Hz) , 7.58 (1H, s), 7.81 (1H, s), 7·83 (1H, s), 7.99 (1H, s), 8.28 (1H, d, J = 8.8 Hz), -479 - This paper size applies China National Standard (CNS) A4 specification (210X297 mm)

裝 訂Binding

1304061 A.- A . ' - BT五、發明説明（474) 8,68 (1H，d，J=5.2 Hz), S.75 (1Η· s)。 實施例392 笠（3-氯-4“環丙胺羰墓V签某玄氣基）-7-(3-fN,N-二乙胺某） 否基）氣）-6〃套啉#醯胺 藉由與實施例7同樣之手法1從4-(3-氯-4-(環丙胺羰基） 胺基苯氧基）-7-幾基-6-峻咕致龜胺（250 mg，0.606 mmol) 及N- (3 -氯丙基）-N，N-二乙胺鹽鉸鹽得到為淡黃色結晶之標 題化合物（119.6 mg，0.227 mmol·，3 7.5%)。 1H-NMR 光譜（DMSO-d6)d(ppm): 0·42 (2H，m)，0.65 (2H，m)， 0.95 (6H, t, J=7.2 Hz), 1.96 (2Hr m)3 2.45-2.59 (7H, m), 4.30 (2H, m), 6.52 (1H, d, J=5.2 Hz)? 7.20 (1H, d, J=2.8 Hz), 7.24 (1H, dd3 J=2.8, 9.2 Hz), 7.49 (1H, d, J=2.8 Hz), 7.50 (1H, s)? 7.79 (1H, s), 7.86 (1H, s)5 7.99 (1H, s), 8.27 (1H, d, J=9.2 Hz)，8·66 (1H，d，J=5.2 Hz), 8.69 (1H，s)。 實施例393 4-脖蕤基）-4-(3-氣-4-((環丙胺基）羰基）胺基）茉氫 基）-7-4啉某）氣）甲基）-1-六f吡啶羧酸第三丁酯 藉由與實施例7同樣之手法，從心（3-氯-4-(環丙胺羰基） 胺基苯氧基）-7-經基-6-峻淋轰龜胺（7〇〇 mg，1.696 mmol) 及4-(溴甲基）-1-六氫吡啶羧瑗第三丁酯得到為白色結晶之 標題化合物（460 mg，0.754 mmol ’ 44.5%)。 iH-NMR 光譜（DMS〇-d6)(J(ppm): 0·42 (2H，m)，0.65 (2H，m)， 1.17-1.25 (3H, m), 1.39 (9H, s), 1.79 (2H, m), 2.10 (1H, m), 2.56 (1H, m), 2.74 (1H, m)? 4.01 (2H, m), 4.12 (2H, m), 6.51 -480 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 29了公*)1304061 A.- A . ' - BT V. Inventive Note (474) 8,68 (1H,d,J=5.2 Hz), S.75 (1Η· s). Example 392 笠(3-Chloro-4"cyclopropylamine carbonyl tomb V-densified basal gas base)-7-(3-fN,N-diethylamine) No group) gas)-6〃 啉 啉 醯 醯 醯The same procedure as in Example 7 was carried out from 4-(3-chloro-4-(cyclopropylaminecarbonyl)aminophenoxy)-7-yl-6-threonamide (250 mg, 0.606 mmol). And N-(3-chloropropyl)-N,N-diethylamine salt, the title compound (119.6 mg, 0.227 mmol·, 3 7.5%) as pale yellow crystals. 1H-NMR spectrum (DMSO- D6)d(ppm): 0·42 (2H,m), 0.65 (2H,m), 0.95 (6H, t, J=7.2 Hz), 1.96 (2Hr m)3 2.45-2.59 (7H, m), 4.30 (2H, m), 6.52 (1H, d, J=5.2 Hz)? 7.20 (1H, d, J=2.8 Hz), 7.24 (1H, dd3 J=2.8, 9.2 Hz), 7.49 (1H, d, J=2.8 Hz), 7.50 (1H, s)? 7.79 (1H, s), 7.86 (1H, s)5 7.99 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.66 ( 1H, d, J = 5.2 Hz), 8.69 (1H, s). Example 393 4-N-methyl 4-((cyclopropylamino)carbonyl)amino) (-7-4 phenyl) meth)methyl)-1-hexafluorocarboxylic acid tert-butyl ester by the same method as in Example 7, from the heart (3-chloro-4-(cyclopropylamine carbonyl)amine Phenoxy group-7- The title compound (460 mg, 0.754) was obtained as white crystals from EtOAc (EtOAc: EtOAc, EtOAc, Methyl ' 44.5%). iH-NMR spectrum (DMS 〇-d6) (J (ppm): 0·42 (2H, m), 0.65 (2H, m), 1.17-1.25 (3H, m), 1.39 (9H , s), 1.79 (2H, m), 2.10 (1H, m), 2.56 (1H, m), 2.74 (1H, m)? 4.01 (2H, m), 4.12 (2H, m), 6.51 -480 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇x 29 public*)

裝 訂Binding

線 1304061 A7Line 1304061 A7

五、發明説明（ OH, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.70 OH, br), 7.71 (1H, br)5 7.97 (1H, s), 8.25 (1H, d, J=9.2 Hz),8.55 (1H, s)，8·64 (1H，d，J=5.2 Hz)。 t施例3 94氯-4-(環丙胺甚湓某、胺某茉氣某Π- f基-4-六 意基）曱氣某）-6-迷啉淼蘊胺 將4-(((6-(胺羰基）-4-(3-氯-4-((環丙胺基）羰基）胺基）苯 氧基）-7-喹啉基）氧）甲基）_卜六氫吡啶羧酸第三丁酯（460 mg，0.754 mmol)於室溫溶於三氟乙酸（2·3 ml)後，並攪拌2 小時。將反應液減壓濃縮，慢慢加入飽和礙酸氫制水溶液 並中和，用乙酸乙酯萃取及用無水硫酸鈉乾燥。餾去溶 媒’得到為粗生成物之4-(3-氯-4-(環丙胺基談基）胺基苯 氧基）-7-((4-六氫吡啶基）甲氧基）-6-喹啉羧醯胺。將其溶 於四氫吱喃（10 ml) -水（10 ml)後，於室溫加入37%曱酸水 溶液（1 ml)，乙酸（0.086 ml，1.51 mmol)及氰基硼氫鈉（95 mg，1.51 mmol)並攪拌20分鐘。將反應液分溶於乙酸乙醋 及水中，將有機層用飽和食鹽水洗淨及用無水硫酸鋼乾 燥。餾去溶媒，然後付諸於矽凝膠管柱層析（溶出液：乙酸 乙酯），將包含目的物之溶出部分濃縮，懸浮於乙酸乙醋 中’將其用己烷稀釋及濾取結晶，藉由通風乾燥，得到為 白色結晶之標題化合物（226.1 mg，0.431 mmol，2步驟： 57.2%) 〇 · * 1H-NMR 光譜（DMSOd6)5(ppm): 0·41 (2H，m)，0.65 (2H，m), -481 - 本紙張尺度適用中國國家標準(CNS) A4规格(210 x 297公釐)V. Description of the invention (OH, d, J = 5.2 Hz), 7.18 (1H, d, J = 2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.70 OH, br), 7.71 (1H, br)5 7.97 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.55 (1H, s), 8 · 64 (1H, d, J = 5.2 Hz). t Example 3 94 chloro-4-(cyclopropylamine 、 、, amine 茉 气 Π f f f f f f f f 某 某 -6 -6 -6 -6 -6 -6-6-6-6 6-(Aminocarbonyl)-4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-quinolinyl)oxy)methyl)- hexahydropyridinecarboxylic acid The third butyl ester (460 mg, 0.754 mmol) was dissolved in trifluoroacetic acid (2.3 ml) at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. Distillation of the solvent to give 4-(3-chloro-4-(cyclopropylamino)aminophenoxy)-7-((4-hexahydropyridyl)methoxy)-6 as a crude product. - Quinoline carboxamide. After dissolving in tetrahydrofuran (10 ml)-water (10 ml), 37% aqueous citric acid (1 ml), acetic acid (0.086 ml, 1.51 mmol) and sodium cyanoborohydride (95) were added at room temperature. Mg, 1.51 mmol) and stirred for 20 minutes. The reaction solution was dissolved in ethyl acetate and water, and the organic layer was washed with brine and dried over anhydrous sulfate. The solvent was distilled off, and then subjected to column chromatography on a gel column (eluent: ethyl acetate), and the eluted fraction containing the objective substance was concentrated and suspended in ethyl acetate. The mixture was diluted with hexane and filtered to crystallize. The title compound (226.1 mg, 0.431 mmol, 2 Step: 57.2%) ???··1H-NMR spectrum (DMSOd6) 5 (ppm): 0·41 (2H, m), 0.65 (2H,m), -481 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

裝 訂Binding

線 1304061 A7 B7 五、發明説明（476 1.37 (2H，m)，1.74-1.89 (5H，m)3 2.15 (3H，s)，2·56 (1H，m)， 2.79 (2H, m), 4.11 (2H, m), 6.51 (1H, d5 J=5.2 Hz), 7.18 (lHj d，J=2.8 Hz)，7·22 (1H，dd，J=2.8，9·2 Hz)，7.47 (1H，山 J=2.8 Hz)，7·49 (1H，s)，7.70 (1H，s)，7·74 (1H，s)，7.96 (1H， s), 8.25 (1H, d, J=9.2 Hz), 8.59 (1H, s)5 8.64 (1H, d, J=5·2 Hz) 〇 ' ， 實施例395 氣-4-((_(環丙胺棊1基）胺基）茇氣某n〒氫基二^ 邊J淋羧酸甲酯 藉由與實施例11同樣之手法，從^^气^氯^气^甲氧基^-甲氧羰基-4-喹啉基）氧苯基）胺基甲酸苯酯（3184 g，6·65 mmol)及環丙胺得到為淡褐色結晶之標題化合物（2·894 g， 6.55 mmol，98·5%) 〇 H-NMR 光 lf(DMS〇-d6)5(ppm): 0.41 (2Η，m)，0.65 (2Η，m)， 2·56 (1H，m)，3·85 (3H，s)，3·96 (3H，s)，6.52 (1H, d，J=5.2 Hz)，7.19 (1H，d，J=2.8 Hz)，7·24 (1H，dd，J=2.8, 9.2 Hz)， 7.50 (1H，d，J=2.8 Hz)，7·52 (1H，s)，7·97 (1H，s)，8·26 (1H， d，J=9.2 Hz)，8.56 (1H，s)，8.68 (1H，d，J=5.2 Hz)。 用下述方法合成起始物質。 製造例395-1 4-(4 -胺基-3-氯笨氣基）-7-曱氣基-6-口奎淋#酸甲酷 將4-胺基-3-氯盼（3.17 g，22.05 mmol)溶於二甲基亞石風 (50 ml) ’欢後於室溫徐徐加入風化鋼（882 mg，22.05 mmol) 並於30分鐘攪摔。加入WO 0050405記載之心氯-7-甲氧基· -482 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 〜 --_ B7 五、發明説明（477) 6- 甲氧羰基林（3.70 g，14.7 mmol)，並於100 °C加熱授拌 3小時。放冷至室溫，將反應液分溶於乙酸乙酯及水中，將 有機層用水及飽和食鹽水洗淨及用無水硫酸鈉乾燥。餾去 溶媒，然後付諸於矽凝膠管柱層析（溶出液：乙酸乙酯）， 將包含目的物之溶出部分濃縮，懸浮於乙酸乙酯中，將其 用己烷稀釋及濾取結晶，藉由通風乾燥，得到為淡褐色結 晶之標題化合物（3.092 g，8.62 mmol，57.4%)。 iH-NMR 光譜（CDCl3)5(ppm): 3·98 (3H，s)，4·0ό (3H，s)， 4·12 (2Η，s)，6·44 (1Η，d，J=5.2 Ηζ)，6·86 (1Η，d，J=8.8 Ηζ)， 6.95 (1H3 dd5 J=2.8, 8.8 Hz), 7.16 (1H, d, J=2.8 Hz), 7.49 (1H，s), 8·64 (1H，d，J=5.2 Hz)，8.80 (1H，s)。 製造例395-2Line 1304061 A7 B7 V. Description of the invention (476 1.37 (2H, m), 1.74-1.89 (5H, m) 3 2.15 (3H, s), 2·56 (1H, m), 2.79 (2H, m), 4.11 (2H, m), 6.51 (1H, d5 J=5.2 Hz), 7.18 (lHj d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9·2 Hz), 7.47 (1H, Mountain J=2.8 Hz), 7·49 (1H, s), 7.70 (1H, s), 7.74 (1H, s), 7.96 (1H, s), 8.25 (1H, d, J=9.2 Hz) , 8.59 (1H, s)5 8.64 (1H, d, J=5·2 Hz) 〇' , Example 395 gas-4-((_(cyclopropylamine 棊 1 yl)amino) hydrazine The same procedure as in Example 11 was carried out in the same manner as in Example 11 to give a methoxyl-methoxycarbonyl-4-methoxycarbonyl-4-quinolinyloxyphenyl)amino group. Phenyl formate (3184 g, 6.65 mmol) and cyclopropylamine gave the title compound (2·894 g, 6.55 mmol, 98.5%) as pale brown crystals 〇H-NMR lf (DMS〇-d6)5 (ppm): 0.41 (2Η, m), 0.65 (2Η, m), 2·56 (1H, m), 3·85 (3H, s), 3·96 (3H, s), 6.52 (1H, d , J=5.2 Hz), 7.19 (1H, d, J=2.8 Hz), 7·24 (1H, dd, J=2.8, 9.2 Hz), 7.50 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7·97 (1H, s), 8·26 (1 H, d, J = 9.2 Hz), 8.56 (1H, s), 8.68 (1H, d, J = 5.2 Hz). The starting material was synthesized by the following method. Production Example 395-1 4-(4-Amino-3-chloroindolyl)-7-fluorenyl-6-hydroxyquinone#Acetyl-Cobalt 4-amino-3-chloropan (3.17 g, 22.05 mmol) dissolved in dimethyl sulphur (50 ml) After the addition, the weathered steel (882 mg, 22.05 mmol) was slowly added at room temperature and stirred for 30 minutes. Add the heart chlorine-7-methoxy·-482 as described in WO 0050405. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 ~ --_ B7 V. Description of invention (477 6-Methoxycarbonylline (3.70 g, 14.7 mmol) and heat-mixed at 100 °C for 3 hours. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and then subjected to column chromatography on a gel column (eluent: ethyl acetate), and the fractions containing the desired material were concentrated, suspended in ethyl acetate, diluted with hexane and filtered to crystals. The title compound (3.092 g, 8.62 mmol, 57.4%). iH-NMR spectrum (CDCl3) 5 (ppm): 3·98 (3H, s), 4·0ό (3H, s), 4·12 (2Η, s), 6·44 (1Η, d, J=5.2 Ηζ),6·86 (1Η,d,J=8.8 Ηζ), 6.95 (1H3 dd5 J=2.8, 8.8 Hz), 7.16 (1H, d, J=2.8 Hz), 7.49 (1H, s), 8· 64 (1H, d, J = 5.2 Hz), 8.80 (1H, s). Manufacturing Example 395-2

Mulg-氯-4-(7-甲氧某-6-甲氧羰基-4〃杏啉基）氳苯某）胺基 甲酸笨酯 藉由與製造例17同樣之手法，從4-(4-胺基-3-氯苯氧基）- 7- 甲氧基-6-喹啉羧酸甲酯（3.09 g，8·61 mmol),得到為淡 褐色結晶之標題化合物（3.184 g，6‘65 mmol，77·2%)。 iH-NMR 光譜（CDCl3)(5(ppm): 3.98 (3Η，s)，4.0ό (3Η，s)， 6.48 (1Η, d, J=5.2 Hz), 7.17 (1H, dd, J=2.8, 9.2 Hz), 7.21- 7.31 (4H，m)，7·41-7·46 (2H，m)，7.50 (2H，br)，8·32 (1H，d， &gt;8·8 Hz)，8·67 (1H，d，J=5.2 Hz), 8·77 (1H，s)。 實施例396 lr_(3 -氯-4-(((環丙胺基）羰某）胺基）苽氣某）·7_甲资基·6-4 g林接酸 L ___ - 483 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（478) 在4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧基）-7-甲氧基· 6 -口奎酸甲g旨（2,87 g，6.50 mmol)中，加入甲醇（48 ml) 及2當量氫氧化鈉水溶液（16 ml)，然後於室溫攪拌1.5小時 及於60°C攪拌15分鐘。將反應液放冷至室溫，加入1當量鹽 酸及中和後’餾去甲醇，濾取析出之淡褐色結晶及充分水 洗後’於70°C乾燥得到標題化合物（2 628 g，614 mmol， 94.6%)。 ^-ΝΜΙ^ — πίν^ΟΟ^ρρπ^ΟΜρΗ,πΟ,ΟΜρΗ,πι)， 2·)6 (1Η，m)，3·96 (3Η，s)，6·51 (1Η，d，J=5.2 Ηζ)，7.17-7.26 (2H，m)’ 7·49 (2H，s)，7·96 (1H，s)，8.26 (1H，d，J=9.2 Hz)， 8·52 (1H，s)，8·66 (1H，d，J=5.2 Hz)，13·08 (1H，br)。 實施例397 氣-4-(((環丙胺某）羰基）胺基&gt;)茉氫某V7_ 甲乳基-6-4g枝#酸 將4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧基）_7-甲氧 基-6-喹啉羧酸（86 mg，〇·2〇 mm〇1)溶於二甲基甲醯胺（2 ml) 後’於冰冷攪拌下加入1_乙基二甲胺丙基）後化二亞 胺鹽酸鹽（77 mg，0·40 mmol)，1-羥基-1H-苯并三唑1水合 物（61 mg，0.40 mmol)，三乙胺（〇.112 ml , 0·80 mm〇1)及 環丙胺（0.055 ml)並於室溫攪拌一夜。將反應液分溶於乙酸 乙醋及水中，將有機層用水及飽和食鹽水洗淨及用無水硫 酸鋼乾燥。餾去溶媒後，懸浮於乙酸乙酯中，將其用己烷 稀釋及濾取結晶·，藉由通風乾燥，得到為白色結晶之標題 化合物（40.0 mg，0.086 mmol，42.6%)。Mulg-chloro-4-(7-methoxy-6-methoxycarbonyl-4-oxalylyl) anthracene amide) amide amide was obtained by the same method as in Production Example 17, from 4-(4- Methylamino-3-chlorophenoxy)- 7-methoxy-6-quinolinecarboxylate (3.09 g, 8.61 mmol). M, 77. 2%). iH-NMR spectrum (CDCl3) (5 (ppm): 3.98 (3 Η, s), 4.0 ό (3 Η, s), 6.48 (1 Η, d, J = 5.2 Hz), 7.17 (1H, dd, J = 2.8, 9.2 Hz), 7.21- 7.31 (4H,m),7·41-7.46 (2H,m), 7.50 (2H,br),8·32 (1H,d, &gt;8·8 Hz),8 67 (1H, d, J = 5.2 Hz), 8.77 (1H, s). Example 396 lr_(3-chloro-4-(((cyclopropylamino)carbonyl)))) ·7_甲资基·6-4 g 林酸酸 L ___ - 483 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (478) 4-(3-Chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-hydroxyl-acid yg (2,87 g, 6.50 mmol) Add methanol (48 ml) and 2 equivalents of aqueous sodium hydroxide solution (16 ml), then stir at room temperature for 1.5 hours and at 60 ° C for 15 minutes. Allow the reaction solution to cool to room temperature, add 1 equivalent of hydrochloric acid and medium After the mixture, the title compound (2 628 g, 614 mmol, 94.6%) was obtained. The title compound (2 628 g, 614 mmol, 94.6%) was obtained. ΟΜρΗ, πΟ, ΟΜρΗ, π ι), 2·)6 (1Η,m),3·96 (3Η,s),6·51 (1Η,d,J=5.2 Ηζ), 7.17-7.26 (2H,m)' 7·49 (2H ,s),7·96 (1H,s), 8.26 (1H,d,J=9.2 Hz), 8·52 (1H,s),8·66 (1H,d,J=5.2 Hz),13· 08 (1H, br). Example 397 gas-4-(((cyclopropylamine)carbonyl)amino)&gt;) jasmine hydrogen V7_ methyl lactyl-6-4g branch #acid 4-(3-chloro-4-(((cyclopropylamine)) , carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (86 mg, 〇·2〇mm〇1) dissolved in dimethylformamide (2 ml) Add 1-ethyl dimethylaminopropyl) to diimine hydrochloride (77 mg, 0.40 mmol), 1-hydroxy-1H-benzotriazole 1 hydrate (61 mg, 0.40) with ice-cooled stirring. Methyl) (triethylamine (〇.112 ml, 0·80 mm 〇1) and cyclopropylamine (0.055 ml) were stirred at room temperature overnight. The reaction solution was dissolved in ethyl acetate and water, and the organic layer was washed with water and saturated brine and dried over anhydrous sulfuric acid. After distilling off the solvent, the title compound (40.0 mg, 0.086 mmol, 42.6%) was obtained as white crystals.

裝 訂Binding

線 ___- 484 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（479Line ___- 484 - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Description of invention (479

W-NMR 光譜（DMSO-d6)5(ppm): 〇·41 (2H，m)，〇·57 (2H，m)， 0·65 (2H，m)，0.69 (2H，m)，2·57 (1H，m)，2·86 (1H，m)，3·97 (3H，s)，6·51 (1H，d，J=5.2 Hz)，7.18 (1H，d，J=2.8 Hz)，7.21 (1H，dd，J=2.8, 9.2 Hz)，7.46 (1H，d，J=2.8 Hz)，7·47 (1H，s)， 7·97 (1H，s)，8.26 (1H，d，J=9.2 Hz)，8.33 (1H，m)，8.40 (1H s)，8.64 (1H，d，J=5.2 Hz)。 實施例398 N6- (2-甲氣乙基）-4-(3 -氯-4-(((環丙胺基）護某立歷某）笨氣 基）-7-甲氫基-6〃奎啉#酸 藉由與實施例397同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喳啉羧酸（86 mg , 〇.2〇 mmol)及2-甲氧基乙胺，得到為白色結晶之標題化合物 (17.8 mg，0.037 mmol，18.3%)。 W-NMR 光譜（DMS〇-d6)(5(ppm): 0.42 (2H，m)，0.65 (2H，m)， 2·57 (1H，m)，3.29 (3H，s)，3.47 (4H，s)，4·01 (3H，s)，6·51 (1H，d，J=5.2 Hz)，7.18 (1H，d，J=2.8 Hz)，7,22 (ih，dd， J=2.8, 9.2 Hz)，7·48 (1H，d，J=2.8 Hz)，7·51 (1H，s)，7·97 (1H，s)，8·26 (1H，d，J=9.2 Hz)，8·43 (1H，s)，8.59 (ih，s)， 8·65 (1H，d，J=5.2 Hz)。 實施例399 嗎福啉基）乙基）-4-(3-氣-4-Γ ((環一两疫羞）羰基） 胺基）笨氧基）-7-甲氧基- 6-4淋券醢 藉由與實_施例·397同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（86 mg，〇.2〇 ____- 485 - 本紙張尺度通用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（ 480)W-NMR spectrum (DMSO-d6) 5 (ppm): 〇·41 (2H, m), 〇·57 (2H, m), 0·65 (2H, m), 0.69 (2H, m), 2· 57 (1H,m),2·86 (1H,m),3·97 (3H,s),6·51 (1H,d,J=5.2 Hz), 7.18 (1H,d,J=2.8 Hz) , 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.46 (1H, d, J = 2.8 Hz), 7·47 (1H, s), 7·97 (1H, s), 8.26 (1H, d , J = 9.2 Hz), 8.33 (1H, m), 8.40 (1H s), 8.64 (1H, d, J = 5.2 Hz). Example 398 N6-(2-Methylethyl)-4-(3-chloro-4-(((cyclopropylamino)))))) The morpholine #acid was obtained from 4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-carboline by the same procedure as in Example 397. The title compound (17.8 mg, 0.037 mmol, 18.3%) was obtained as white crystals from EtOAc (EtOAc: EtOAc (EtOAc) 5 (ppm): 0.42 (2H, m), 0.65 (2H, m), 2·57 (1H, m), 3.29 (3H, s), 3.47 (4H, s), 4·01 (3H, s) ,6·51 (1H,d,J=5.2 Hz), 7.18 (1H,d,J=2.8 Hz), 7,22 (ih,dd, J=2.8, 9.2 Hz),7·48 (1H,d , J=2.8 Hz), 7·51 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.43 (1H, s), 8.59 ( Ih, s), 8·65 (1H, d, J = 5.2 Hz). Example 399: oxalinyl)ethyl)-4-(3- -4-pyrene) Amino)phenyloxy)-7-methoxy-6-4 was obtained from 4-(3-chloro-4-(((cyclopropylamino)) by the same procedure as in Example 397. Carbonyl)amino)phenoxy)-7-methoxy-6 -Quinolinic acid (86 mg, 〇.2〇 ____-485 - This paper is the standard Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Description of invention (480)

mmol)及N-( 2-胺基乙基）嗎福琳，得到為〉、炎 題化合物（62.9 mg，0.116 mmol，57.9%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 0.42 (2H …、 ，）’ 〇·65 (2Η，m)， 2·43 (4Η，br)，2.47-2.51 (2Η，m)，2·56 (1Η 。 5 3*43 (2H, m), 3.60 (4H，m)，4.04 (3H，s)，6·51 (1H，d，u . Hz)&gt; 7.18 (1H, d，J=2.8 Hz)，7·22 (1H，dd，J=2.8，9 2)，7·48 (1H，d， J=2.8 Hz), 7.52 (1H, s)3 7.97 (1H, s), 8.26 (]u ,、W，d，j=9 2 Hz、 8.48 (1H, m), 8.66 (1H, d5 J=5.2 Hz), 8.67 (iH s) · 實施例400 色結晶之標 N6- ( 3 - (4-嗎福淋基）丙基）-4- Π -氧-4- 工 ' ~ 基）裁莘) 胺基）表乳基）-7-甲乳基-6-峰〃林被酿 藉由與實施例·397同樣之手法，從4-(3-翕4 ^氧-4·(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（86 mg，〇2() mmol)及N-( 3-胺基丙基）嗎福啉，得到為淡褐色結晶之炉 題化合物（84·7 mg，0.153 mmol，76.1 °/〇)。 iH-NMR 光譜（DMSO-d6)5(ppm): 0·42 (2H，m)，〇·65 (2H m) 1.69 (2H，m)，2·33-2·37 (6H，m)，2·56 (1H，m)，3·3〇-3 37 (2H，m)，3.56 (4H，m)，4·02 (3H，s)，6.51 (1H，d，J=5.6 Hz)， 7.20 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7 48 (1H，d，J=2.8 Hz), 7·52 (1H，s)，7·98 (1H，s)，8·27 (1H，d， J=9.2 Hz), 8.40 (1H, m), 8.52 (1H, s), 8.66 (1H, d, J-5.6 Hz)。 實施例401 . N6-(2-(二乙胺基）乙基）-4-(3-產.-4-((〔瑗丙胺基）羰基）胺 -486 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)Methyl) and N-(2-aminoethyl) carbaryl were obtained as the inflammatory compound (62.9 mg, 0.116 mmol, 57.9%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H ..., ,)' 〇·65 (2Η, m), 2·43 (4Η, br), 2.47-2.51 (2Η, m), 2 ·56 (1Η. 5 3*43 (2H, m), 3.60 (4H, m), 4.04 (3H, s), 6·51 (1H, d, u. Hz)&gt; 7.18 (1H, d, J =2.8 Hz),7·22 (1H,dd,J=2.8,9 2),7·48 (1H,d, J=2.8 Hz), 7.52 (1H, s)3 7.97 (1H, s), 8.26 (]u , , W, d, j=9 2 Hz, 8.48 (1H, m), 8.66 (1H, d5 J=5.2 Hz), 8.67 (iH s) · Example 400 Color Crystallization N6- ( 3 - (4-4-folfyl)propyl)-4- Π-oxy-4-gong' ~ base) 莘) Amino) acetonyl)-7-methyllacyl-6-peak eucalyptus is brewed From the same procedure as in Example 397, 4-(3-翕4^-oxy-4·(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quina Porphyrincarboxylic acid (86 mg, 〇2() mmol) and N-(3-aminopropyl)morpholine gave the title compound as light brown crystals (84·7 mg, 0.153 mmol, 76.1 ° / 〇 ). iH-NMR spectrum (DMSO-d6) 5 (ppm): 0·42 (2H, m), 〇·65 (2H m) 1.69 (2H, m), 2·33-2·37 (6H, m), 2·56 (1H,m),3·3〇-3 37 (2H,m),3.56 (4H,m),4·02 (3H,s),6.51 (1H,d,J=5.6 Hz), 7.20 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7 48 (1H, d, J=2.8 Hz), 7·52 (1H, s), 7· 98 (1H, s), 8.27 (1H, d, J = 9.2 Hz), 8.40 (1H, m), 8.52 (1H, s), 8.66 (1H, d, J-5.6 Hz). Example 401. N6-(2-(Diethylamino)ethyl)-4-(3-product.-4-((瑗propylamino)carbonyl)amine-486 - This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm)

裝 訂Binding

線 4811304061 A7 B7 基）苯氣某V-7-甲氣某-6-4啉羧醯胺 藉由與實施例397同樣之手法，從4-(3-氣-4-(((環丙胺基） 談基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（86 mg，〇 2Q mmol)及N-(2-胺基乙基）-N，N-二乙胺，得到為淡褐色結晶 之標題化合物（67·7 mg，0.129 mmol，64.0%)。 [H-NMR 光譜（DMS〇-d6)5(ppm): 0·42 (2H，m)，〇·65 (2H m) 0.98 (6H，t，J=7.2 Hz)，2.47-2.59 (7H，m)，3.37 (2H，m)，（〇3, (3H，s)，.6.51 (1H，d，J=5.2 Hz)，7·18 (1H，d，J=2.8’Hz)，’ 7_22 (1H，dd，J=2.8, 8.8 Hz)，7·47 (1H，d，J=2.8 Hz)，7·52 (1H s) 7.97 (1H，s)，8.25 (1H，d，J=8.8 Hz)，8·48 (1H，m)，8 65 (m’ d，J=5.2 Hz), 8.69 (1H，s)。 ’ 實施例402 3- ( 1-咻咯啶棊）丙基）-4- ( 3-氯-4·:乂辽凝某） 胺_基）苯氧基）-7-甲氫基-6-4啉藉醯胺 藉由與實施例397同樣之手法，從4-(3-氣-4-(((環丙胺基） 談基）胺基）苯氧基）-7-甲氧基-6-口奎琳幾酸（86 mg， mmol)及1-(3-胺基丙基）吡咯啶，得到為淡褐色結晶之我題 化合物（87.0 mg，0.162 mmol，80.4%)。 iH-NMR 光譜（DMS〇-d6)&lt;5(ppm): 0.41 (2H，m)，〇.65 (2H m) 1.65-1.72 (6H, m), 2.41-2.49 (6H, m), 2.56 (ιΗ, m) 3 28· 3.36 (2H, m), 4.01 (3H, s), 6.51 (1H, d3 1=5.2 Hz), 7.18 (1H m)，7.22 (1H，m)，7.47 (1H，d，J=2.8 Hz), 7·5〇 (ipj s) 7 96 (1H，s)，8:25 (1Ή，dd，J=1.2, 9·2 Hz)，8.41 (1H，m)，8 51 〇H s)，8·65 (1H，d，J=5.2 Hz) o -487 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）Line 4811304061 A7 B7 base) benzene gas V-7-methyl gas a -6-4 carboxy carboxamide The same procedure as in Example 397, from 4-(3- gas-4-(((cyclopropylamino)) ) 胺)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (86 mg, 〇2Q mmol) and N-(2-aminoethyl)-N,N-diethyl The title compound (67. 7 mg, 0.129 mmol, 64.0%). [H-NMR spectrum (DMS 〇-d6) 5 (ppm): 0·42 (2H, m), 〇·65 (2H m) 0.98 (6H, t, J = 7.2 Hz), 2.47-2.59 (7H, m), 3.37 (2H, m), (〇3, (3H, s), .6.51 (1H, d, J=5.2 Hz), 7·18 (1H, d, J=2.8'Hz), ' 7_22 (1H, dd, J=2.8, 8.8 Hz), 7·47 (1H, d, J=2.8 Hz), 7·52 (1H s) 7.97 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8·48 (1H, m), 8 65 (m' d, J = 5.2 Hz), 8.69 (1H, s). Example 402 3-(1-pyridinium)propyl)- 4-(3-Chloro-4·: 乂 凝 )) Amine _ yl) phenoxy)-7-methylhydro-6-4 phenyl carbamide The same procedure as in Example 397, from 4- (3-Gas-4-((cyclopropylamino) benzyl)amino)phenoxy)-7-methoxy-6-hydroxypyrimidine (86 mg, mmol) and 1-(3- Aminopropyl)pyrrolidine gave the title compound (87.0 mg, 0.162 mmol, 80.4%) as pale brown crystals. iH-NMR spectrum (DMS 〇-d6) &lt; 5 (ppm): 0.41 (2H, m), 〇.65 (2H m) 1.65-1.72 (6H, m), 2.41-2.49 (6H, m), 2.56 (ιΗ, m) 3 28· 3.36 (2H, m), 4.01 (3H, s), 6.51 (1H, d3 1=5.2 Hz), 7.18 (1H m), 7.22 (1H, m), 7.47 (1H, d, J = 2.8 Hz), 7·5 〇 (ipj s) 7 96 (1H, s), 8:25 (1Ή, dd, J=1.2, 9·2 Hz), 8.41 (1H, m), 8 51 〇H s),8·65 (1H,d,J=5.2 Hz) o -487 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

裝 訂Binding

1304061 ' - A7 _ —_ B7五、發明説明（卿）實施例403 氯-4-(((環丙胺卷j羰基）胺 基1苯·氧基上啉淼醢胺 藉由與實施例397同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7_曱氧基-6〃奎啉羧酸（86 mg , 〇2〇 mmoiy及2-(2-胺基乙基）吡啶，得到為淡褐色結晶之標題化 合物（78.4 mg，0.147 mmol，73.7%)。 H-NMR 光爾（DMSO-d6)5(ppm): 0.41 (2H，m)，0.65 (2H，m)， 2·56 (1H，m)，3·02 (2H，m)，3·68 (2H，m)，3·97 (3H，s)，6·51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.21-7.24 (2H, m),7·32 (1H，d，J=7.6 Hz)，7.47-7.49 (2H, m)，7·72 (1H，m)， 7.97 (1H，s)，8·26 (1H，d，卜8.8 Hz)，8.53-8.59 (3H，m)，8.65 (1H，d，J=5.2 Hz)。 實施例404 M-( 2-(甲磺醯基）乙某(3-氣環丙胺某）羰某）胺 基_) +乳基）-7-甲氧基- 6-4淋藉醯胺 藉由與實施例397同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）冬氧基）-7-甲氧基-6-峻〃林致酸（86 mg，0.20 mmol)及2-(甲磺醯基）乙胺，得到為淡褐色結晶之標題化合 物（58.8 mg，0·11〇 mmol，55.2%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 0·41 (2H，m)，0·65 (2H，m)， 2·56 (1Η，m)，3.06 (3Η，s)，3·41 (2Η，m)，3.75 (2Η，m)，4·01 (3H, s), 6.51 (1Ή, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, 1=2.8 Hz), 7.52 (1H, s), _ - 488 - _ 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）1304061 ' - A7 _ —_ B7 V. Inventive Note (Qing) Example 403 Chloro-4-((cyclopropylamine roll jcarbonyl)amino 1 phenoxylated guanamine The same as Example 397 Of 4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (86 mg, 〇2〇mmoiy) And 2-(2-Aminoethyl)pyridine gave the title compound (78.4 mg, 0.147 mmol, 73.7%) as pale brown crystals. H-NMR (DMSO-d6) 5 (ppm): 0.41 (2H) ,m),0.65 (2H,m), 2·56 (1H,m),3·02 (2H,m),3·68 (2H,m),3·97 (3H,s),6·51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.21-7.24 (2H, m), 7·32 (1H, d, J=7.6 Hz), 7.47-7.49 ( 2H, m),7·72 (1H,m), 7.97 (1H,s),8·26 (1H,d,b 8.8 Hz),8.53-8.59 (3H,m),8.65 (1H,d,J = 5.2 Hz). Example 404 M-(2-(methylsulfonyl)ethyl (3-cyclohexylamine)carbonyl)amino-)-)-milyl)-7-methoxy- 6-4 From the same procedure as Example 397, 4-(3-chloro-4-(((cyclopropylamino)carbonyl)))-oxy)-7-methoxy-6-jun 〃 Acid (86 mg, 0.20 mmol) and 2-(methylsulfonyl)ethylamine afforded the title compound (58.8 mg, 0·11 mmol, 55.2%) as pale brown crystals. D6) 5 (ppm): 0·41 (2H, m), 0·65 (2H, m), 2·56 (1Η, m), 3.06 (3Η, s), 3·41 (2Η, m), 3.75 (2Η,m),4·01 (3H, s), 6.51 (1Ή, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, 1=2.8 Hz), 7.52 (1H, s), _ - 488 - _ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂Binding

線 1304061 A7 B7 五、發明説明（ 7·97 (1H，s)，8.26 (1H，d，J=9.2 Hz)，8.66 (1H，d，卜5.9 Hz) 8.67 (1H，s‘)，8.75 (1H，m)。 ’ … ’ 實施例405 唑基 胺基）茉 氧基）-7-甲最，基-6-4淋#醯胺 藉由-與實施例397同樣之手法，從4-(3-氯-4_(((環丙胺基） 羰基）胺基）苯氧基）-7-曱氧基-6-喹啉羧酸（86 mg，〇2〇 mmol)及2-胺基咪唑，得到為淡褐色結晶之標題化合物 (27.0 mg ’ 0.055 mmol，27.3%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 0·41 (2H，m)，〇·65 (2H，m)， 2·56 (1H，m)，4·03 (3H，s)，6·55 (1H，d，J=5.2 Hz)，6·72 (1H， m)，6·85 (1H，m)，7.18 (1H，d，J=2.8 Hz)，7.24 (1H，dd，J=2.8, 8.8 Hz)，7.48 (1H，d，J=2.8 Hz)，7.55 (1H，s)，7·97 (1H，s)， 8.26 (1H, d，J=8.8 Hz)，8·52 (1H，s)，8·68 (1H，d，J=5 2 Hz)， 11.21 (1H，br)，11.80 (1H，m)。 實施例4 0 6 唑 _2-基）-4-(3-氣-4-(((瑷丙胺基）遙^)胺某） 蕙氧基）-7-甲氣基-6-4啉藉醯胺 藉由與實施例397同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（86 mg，〇.20 mmol)及2-胺基噻唑，得到為淡褐色結晶之標題化合物 (83.7 mg，0.164 mmol，81.7%) 〇 h-NMR 光譜（DMSO-d6)(5(ppm): 0·41 (2H，m)，〇·65 (2H，m)， 2.56 (1Η，m)，4·03 (3Η，s)，6·56 (1Η, dd，5·2 Ηζ)，7·18 -489 - 本紙張尺度適用中國國家標準(CNS) Α4規格（210 X 297公釐）Line 1304061 A7 B7 V. Description of the invention (7·97 (1H, s), 8.26 (1H, d, J = 9.2 Hz), 8.66 (1H, d, 5.9 Hz) 8.67 (1H, s'), 8.75 ( 1H,m). '...' Example 405, oxazolylamino)mosyloxy)-7-methyl, -6-6 醯# amide was obtained by the same procedure as in Example 397, from 4-( 3-Chloro-4_(((cyclopropylamino)carbonyl)amino)phenoxy)-7-decyloxy-6-quinolinecarboxylic acid (86 mg, 2 mmol) and 2-aminoimidazole, The title compound (27.0 mg '0.055 mmol, 27.3%) was obtained as pale brown crystals. iH-NMR spectrum (DMSO-d6) 5 (ppm): 0·41 (2H, m), 〇·65 (2H, m), 2·56 (1H, m), 4·03 (3H, s), 6·55 (1H,d,J=5.2 Hz),6·72 (1H, m),6·85 (1H,m), 7.18 (1H,d,J=2.8 Hz), 7.24 (1H,dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.55 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8· 52 (1H, s), 8.68 (1H, d, J = 5 2 Hz), 11.21 (1H, br), 11.80 (1H, m). Example 4 0 6 oxazol-2-yl)-4-(3-gas-4-(((propylamino)))) methoxy)-7-methyl--6-phenyl The indoleamine was obtained from 4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate by the same procedure as in Example 397. The title compound (83.7 mg, 0.164 mmol, 81.7%) was obtained as pale brown crystals (yield: EtOAc-d6) (5 (ppm) : 0·41 (2H,m),〇·65 (2H,m), 2.56 (1Η,m),4·03 (3Η,s),6·56 (1Η, dd,5·2 Ηζ),7 ·18 -489 - This paper size applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm)

裝 訂Binding

1304061 〜 … A7 __ B7 五、發明説明（484) (1H，s)，7·23 (1H，m)，7·30 (1H，s)，7.47-7.57 (3H，m)，7.97 (1H，s)，8·26 (1H，dd，J=1.6, 8.8 Ηζ)，8·53 (1H，s)，8·69 (1H， dd，J=1.6, 5.2 Hz)，12·28 (1H，s)。 實施例407 ΜΑ-(2-吡碇基）-4-(3-氯-4-((〔環丙胺基）羰基）胺某）茏氧 蓋_)-7-_甲氧基_6-g杳啉藉醯胺 藉由與實施例397同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-曱氧基-6-喹啉羧酸（43 mg , 0.10 mmol)及2-胺基吡啶，得到為淡褐色結晶之標題化合物 (17.0 mg，〇·〇34 mmol，33.6%) 〇 ^-NMR 光譜（DMSO-d6)5(ppm): 0·41 (2H，m)，0.65 (2H，m)， 2.56 (1H，m)，4·09 (3H，s)，6·55 (1H，d，J=5.2 Hz)，7·15·7·26 (3H，m)5 7.50 (1H，s)，7.59 (1H，s)，7·86 (1H，m)，7·98 (1H， s)，8·26 (2H，d，J=9.2 Hz)，8·36 (1H，m)，8.68-8.70 (2H，m)， 10.70 (1H，s) 〇 實施例408 N6-(3-nl：咬:基）-4-(3-氯- 4-((7環丙胺基）羧基基）笨氣 基）-7-甲氣基- 6-4淋致驢胺 藉由與實施例397同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（43 mg , 0.10 mmol)及3-胺基吡啶，得到為淡褐色結晶之標題化合物 (46.4 mg，0.092 mmol，92.1%)。 W-NMR 光譜（DMS〇-d6)5(ppm)·· 〇·41 (2H，m)，〇·65 (2H，m)， 2.56 (1Η, m), 4.09 (3H, s), 6.56 (1H, d, J=5.2 Hz), 7.23-7.41 -490 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 、 … A7 ___B7 五、發明説明（~~&quot; (3H，m)，7·46 (1H，s)，7.57 (1H，s)，8·03 (1H，s)，8.18-8.31 (3H，m)，8.48 (1H，s)，8·68 (1H，d，J=5.2 Ηζ)，8·80 (1H，s)， 10.58 (1H，s)。 實施例409 R6-(4-吡啶基）-4-(3-氯-4-(((環丙胺某）羰基）胺甚、苯氣 基）-7-甲氧基-6-邊淋義酿胺 藉由與實施例397同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（43 mg，0.10 mmol)及4-胺基吡淀，得到為淡褐色結晶之標題化合物 (31.1 mg，0.062 mmol，61.7%)。 iH-NMR光譜（DMSO-d6)5(ppm): 0·41 (2H，m)，0·65 (2H，m)， 2.56 (1Η5 m), 4.01 (3Η, s), 6.56 (1H, d, J=5.2 Hz), 7.21-7.24 (2H，m)，7·47 (1H，d，J=2.8 Hz)，7·57 (1H，s)，7.71 (2H，d， J=5.6 Hz), 7.99 (1H, s), 8.26 (1H, d, J-9.2 Hz), 8.44-8.48 (3H，m)，8·69 (1H，d，J=5.2 Hz)，10.73 (1H，s)。 實施例4 10 N6-( 2-羥乙某）-4-(3-氣-4-(((環丙胺基丄蓋基）苯氫 基）-7-曱氣基-6〃套啉羧醯胺 藉由與實施例397同樣之手法，從4-(3-氯一-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-4啉羧酸（86 mg，0.20 mmol)及2-胺基乙醇，得到為白色結晶之標題化合物（34.4 mg，0.073 mmol，36.3%) 〇 ^H-NMR 光譜（DMSO-d6)5(ppm): 0·41 (2H，m)，0.65 (2H，m)， 2.56 (1H，m)，3·40 (2H，m)，3.55 (1H，m)，4.03 (3H，s)，4·80 _- 491 - _______ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B71304061 ~ ... A7 __ B7 V. Description of invention (484) (1H, s), 7·23 (1H, m), 7·30 (1H, s), 7.47-7.57 (3H, m), 7.97 (1H, s),8·26 (1H,dd,J=1.6, 8.8 Ηζ), 8.53 (1H, s), 8.69 (1H, dd, J=1.6, 5.2 Hz), 12·28 (1H, s). Example 407 ΜΑ-(2-Pyridinyl)-4-(3-chloro-4-((cyclopropylamino)carbonyl)amine) oxime cap _)-7--methoxy _6-g The porphyrin was grafted with decylamine from 4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-decyloxy-6- by the same procedure as Example 397. The title compound (17.0 mg, 〇·〇 34 mmol, 33.6%) was obtained as pale brown crystals of EtOAc (EtOAc: EtOAc). (ppm): 0·41 (2H, m), 0.65 (2H, m), 2.56 (1H, m), 4·09 (3H, s), 6·55 (1H, d, J = 5.2 Hz), 7·15·7·26 (3H,m)5 7.50 (1H,s),7.59 (1H,s),7·86 (1H,m),7·98 (1H, s),8·26 (2H , d, J = 9.2 Hz), 8·36 (1H, m), 8.68-8.70 (2H, m), 10.70 (1H, s) 〇 Example 408 N6-(3-nl: bite: base)-4 -(3-Chloro-4-((7-cyclopropylamino)carboxy)phenyl)-carboyl-6-4-carboxamide was used in the same manner as in Example 397, from 4-( 3-Chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (43 mg, 0.10 mmol) and 3-aminopyridine Light brown crystal The title compound (46.4 mg, 0.092 mmol, 92.1%). W-NMR spectrum (DMS〇-d6) 5 (ppm)····41 (2H,m), 〇·65 (2H,m), 2.56 (1Η, m), 4.09 (3H, s), 6.56 ( 1H, d, J=5.2 Hz), 7.23-7.41 -490 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061, ... A7 ___B7 V. Invention description (~~&quot; ( 3H,m),7·46 (1H,s),7.57 (1H,s),8·03 (1H,s),8.18-8.31 (3H,m),8.48 (1H,s),8·68 ( 1H, d, J = 5.2 Ηζ), 8·80 (1H, s), 10.58 (1H, s). Example 409 R6-(4-pyridyl)-4-(3-chloro-4-((( Cyclopropylamine carbonyl)amine benzoate phenyl-)-7-methoxy-6-dihydro-amine was obtained by the same procedure as in Example 397, from 4-(3-chloro-4-((( Cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (43 mg, 0.10 mmol) 31.1 mg, 0.062 mmol, 61.7%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 0·41 (2H, m), 0·65 (2H, m), 2.56 (1Η5 m), 4.01 ( 3Η, s), 6.56 (1H, d, J=5.2 Hz), 7.21-7.24 (2H,m),7·47 (1H,d,J=2.8 Hz),7·57 (1H,s),7.71 (2H d, J = 5.6 Hz), 7.99 (1H, s), 8.26 (1H, d, J-9.2 Hz), 8.44-8.48 (3H, m), 8.69 (1H, d, J = 5.2 Hz), 10.73 (1H, s). Example 4 10 N6-(2-hydroxyethyl)-4-(3-carb-4-(((cyclopropylaminoguanylidene))phenyl)-7-indole -6 〃 〃 醯 carboxy carbamide was used in the same manner as in Example 397, from 4-(3-chloro-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy- The title compound (34.4 mg, 0.073 mmol, 36.3%) was obtained as a white crystal. </ RTI> </ RTI> NMR NMR (DMSO-d6) 5 ( Ppm): 0·41 (2H, m), 0.65 (2H, m), 2.56 (1H, m), 3·40 (2H, m), 3.55 (1H, m), 4.03 (3H, s), 4 ·80 _- 491 - _______ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7

(1H, t, J=5.6 Hz), 6.56 (1H, d, J-5.2 Hz), 7.20 (1H, d, J=2.8(1H, t, J=5.6 Hz), 6.56 (1H, d, J-5.2 Hz), 7.20 (1H, d, J=2.8

Hz)，7·25 (1H，dd，J=2.8，9.2 Hz)，7.50 (1H，d，J=2.8 Hz)， 7.53 (1H，s)，7·99 (1H，s)，8.28 (1H，d，J=9.2 Hz)，8.42 (1H，’ m)，8·65 (1H，s)，8·67 (1H，d，J=5.2 Hz)。 ’ 實施例4 11 丙基二^iziiXM 丙胺某^某^ 基）_7-甲氧基-6 -4啦幾酿胺 藉由與實施例397同樣之手法，從心（3_氯-4_(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喳啉羧酸（86 mg，〇 2〇 mmol)及3-胺基丙醇，得到為白色結晶之標題化合物（5ΐ ·2 mg，0.106 mmol，52.5%)。 W-NMR 光譜（DMSO-d6)5(ppm): 〇·41 (2H，m)，〇·65 (2H，m)， 1·67 (2H，m)，2·56 (1H，m)，3·36 (2H，m)，3·50 (2H，m)，4.02 (3H，s)，4·56 (1H，t，J=5.2 Hz)，6·51 (1H，d，J=5.2 Hz)，7.18(1H, d5 J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H5 d, J=2.8 Hz)，7.50 (1H，s)，7.97 (1H，s)，8·26 (1H，d，J=9.2 Hz)， 8.48 (1H，m)，8.57 (1H，s)，8.65 (1H，d，J=5.2 HZ)。實施例412Hz), 7·25 (1H, dd, J=2.8, 9.2 Hz), 7.50 (1H, d, J=2.8 Hz), 7.53 (1H, s), 7·99 (1H, s), 8.28 (1H , d, J = 9.2 Hz), 8.42 (1H, 'm), 8·65 (1H, s), 8.67 (1H, d, J = 5.2 Hz). 'Example 4 11 propyl di^iziiXM propylamine ^^^^)_7-methoxy-6 -4 lauramide by the same method as in Example 397, from the heart (3_chloro-4_(( (cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-carbolinecarboxylic acid (86 mg, 〇2〇mmol) and 3-aminopropanol give the title of white crystals Compound (5 ΐ · 2 mg, 0.106 mmol, 52.5%). W-NMR spectrum (DMSO-d6) 5 (ppm): 〇·41 (2H, m), 〇·65 (2H, m), 1·67 (2H, m), 2·56 (1H, m), 3·36 (2H,m),3·50 (2H,m),4.02 (3H,s),4·56 (1H,t,J=5.2 Hz),6·51 (1H,d,J=5.2 Hz), 7.18 (1H, d5 J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H5 d, J=2.8 Hz), 7.50 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J = 9.2 Hz), 8.48 (1H, m), 8.57 (1H, s), 8.65 (1H, d, J = 5.2 HZ). Example 412

裝 訂Binding

線 N6- ((2-身基1- (¾甲基）乙基」-4- (3-氧-4-丙胺某）凝 基）胺基）苯氧基）-7-甲氣某-6-π奎啉淼醯眩 將4-(3 -氯-4-(((環丙胺基）羰基）胺基）苯氧基甲氧 基-6-喹琳羧酸（86 mg，0.20 mmol)於氮蒙氣下溶於二甲基 甲醯胺（4· ml)，於室溫下依次加入蛇床醇ο? mg ,心4〇 mmol)，三乙胺（〇·2 ml)及（1H-1，2,3-苯并三嗅-1·某氧）（三 -492 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（487)Line N6-((2-meryl 1-(3⁄4methyl)ethyl)-4-(3-oxo-4-propylamine) acetyl)amino)phenoxy)-7-methyl -6 -π-quinoline oxime 4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxymethoxy-6-quinolincarboxylic acid (86 mg, 0.20 mmol) Nitrogen is dissolved in dimethylformamide (4 ml), and then added to the bed at room temperature, ?? mg, 4 〇 mmol), triethylamine (〇·2 ml) and (1H- 1,2,3-benzotrisole-1·an oxygen) (three-492 - this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (487)

(二甲胺基））銹六氟磷酸鹽（177 mg，〇·40 mmol)後，搜掉8 小時。將反應液分溶於乙酸乙酯及水中，並將有機層用水 及飽和食鹽水洗淨及用無水硫酸鈉乾燥。餾去溶媒，然後 藉由矽凝膠管柱層析（溶出液：乙酸乙酯/甲醇^9/丨）精製。 將包含目的物之溶出部分減壓濃縮後，懸浮於乙酸乙醋 中’將其用己烷稀釋及濾取結晶，藉由通風乾燥，得到為 白色結晶之標題化合物（75.8 11^，0.151111111〇1，75 3%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 0.42 (2H，m)，0.65 (2H，m)， 2·56 (1H，m)，3.50 (2H，m)，3·56 (2H，m)，3·96 (1H，m)，4·03 (3H, s)，4.80 (2H，t，J=5.2 Hz)，6·51 (1H，d，J=5.2 Hz) 7 19 (1H, d, J—2.8 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H d J=2.8 Hz), 7.53 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.29 (1H，m)，8·66 (1H，d，J=5.2 Hz)，8·72 (1H，s)。實施例4 1 3 - (1，3_二乳戍;哀-2猶基曱基）-4-(3 -氣- 4- (((環兩释基）巍 基)胺基）茉氧基）-7-甲氧基-6-口杏呲教醯胺 藉由與實施例412同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（200 mg，〇.467 mmol)及2-胺基甲基-1，3-二氧戊環，得到為白色結晶之標 題化合物（190.3 mg，0.371 mmo 卜 79.4%)。 h-NMR 光譜（DMS〇-d6)5(ppm): 0.41 (2H，m)，0.65 (2H m)， 2.56 (1H，m)，3.51 (2H，m)，3·85 (2H，m)，3·96 (2H，m)，4.04 (3H，s)，5..04 (m，m)，6.51 (1H，d，Hz)，7·20 (ih，d， J=2.8 Hz)，7.25 (1H，dd，J=2.8, 9.2 Hz)，7.49 (1H，d，J=2.8-493 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）After (dimethylamino) rust hexafluorophosphate (177 mg, 〇·40 mmol), it was searched for 8 hours. The reaction mixture was dissolved in ethyl acetate and water. The solvent was distilled off, and then purified by hydrazine gel column chromatography (eluent: ethyl acetate/methanol). The fractions containing the desired product are concentrated under reduced pressure and then taken up in ethyl acetate. EtOAc EtOAc EtOAc EtOAc , 75 3%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H, m), 0.65 (2H, m), 2·56 (1H, m), 3.50 (2H, m), 3.56 (2H, m),3·96 (1H,m),4·03 (3H, s), 4.80 (2H,t,J=5.2 Hz),6·51 (1H,d,J=5.2 Hz) 7 19 (1H , d, J—2.8 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H d J=2.8 Hz), 7.53 (1H, s), 7.97 (1H, s), 8.26 (1H , d, J = 9.2 Hz), 8.29 (1H, m), 8.66 (1H, d, J = 5.2 Hz), 8.72 (1H, s). Example 4 1 3 - (1,3_di- 戍; -2-2 helylene)-4-(3- gas-4-(((cyclo))))) -7-methoxy-6-hydroxyglycolide by the same procedure as in Example 412, from 4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy) Benzyl-7-methoxy-6-quinolinecarboxylic acid (200 mg, 〇. 467 mmol) and 2-aminomethyl-1,3-dioxolane afforded the title compound as white crystals (190.3 Mg, 0.371 mmo b 79.4%). H-NMR spectrum (DMS 〇-d6) 5 (ppm): 0.41 (2H, m), 0.65 (2H m), 2.56 (1H, m), 3.51 (2H, m), 3·85 (2H, m) ,3·96 (2H,m),4.04 (3H,s),5..04 (m,m),6.51 (1H,d,Hz),7·20 (ih,d, J=2.8 Hz), 7.25 (1H, dd, J=2.8, 9.2 Hz), 7.49 (1H, d, J=2.8-493 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)

裝 訂Binding

1304061 -- A7 '' * . ______B7 五、發明説明（~~) ^— ^ - Ηζ)，7·)4 (1H，s)，7·99 (1H，s)，8·27 (1H，d，J=9.2 Hz)，8.48 (1H，m)，8·64 (1H，s)，8·68 (1H，d，：ί=5·2 Hz)。 ’ 實施例414 ML(第三H氧基.)-4- (3 -氣-4“環丙胺基m基1基）茉產 羞」7-甲氧某-ό- 口奎n林藉酿胺 藉由·與實施例412同樣之手法，從4-(3_氯-4_(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基·6·喹啉羧酸（428 mg , loo mmol)及第三丁氧胺鹽酸鹽，得到為白色結晶之標題化合 物（360 mg，0.722 mmol，72.2%) 〇 iH-NMR 光譜（DMSO-d6)(5(ppm): 0.42 (2H，m)，0.65 (2H，m)， 1.25 (9H，s)，2·56 (1H，m)，3·97 (3H，s)，6·52 (1H，d，J=5.2 Hz)，7.18 (1H，d，J=2.8 Hz)，7·22 (1H，dd，J=2.8，9.2 Hz)， 7·47 (1H，d，J=2.8 Hz)，7.49 (1H，s)，7·97 (1H，s)，8·24 (1H， s)，8.26 (1H，d，J=9.2 Hz)，8·65 (1H，d，J=5.2 Hz)，10.75 (ih， s) 〇 實施例4 15 Ν6·(2-氣乙基）-4·(3-氯- 4- (((環丙腔基）藏基）胺基）笨氣 基）-7-甲氣基-6-。奎g林#酿胺 藉由與實施例412同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（171 mg，〇.40 mmol)及2-氟乙胺鹽酸鹽，得到為白色結晶之標題化合物 (130.7 mg，0·276 mmol，69.1%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): 0·41 (2H，m)，0.65 (2H，m)， 2.56 (1H, m), 3.59 (1H, m), 3.67 (1H, m), 4.03 (3H, s), 4.50 -494 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 、 A7 ~ ____B7_ 五、發明説明（~~) ' (1H，m)，4·62 (1H，m)，6·52 (1H，d，J=5.2 Hz)，7.19 (1H，d， J=2.8 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.49 (1H, d, J=2.8 Hz), 7.53 (1H, s), 7.99 (1H3 s), 8.28 (1H, d, J=9.2 Hz), 8.58-8·62 (2H，m)，8.67 (1H，d，J=5.2 Hz)。 實施例4 16 Μ·-(2-(甲 。基）-413-氯胺某） .乳基）-甲氣基-6- 4说游硫脖 藉由與實施例412同樣之手法，從4-(3_氯_4_(((環丙釦基） 羰基）胺基）苯氧基）-7-甲氧基·6-喹啉羧酸（i71 mg，〇 4〇 mmol)及2-(甲硫基）乙胺，得到為白色結晶之標題化合物 (146.2 mg，0.292 mmol，73.0%) 〇 iH-NMR 光譜（DMS〇-d6)5(ppm): 0.42 (2H，m)，0.65 (2H，m) 2·10 (3H，s)，2·56 (1H，m)，2.67 (2H，m)，3.50 (2H，m)，4·02 (3H，s)，6.51 (1H，d，J=5.2 Hz)，7.18 (1H，d，J=2.8 Hz)，7·22 (1H，dd，J=2.8, 9·2 Hz)，7·48 (1H，d，J=2.8 Hz)，7.51 (ih，s)， 7·97 (1H，s)，8·26 (1H，d，J=9.2 Hz)，8·56 (1H，m)，8·61 (1H， s)，8.65 (1H，0，J=5.2 Hz)。 ’ 實施例417 氧基-4-(3-氣-.4-(((環丙胺某）蒜某）胺某基）_7· 甲氧基-6- 4:淋#酿胺 藉由與實施例412同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（171 mg，0.40 rnniol)及甲氧胺鹽酸鹽’仔到為白色結晶之標題化合物 (109.3 mg，0.239 mmo卜 59.9%)。 _____- 495 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） 1304061 A7 B7 五、發明説明（490) iH-NMR光譜（DMSO-d6)5(ppm): 0.42 (2H，m)，0.65 (2H，m)， 2.56 (1H，m)，3·74 (3H，s)，3·99 (3H，s)，6·54 (1H，d，J=5.21304061 -- A7 '' * . ______B7 V. Description of invention (~~) ^— ^ - Ηζ),7·)4 (1H,s),7·99 (1H,s),8·27 (1H,d , J=9.2 Hz), 8.48 (1H, m), 8·64 (1H, s), 8.68 (1H, d,: ί=5·2 Hz). Example 414 ML (Third Hoxy.)-4-(3- gas-4 "cyclopropylamino]m-yl 1)) 产 」" 7-methoxy-ό- 口 n n By the same procedure as in Example 412, 4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid ( 428 mg, loo mmol), and the title compound (360 mg, 0.722 mmol, 72.2%) </i>iH-NMR spectrum (DMSO-d6) (5 (ppm): 0.42 (2H,m), 0.65 (2H,m), 1.25 (9H,s),2·56 (1H,m),3·97 (3H,s),6·52 (1H,d,J=5.2 Hz ), 7.18 (1H, d, J = 2.8 Hz), 7.22 (1H, dd, J = 2.8, 9.2 Hz), 7·47 (1H, d, J = 2.8 Hz), 7.49 (1H, s) ,7·97 (1H,s),8·24 (1H, s), 8.26 (1H,d,J=9.2 Hz),8·65 (1H,d,J=5.2 Hz),10.75 (ih, s 〇Example 4 15 Ν6·(2-Vethylethyl)-4·(3-chloro-4-(((cyclopropyl)))))))))) 6-.Quin Glin #7-methoxyl from 4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy by the same procedure as in Example 412 -6-quinoline The title compound (130.7 mg, 0·276 mmol, 69.1%) was obtained as white crystals (yield: </ br> </ br> </ br> (ppm): 0·41 (2H, m), 0.65 (2H, m), 2.56 (1H, m), 3.59 (1H, m), 3.67 (1H, m), 4.03 (3H, s), 4.50 - 494 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061, A7 ~ ____B7_ V. Invention description (~~) ' (1H, m), 4·62 (1H, m), 6·52 (1H,d,J=5.2 Hz), 7.19 (1H,d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.49 (1H, d, J=2.8 Hz) ), 7.53 (1H, s), 7.99 (1H3 s), 8.28 (1H, d, J = 9.2 Hz), 8.58-8·62 (2H, m), 8.67 (1H, d, J = 5.2 Hz). Example 4 16 Μ·-(2-(methyl.yl)-413-chloramine). (Mercapto)-Methane-6- 4 is said to be the same as in Example 412, from 4 -(3_Chloro_4_((cyclopropenyl)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (i71 mg, 〇4〇mmol) and 2-( The title compound was obtained as white crystals (146.2 mg, 0.292 mmol, 73.0%) 〇iH-NMR spectrum (DMS 〇-d6) 5 (ppm): 0.42 (2H, m), 0.65 (2H , m) 2·10 (3H, s), 2·56 (1H, m), 2.67 (2H, m), 3.50 (2H, m), 4·02 (3H, s), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9·2 Hz), 7·48 (1H, d, J=2.8 Hz), 7.51 (ih,s), 7·97 (1H,s),8·26 (1H,d,J=9.2 Hz),8·56 (1H,m),8·61 (1H, s), 8.65 ( 1H, 0, J = 5.2 Hz). 'Example 417 oxy-4-(3-gas-.4-((cyclopropylamine))) a certain group) _7·methoxy-6- 4: leaching of the amine by the example 412 In the same manner, 4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (171 mg, 0.40 rnniol And methoxyamine hydrochloride as the title compound (109.3 mg, 0.239 mmo, 59.9%) as white crystal. _____- 495 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 PCT) 1304061 A7 B7 V. Inventive Note (490) iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H, m), 3.74 (3H,s),3·99 (3H,s),6·54 (1H,d,J=5.2

Hz)，7.20 (1H，d，J=2.8 Hz)，7·25 (1H，dd，J=2.8, 9.2 Hz)， 7.48 (1H，d，J=2.8 Hz)，7·49 (1H，s)，7·99 (1H，s)，8·28 (1H， d，J=9.2 Hz)，8.43 (1H，s)，8·67 (1H，d，J=5.2 Hz)，11.46 (1H， s) ° 實施例41 8 Ν-(4-(Γ7-(芊氧基V6-氨某-4-4啉基W氧-2-氪茉 環丙基脲 將4-(4 -胺基-3-氯苯氧基）-7-爷氧基-6-氰基π奎淋（8·〇37 g，20·0 mmol)於氮蒙氣下溶於二甲基甲醯胺（4〇 mi)，於室 溫下滴入毗啶（1·94 ml，24.0mmol)及氯甲酸苯酯（3.01 ml，24·0 mmol)並攪拌1小時。滴入環丙胺（3 46 ml , 5〇 mmol)，並再授拌3小時。在反應液中加入水（4〇〇以）及乙 醚（400 ml)並授拌一夜’然後滤取折出之結晶，用水及乙 謎洗淨及藉由70t乾燥’得到為淡褐色結晶之標題化合物 (8.570 g，17.7 mmol，88.4%)。 WNMR 光譜（DMSO-d6)5(PPm): 0.42 (2H，m)，〇 65 (2H，m)，Hz), 7.20 (1H, d, J = 2.8 Hz), 7·25 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7·49 (1H, s ), 7·99 (1H, s), 8·28 (1H, d, J=9.2 Hz), 8.43 (1H, s), 8.67 (1H, d, J = 5.2 Hz), 11.46 (1H, s) ° Example 41 8 Ν-(4-(Γ7-(芊-oxy-V6-Ammonia-4-4 phenyl)-oxo-2-oxime-cyclopropylurea 4-(4-amino-3) -Chlorophenoxy)-7-yloxy-6-cyano π quinolate (8·〇37 g, 20·0 mmol) dissolved in dimethylformamide (4〇mi) under nitrogen atmosphere Dihydropyridine (1·94 ml, 24.0 mmol) and phenyl chloroformate (3.01 ml, 24.0 mmol) were added dropwise at room temperature and stirred for 1 hour. Cyclopropylamine (3 46 ml, 5 mmol) was added dropwise. And then mix for 3 hours. Add water (4 ounces) and diethyl ether (400 ml) to the reaction solution and mix for one night' then filter out the crystals, wash with water and puzzle, and dry with 70t. 'The title compound (8.570 g, 17.7 mmol, 88.4%) was obtained as pale brown crystals. WNMR spectrum (DMSO-d6) 5 (PPm): 0.42 (2H, m), 〇65 (2H, m),

2·56 (1H，m)，5·45 (2H，s)，6·58 (1H，d，2 Hz)，7.19 (1H d，J=2.8 Hz)，7.25 (1H，dd，J=2.8, 9·2 Hz)，7·36 (1H，吨 7.44 (2H，t，J=7.2 Hz)，7·50 (1H，d，Ju Hz)，7·54 (2H d J=7.2 Hz)，7.71 (1H，s)，7·98 (1H，s)，8,27 (1H，d，J=9.2 Hz) 8.73 (lH，.d; J=5:2 Hz), 8·77 (1H，s)。 ’ · ’ 實施例4 19 -496 - 1304061 ^ ' * A7 -—— —____B7____ 五、發明説明（491) 氰棊，7JW二Λ胺某）丙氧基）-4-支啉笔之 乳）+基-環丙某月辱 藉由與實施例83同樣之手法，從N-(4-((7-(苄氧基）-6-氰 基-4〇奎琳基））氧-孓氯苯基）-N，_環丙基脲（8.53 g，17.6 mmol) ’得到為淡褐色結晶之N-(4-(6-氰基-7_羥基-4-喹啉 基）氧氯苯基環丙基脲粗生成物（5·67 g)。然後藉 由與貫施例7同樣之手法，從該粗生成物（500 mg，1.6〇 mmol)及N-(3-氯丙基）-n，N-二乙胺鹽酸鹽，得到為淡黃色 結晶之標題化合物（2〇〇 mg，0.3 94 mmol，24.6%)。 iH-NMR 光譜（CDCl3)5(PPm): 0.79 (2H，m)，0.96 (2H，m)， 1.05 (6H，t，J=7.2 Hz), 2·06 (2H，m)，2·52-2·60 (5H，m)， 2.67-2.73 (3H，m)，4·29 (2H，t，J=6.0 Hz)，5.00 (1H，s)，6·49 (1H, d, J=5.2 Hz), 7.12 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, s)? 7.72 (1H, s), 8.44 (1H3 d, J=8.8 Hz), 8.66 (1H, s), 8.68 (1H, d，J=5.2 Hz)。 實施例420 4-(((4-(3-氣-4-((環丙胺基）羰某）脖基笨氣基）-6-氰基-7-邊_啉基）氧）甲基）-1 ·六氫吡啶羧酸第三丁酯 藉由與實施例7同樣之手法，從N-( 4-(6-氰基-7-羥基-4-σ奎琳基）氧-2-氣；^基）-Νς-環丙腺粗生成物（1.00 g，3.20 mmol)及4-(溴甲基）-1-六氫叶(：啶幾酸第三丁酯，得到為白 色結晶之標題化合物（275.8 mg ’ 0.466 mmol，14.6%)。 j-NMR 光譜（CDCl3)(5(ppm): 0·79 (2H, m)，0·96 (2H，m)， 1.33 (3H, m), 1.48 (9H, s), 1.93 (2H, m), 2.16 (1H, m), 2.68 __- 497 -___ 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公爱） 1304061 五、發明説明 A7 B72·56 (1H,m),5·45 (2H,s),6·58 (1H,d,2 Hz), 7.19 (1H d,J=2.8 Hz), 7.25 (1H,dd,J=2.8 , 9·2 Hz), 7·36 (1H, ton 7.44 (2H, t, J=7.2 Hz), 7·50 (1H, d, Ju Hz), 7·54 (2H d J=7.2 Hz), 7.71 (1H, s), 7·98 (1H, s), 8, 27 (1H, d, J = 9.2 Hz) 8.73 (lH,.d; J=5:2 Hz), 8·77 (1H, s). ' ' ' Example 4 19 - 496 - 1304061 ^ ' * A7 -—— - ____B7____ V. Description of invention (491) Cyanogenic hydrazine, 7JW diamine, a) propoxy)-4-bronline pen Milk) + keto-cyclopropene was sterilized by the same procedure as in Example 83, from N-(4-((7-(benzyloxy)-6-cyano-4-indolyl))oxy-孓Chlorophenyl)-N,_cyclopropylurea (8.53 g, 17.6 mmol) 'N-(4-(6-Cyano-7-hydroxy-4-quinolinyl)oxychloride as a pale brown crystal Crude phenylcyclopropylurea (5·67 g), then the crude product (500 mg, 1.6 mmol) and N-(3-chloropropyl) were obtained by the same procedure as in Example 7. The title compound (2 mg, 0.394 mmol, 24.6%) was obtained as pale yellow crystals. iH-NMR spectrum (CDCl3) 5(PPm): 0.79 (2H, m), 0.96 (2H, m), 1.05 (6H, t, J = 7.2 Hz), 2·06 (2H, m), 2·52-2·60 (5H, m), 2.67-2.73 (3H,m),4·29 (2H,t,J=6.0 Hz),5.00 (1H,s),6·49 (1H, d, J=5.2 Hz), 7.12 (1H , dd, J=2.8, 8.8 Hz), 7.48 (1H, s)? 7.72 (1H, s), 8.44 (1H3 d, J=8.8 Hz), 8.66 (1H, s), 8.68 (1H, d, J = 5.2 Hz). Example 420 4-(((4-(3-(4-(4-(4-(4-))))))))))) Oxy)methyl)-1·hexahydropyridinecarboxylic acid tert-butyl ester by the same method as in Example 7, from N-(4-(6-cyano-7-hydroxy-4-σyrylinyl) Oxygen-2-gas; ^))-Νς-cyclopropyl gland crude product (1.00 g, 3.20 mmol) and 4-(bromomethyl)-1-hexahydrofolate (: butyl succinate) The title compound (275.8 mg '0.466 mmol, 14.6%). j-NMR spectrum (CDCl3) (5 (ppm): 0·79 (2H, m), 0·96 (2H, m), 1.33 (3H, m), 1.48 (9H, s), 1.93 (2H, m ), 2.16 (1H, m), 2.68 __- 497 -___ This paper size applies to China National Standard (CNS) A4 specification (210 x 297 public) 1304061 V. Invention description A7 B7

(1H，m)，2·79 (2H，m)，4·06 (2H，d，J=6.8 Hz)，4.20 (2H，m)， 4.99 (1H, s), 6.50 (1H, d5 J=5.2 Hz), 7.12 (1H, dd, J=2.8, 9.2 Hz), 7.43 (1H, d3 J=2.8 Hz), 7.72 (1H, s), 8.44 (1H5 d, J=9.2(1H,m),2·79 (2H,m),4·06 (2H,d,J=6.8 Hz), 4.20 (2H,m), 4.99 (1H, s), 6.50 (1H, d5 J= 5.2 Hz), 7.12 (1H, dd, J=2.8, 9.2 Hz), 7.43 (1H, d3 J=2.8 Hz), 7.72 (1H, s), 8.44 (1H5 d, J=9.2

Hz)，8·66 (1H，s)，8.68 (1H，d，J=5.2 Hz)。 實施例421 笨基w-環丙基服 在4-(((4-(3-氯-4-((環丙胺基）羰基）胺基苯氧基卜6_氰 基-7-喹啉基）氧）甲基）β1-六氫吡啶羧酸第三丁酯mg , 0.846 mm〇1)中，於室溫加入三氟乙酸（2·5 mi)並攪拌w、 時。將反應液在冰水浴冷卻下，用水（3 5 ml)稀釋，慢慢加 入碳酸氫鈉（3.5 g)及中和，以及用乙酸乙酯萃取。將有機 層用水及飽和食鹽水洗淨並用無水硫酸鈉乾燥。餾去溶 媒，懸’年於乙酸乙酯中，濾取藉由用己烷稀釋而析出之結 晶，然後通風乾燥，得到為白色結晶之標題化合物（4144 mg，0.842 mmo卜 99.6%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 〇·4ΐ (2H，m)，〇·65 (2H，m)， 1.49 (2Η, m), 1.92-1.97 (3H, m)5 2.48 (1H? m)5 2.56 (1H3 m)/ 2.86-2.93 (3H，m)，4·19 (2H，d，J=6.0 Hz)，6,58 (1H，dd， J-1.2, 5.2 Hz), 7.20 (1H, s), 7.24 (1H5 d5 J=9.2 Hz), 7.48 (1H，d，J-1·2 Hz)，7·63 (1H，s)，7.99 (1H, s)，8 27 (1H d J=9.2 Hz)，8.72-8.75 (2H，m)。 實施例422 . Ν·:·Ι 2-氯-4二(（6-氰棊-7- ( (1二甲棊二^六氤y比啥華、甲氳某 -498 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 、 A7 …_ B7 五、發明説明(^^ 4-喹啉基）氫）笨基）-N’-環丙某Μ 將Ν-(2-氯-4-((6-氰基-7-(4-六氫吡啶甲氧基）-4-喹啉基） 氧）苯基）-N’-環丙基脲（540 mg，0,846 mmol)溶解於四氫呋 喃（20 ml) -甲醇（20 ml)後，於室溫加入3 7。/〇甲醛水溶液（i ml) ’ 乙酸（0.10 ml，1.69 mmol)及氰基硼氫鈉（1〇6 mg , 1.69 mmol)並攪拌1小時。將反應液分溶於乙酸乙酯及飽和 碳酸氫鈉水溶液中，將有機層用飽和食鹽水洗淨並用無水 硫酸鈉乾燥。藉由餾去溶媒，懸浮於乙酸乙酯中，用己燒 稀釋’濾取結晶，然後通風乾燥，得到為白色結晶之標題 化合物（282 mg，0.557 mmol，65.9%)。 iH-NMR光譜（DMS〇-d6) (5 (ppm): 〇·41 (2H，m)，0·66 (2H，m)， 1.39 (2H，m)，1._75-1·90 (5H，m)，2·15 (3H，s)，2·56 (1H，m)， 2·79 (2H，d，J=7.2 Hz)，4.14 (2H，d，J=5.6 Hz)，6·57 (1H，d， J=5.2 Hz)，7.19 (1H，d，J=2.8 Hz)，7.24 (1H，dd，J=2.8，9·2 Hz)，7.49 (1H，d，J=2.8 Hz)，7.58 (1H，s)，7.98 (1H，s)，8·27 (1H，d，J=9.2 Hz)，8.71-8.75 (2H，m)。 實施例423 ^Ι1ιίΙ.7-(3-溴丙氧羞丄-土.氰基-421：啉某）氫-2-轰.笔 環丙某Μ 藉由與實施例7同樣之手法’從Ν-( 4-(6-氰基-7-¾基_4-喹琳基）氧-2-氯苯基）-N、環丙基脲粗生成物（5〇〇 ^ , 1 6〇 mmol)及l，3-二溴丙烷，得到為淡褐色結晶之標題化合物 (129 mg，·〇.·250 mmol，15.6%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): 0·43 (2H，m)，0·65 (2H，m) -499 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) —- 1304061 、 A7 一 —____ B7 五、發明説明（4私） 2·37 (2H，m)，2·56 (1H，m)，3·65 (2H，m)，4·41 (2H，m)，6.60 (1H，d，J=5.2 Hz)，7.20 (1H，d，J=2.8 Hz)，7·26 (1H，dd， J=2.8, 8.8 Hz), 7.51 (1H? d, J=2.8 Hz), 7.65 (iH, s), 7.99 (1H，s)，8·28 (1H，d，J=8.8 Hz)，8.73-8.78 (2H，m)。 f施例424 -氣·_4:: ( 6二氰基-7- (3 - (1 -吡咯之g奋琳基） 星丄苯基）-N、環丙甚Μ 將N-(4-((7-(3 -溴丙氧基）-6 -氰基-4-4:琳基）氧）_2-氯苯 基）-Ν’ -環丙基腸（116 mg，0.225 mmol)溶於二甲基甲酿胺 (1.2 ml)及加入吡咯啶（〇·2 ml)並於室溫攪拌4小時。將反應 液分溶於乙酸乙酯及水中，將有機層用飽和食鹽水洗淨及 用無水硫酸鈉乾燥。鸯去溶媒，然後付諸於碎凝膠管柱層 析（溶出液：乙酸乙爱），將包含目的物之溶出部分濃縮， 懸浮於乙酸乙酯中，將其用己烷稀釋及濾取結晶，藉由通 風乾燥’得到為白色結晶之標題化合物（57.3 mg，0.113 mmol，50·3ο/〇)。 &quot;H-NMR 光譜（DMS〇-d6)5(ppm): 0·42 (2Η，m)，0.65 (2Η，m)， 1.68 (4H，br)，1·99 (2H，m)，2.45-2.61 (7H，m)，4·33 (2H，m)， 6.56 (1H，d，J=5.2 Hz)，7·19 (1H，d，J=2.8 Hz)，7.24 (1H，dd， J=2.8, 9.2 Hz), 7.49 (1H, d, J=2.8 Hz), 7.59 (1H, s), 7.98 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.72 (1H, d5 J=5.2 Hz), 8.73 (1H，s)。 實施例425 * 士.（2-氯-4-(76·氨某-7-if 1-甲某-3-六氤吡啶基）甲氣某 _____ ___- 500 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 1304061Hz), 8.66 (1H, s), 8.68 (1H, d, J = 5.2 Hz). Example 421 Stupyl w-cyclopropyl was taken up in 4-((4-(3-chloro-4-((cyclopropylamino)carbonyl))aminophenoxy) 6-cyano-7-quinolinyl Oxy)methyl)β1-hexahydropyridinecarboxylic acid tert-butyl ester mg, 0.846 mm 〇1), trifluoroacetic acid (2.5 mi) was added at room temperature and stirred for w. The reaction solution was diluted with water (3 5 ml), and then sodium hydrogencarbonate (3.5 g) was added and neutralized, and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the title compound (4144 mg,,,,,,,,,,,,,,,,,,,,,,,,,, iH-NMR spectrum (DMSO-d6) 5 (ppm): 〇·4ΐ (2H, m), 〇·65 (2H, m), 1.49 (2Η, m), 1.92-1.97 (3H, m)5 2.48 ( 1H? m)5 2.56 (1H3 m)/ 2.86-2.93 (3H,m),4·19 (2H,d,J=6.0 Hz),6,58 (1H,dd, J-1.2, 5.2 Hz), 7.20 (1H, s), 7.24 (1H5 d5 J=9.2 Hz), 7.48 (1H, d, J-1·2 Hz), 7·63 (1H, s), 7.99 (1H, s), 8 27 ( 1H d J=9.2 Hz), 8.72-8.75 (2H, m). Example 422 . Ν·:·Ι 2-chloro-4 bis ((6-cyanoindole-7- ((1 dimethyl hydrazine bis hexafluorene 啥 啥 、, 氲 氲 - - 498 - This paper scale applies to China National Standard (CNS) A4 Specification (210X297 mm) 1304061, A7 ... _ B7 V. Description of Invention (^^ 4-quinolinyl) Hydrogen) Stupid)-N'-Cyclopropanyl Μ Ν-(2- Chloro-4-((6-cyano-7-(4-hexahydropyridinemethoxy)-4-quinolinyl)oxy)phenyl)-N'-cyclopropylurea (540 mg, 0,846 mmol) After dissolving in tetrahydrofuran (20 ml)-methanol (20 ml), add 7 7 / hydrazine aqueous solution (i ml) ' acetic acid (0.10 ml, 1.69 mmol) and sodium cyanoborohydride (1 〇 6 mg) at room temperature. , 1.69 mmol), and stirred for 1 hour. The reaction mixture was dissolved in ethyl acetate and aq. The title compound (282 mg, 0.557 mmol, 65.9%) was obtained as white crystals from ethyl acetate (m. : 〇·41 (2H,m),0·66 (2H,m), 1.39 (2H,m),1._75 -1·90 (5H,m),2·15 (3H,s),2·56 (1H,m), 2·79 (2H,d,J=7.2 Hz), 4.14 (2H,d,J= 5.6 Hz),6·57 (1H,d, J=5.2 Hz), 7.19 (1H,d,J=2.8 Hz), 7.24 (1H,dd,J=2.8,9·2 Hz), 7.49 (1H, d, J = 2.8 Hz), 7.58 (1H, s), 7.98 (1H, s), 8.27 (1H, d, J = 9.2 Hz), 8.71-8.75 (2H, m). Example 423 ^Ι1ιίΙ .7-(3-Bromopropoxy oxalin-soil. cyano-421: porphyrin) hydrogen-2-Han. Pen ring Μ Μ By the same method as in Example 7 'from Ν-( 4-( 6-Cyano-7-3⁄4yl-4-quinolinyloxy-2-chlorophenyl)-N, crude cyclopropyl urea (5〇〇^, 16 6 mmol) and 1,3- The title compound (129 mg, ····································· 0·65 (2H,m) -499 - This paper size is applicable to China National Standard (CNS) Α4 specification (210X297 mm) —- 1304061, A7 one-____ B7 V. Invention description (4 private) 2·37 (2H , m), 2·56 (1H, m), 3·65 (2H, m), 4·41 (2H, m), 6.60 (1H, d, J = 5.2 Hz), 7.20 (1H, d, J =2.8 Hz), 7·26 (1 H, dd, J=2.8, 8.8 Hz), 7.51 (1H? d, J=2.8 Hz), 7.65 (iH, s), 7.99 (1H, s), 8·28 (1H, d, J=8.8 Hz ), 8.73-8.78 (2H, m). fExample 424 - gas · _4:: (6 dicyano-7-(3 - (1 - pyrrole)) N phenyl)-N, propyl propyl Μ N-(4-( (7-(3-Bromopropoxy)-6-cyano-4-4:linyl)oxy)_2-chlorophenyl)-indole-cyclopropene (116 mg, 0.225 mmol) dissolved in two Methyl amide (1.2 ml) and pyrrolidine (〇 2 ml) were added and stirred at room temperature for 4 hours. The reaction solution was dissolved in ethyl acetate and water, and the organic layer was washed with saturated brine. Drying with anhydrous sodium sulfate, removing the solvent, and then subjecting it to a gel column chromatography (eluent: ethyl acetate), concentrating the eluted fraction containing the desired product, suspending it in ethyl acetate, and using hexane The title compound (57.3 mg, 0.113 mmol, 50·3ο / 〇) was obtained as white crystals. &quot;H-NMR spectrum (DMS 〇-d6) 5 (ppm): 0 ·42 (2Η,m), 0.65 (2Η,m), 1.68 (4H,br),1·99 (2H,m),2.45-2.61 (7H,m),4·33 (2H,m), 6.56 (1H, d, J=5.2 Hz), 7·19 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.49 (1H, d, J=2.8 Hz) , 7.59 (1H, s), 7. 98 (1H, s), 8.27 (1H, d, J = 9.2 Hz), 8.72 (1H, d5 J = 5.2 Hz), 8.73 (1H, s). Example 425 * 士.(2-chloro-4- (76·Ammonia-7-if 1-methyl -3-hexapyridine) A gas _____ ___- 500 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061

林基）氣）笨基環丙基脲Linji) gas) stupid cyclopropyl urea

將4-(4-胺基-3-氣苯氧基）-6-氰基-7-((1-甲基-3-六氫毗 咬基）曱氧基啉（246 mg，0.582 mmol)於氮蒙氣下溶於 —甲基甲醯胺（6 ml)，然後於室溫滴入吡竞（ο」9 ml，2.33 mmol)及氯甲酸苯酯（〇.i5ml，1· 16 mmol)並攪拌1小時。滴 入環丙胺（0.20ml，2·91 mmol)，再攪拌3小時。將反應液分 i於乙酸乙酯及飽和竣酸氫鈉水溶液中，將有機層用水及 飽和食鹽水洗淨及用無水硫酸鈉乾燥。餾去溶媒，懸浮於 甲醇中，將其用水稀釋及濾取結晶，藉由在70。〇乾燥，得 % 到為淡页色結晶之標題化合物（198.7 mg，0.393 mmol， 67.5%) 〇 iH-NMR 光譜（DMSO-d6)(5(ppm): 0·41 (2Η，m)，〇·65 (2Η，m)， 1·18 (1H，m)，1·54 (1H，m)，1·68 (1H，m)，ι·79 (1H，m)，19〇4-(4-Amino-3- phenoxy)-6-cyano-7-((1-methyl-3-hexahydropyridyl) oxime (246 mg, 0.582 mmol) Dissolve in a nitrogen atmosphere - methylformamide (6 ml), then add pyridine (ο 9 ml, 2.33 mmol) and phenyl chloroformate (〇.i5 ml, 1 · 16 mmol) at room temperature. After stirring for 1 hour, cyclopropylamine (0.20 ml, 2.91 mmol) was added dropwise, and the mixture was stirred for additional 3 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate, and the organic layer was washed with water and brine. Washed and dried over anhydrous sodium sulfate. The title compound (198.7 mg, EtOAc, m. 0.393 mmol, 67.5%) 〇iH-NMR spectrum (DMSO-d6) (5 (ppm): 0·41 (2Η, m), 〇·65 (2Η, m), 1·18 (1H, m), 1 ·54 (1H,m),1·68 (1H,m), ι·79 (1H,m),19〇

(2H，m)，2·11 (1H，m)，2·17 (3H，s)，2.56 (1H，m)，2·65 (1H, m)，2·85 (1H，m)，4.18 (2H，d，J=6.4 Hz)，6·59 (1H，d，J=5.2 Hz)，7.20 (1H，d，J=2.8 Hz)，7·26 (1H，dd，J=2.8, 9.2 Hz)， 7·51 (1H, s)5 7·60 (1H，s)，8·00 (1H，s)，8.29 (1H，d，卜9.2(2H,m),2·11 (1H,m),2·17 (3H,s),2.56 (1H,m),2·65 (1H, m),2·85 (1H,m), 4.18 (2H,d,J=6.4 Hz),6·59 (1H,d,J=5.2 Hz), 7.20 (1H,d,J=2.8 Hz),7·26 (1H,dd,J=2.8, 9.2 Hz), 7·51 (1H, s)5 7·60 (1H, s), 8·00 (1H, s), 8.29 (1H, d, 9.2

Hz)，8.74-8.76 (2H，m)。 如下述合成起始物質。 复並例425-1 1:(4-胺某-3-藍.茉氣基）-6二—氰基-7-((1-甲甚^^氮，比 里氧基啉 藉由與實施例83同樣之手法，從4-(4-胺基-3-氯苯氧基）_ 7 -苄氧基-6-氰基p奎琳（3.728 g，9.28 mmol)得到為淡褐色 -501 - 1尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 一、· B7 五、發明説明（496) 結晶之4-(4-胺基-3-氯笨氧基）-6-氰基-7-羥基4啉耝生成 物（3.306 g)。然後籍甴與實施例7同樣之手法，從該粗生成 物（ 500 mg，1.60 mmol)及3-氯甲基-1-甲基六氫吡啶鹽酸 鹽，得到為淡褐色結晶之標題化合物（246 mg，0.581 mmol，36.4%) 〇 ^-NMR 光譜（CDC1;)&lt;5(ppm): 1·25 (1H，m)，1.62-2.01 (5H? m)，2·27 (1H，m)，2.33 (3H，s)，2·33 (1H，m)，2·76 (1H，m)， 4.05-4.15 (4H5 m), 6.46 (1H? d, J=5.2 Hz), 6.86 (1H, d, J=8.8 Hz)，6·93 (1H，dd，J=2.8, 8.8 Hz)，7·14 (1H，d，J=2.8 Hz)， 7·43 (1H，s)，8.65-8.67 (2H，m)。Hz), 8.74 - 8.76 (2H, m). The starting materials were synthesized as described below. Complex bake 425-1 1: (4-amine -3-blue. jasmine)-6 bis-cyano-7-((1-methyl-^^-nitrogen, piroxyl by means of implementation Example 83 was obtained from 4-(4-amino-3-chlorophenoxy)-7-benzyloxy-6-cyano p-quineline (3.728 g, 9.28 mmol) as pale brown-501. 1 scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 I, · B7 V. Description of invention (496) Crystallized 4-(4-amino-3-chlorophenyloxy)-6 -Cyano-7-hydroxytetralinium product (3.306 g). The crude product (500 mg, 1.60 mmol) and 3-chloromethyl-1-methyl The title compound (246 mg, 0.581 mmol, 36.4%) was obtained as pale brown crystals. </RTI> NMR spectrum (CDC1;) &lt;5 (ppm): 1·25 (1H, m) , 1.62-2.01 (5H? m), 2·27 (1H, m), 2.33 (3H, s), 2·33 (1H, m), 2·76 (1H, m), 4.05-4.15 (4H5 m ), 6.46 (1H? d, J=5.2 Hz), 6.86 (1H, d, J=8.8 Hz), 6.93 (1H, dd, J=2.8, 8.8 Hz), 7·14 (1H, d, J = 2.8 Hz), 7·43 (1H, s), 8.65-8.67 (2H, m).

實施例426 氢-4-((¾丙琮甚）諾篡）胺某笨氣基）-6-教某-奎啉基）氣）乙基）-1-六氬毗畦栽酸第三丁酯 將4-(((4-(4-胺基-3·氯苯氧基）-6-氰基-7-喹啉基）氧）乙 基）-1-六氩吡啶複酸第主丁酯（486.5 mg，0.930 mmol)於氮 蒙氣下溶於二甲基曱醯综（5 ml)，然後於室溫滴入吡啶 (0.170 ml，2.09 mmol)及氯曱酸苯酯（0.175ml，1·34 mmol) 並擾拌1小時。滴入環丙磨（0.322ml，4.65 mmol)，並再擾 拌一夜。將反應液分溶於乙酸乙酯及飽和竣酸氫鈉水溶液 中，將有機層用水及飽和食鹽水洗淨及用無水硫酸鈉乾 燥。餾去溶媒，然後付諸於矽凝膠管柱層析（溶出液：乙酸 乙酯），將包含目的物之溶出部分濃縮，懸浮於乙酸乙酯 中，將其用·己垸.稀釋及濾衣結晶，藉由通風乾燥，得到為 淡黃色結晶之標題化合物（343 mg，〇·566 mmol，60.8%)。 _ - 502 - 張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 、 B7 五、發明説明（497) 1H-NMR 光譜（CDCl3)5(ppm): 0.80 (2H，m)，0·95 (2H，m)， 1.2 卜 1.28 (3H，m)，1·47 (9H，s)，1·77 (2H，m)，1·89 (2H，m)， 2.67 (1H，m)，2·75 (2H，m)，4,12 (2H，m)，4.28 (2H, m)，4.97 (1H, s)，6.50 (1H，d，J=5.2 Hz)，7.12 (1H，dd，J=2.8, 8,8 Hz)， 7·25 (1H，d，J=2.8 Hz), 7·45 (1H，s)，7·72 (1H，s)，8.44 (1H， d，J=8:8 Hz)，8·66 (1H，s)，8·68 (1H，d，J=5.2 Hz)。 如下述合成起始物質e _造例426-1 4-(2-(((4 -胺基-3-氯苯氧基）-6 -氨基♦成某）氣）己基）-1-六氤吡啶羧酸第三丁酯 藉由與實施例7同樣之手法，從4-(4-胺基-3-氯苯氧基）-6-氰基-7-羥基喳啉粗生成物（742 mg，2·38 mmol)及4-(溴 乙基）-卜六氫吡啶羧酸第三丁酯，得到為淡褐色結晶之標 題化合物（492·6 mg，0.942 mmol，39.6%)。 iH-NMR 光譜（CDCl3)5(ppm): Ml-1.31 (4H，m)，1.46 (9H， s)，1·77 (2H，m)，1·90 (2H，m)，2·52,2·56 (3H，m)，4·11 (2H， m)，4·27 (2H，m)5 6·48 (1H，d，J=5.2 Hz)，6.86 (1H，d，卜9.2 Hz)，6·93 (1H，dd，J=2.8，9.2 Hz)，7,14 (1H，d，J=2.8 Hz)， 7.44 (1H，s)，8.66-8.68 (2H，m)。 實施例427 氯氰基-7-(2-(4-六-氫吨乙氲某违啉 基）$)冬基）-N’ -環丙基月尿 在‘（（（·4:(3-氯-4-((環丙胺基）羰基）胺基苯氧基卜6•氰 基-了·5&quot;奎琳基）氧）乙基）-l-x氫1^比淀幾酸第三丁 g旨（343 mg , _____ - 503 - 紙張尺度國國家標準(CNS) A4規格(21〇 χ 297公釐^ ' —-：- A7 B7 498 &gt; 1304061 五、發明説明（ 0.5 66 mmol)中，於室溫加入三氟乙酸（3 〇 ml)並攪拌i小 時。將反應液在冰水浴冷卻下，用水（4〇 ml)稀釋，慢慢加 入竣酸氫鈉（4.0 g)及中和，以及用乙酸乙酯萃取。將有機 層用水及飽和食鹽水洗淨並用無水硫酸鈉乾燥。餾去溶 媒，懸浮於乙酸乙酯中，濾取藉由用己烷稀釋而析出之結 晶，然後通風乾燥，得到為淡黃色結晶之標題化合物（286 mg，0.5 66 mmol，定量的）。 iH-NMR光譜（CDCl3)5(ppm): 0.78 (2H，m)，0·95 (2H，m)， 1.63 (2H，m)，1.96-2.05 (5H，m)，2.66 (1H，m)，2.90 (2H，m)， 3.41 (2H，m)，4.27-4.30 (3H，m)，5.10 (1H，s)，6.50 (1H，d， J=5.2 Hz)，7·12 (1H，dd，J=2.8，8·8 Hz)，7.27 (1H，d，J=2.8 Hz)，7·46 (1H，s)，7·73 (1H，s)，8·44 (1H，d，J=8.8 Hz)，8.66 (1H，s)，8·68 (1H，d，J=5.2 Hz)。 實施例428 止（2-氯二j- (( 6-氰基-7- (2- (1-甲基-4-六氪tr比咬基）乙争· 基）-4〃奎淋基）氧）笨基）-N、環丙基月尿 將N-(2-乳-4-((6 -说基- 7- (2-(4-ττ氫p比淀乙氧基奎 淋基）氧）笨基）-Ν· -環丙基月尿（286 mg，0.566 mmol)溶解於 四氫呋喃（5 ml)-甲醇（5 ml)後，於室溫加入37%甲醛水溶 液（0.5 ml)，乙酸（0.065 ml，1.13 mmol)及氰基硼氫趣 (7 lmg，1 · 13 mmol)並擾拌1小時。將反應液分溶於乙酸乙 酯及飽和礙酸氫納水溶液中，將有機層用飽和食鹽水洗淨 並用無水.硫酸鈉乾燥。藉由餾去溶媒，懸浮於乙酸乙醋 中，用己烷稀釋，濾取結晶，然後通風乾燥，得到為淡黃 -504 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 13〇4〇61 _ 、 A7 ------ B7 五、發明説明（4的） 色結晶之標題化合物（2 18.2 mg，0.420 mmol，74.1%)。 iH-NMR 光譜（DMSO-d6)&lt;5(ppm): 0.41 (2H，m)，0·65 (2H，m)， 1.23 (2Η，m)，1.50 (1Η，m)，1.71-1.88 (6Η，m)，2.15 (3Η，s)， 2.56 (1H，m)，2.75 (2H，m)，4·33 (2H，t，J=6.4 Hz)，6.58 (1H， d，J=5.2 Hz)，7.20 (1H，d，J=2.8 Hz)，7·26 (1H，dd，J=2.8, 9.2 H2)，7·50 (1H，d，J=2.8 Hz)，7.62 (1H，s)，8·00 (1H，s)， 8.28 (1H，d，J=9.2 Hz)，8.73-8.75 (2H，m)。 免施例4 29 氯-4-(( 6-氰基-7-( ((2R)-3-(二乙胺某）-2-淼奚石 I、 氣4-4啉基）氫）苽某）-N、環丙脲 將（4-(4-胺基-3-氯苯氧基）-6-氰基- 7-(( (2R)-3-(二乙胺 基）-2-羥基丙基）氧）喹啉）（96.9 mg，0.22 mmol)於氮蒙氣 下溶於二甲基甲醯胺（1 ml)，然後於室溫滴入吡啶（〇 〇27 ’ 0.3 3 mmol)及氯甲酸苯酯（〇.〇35ml，〇·28 mmol)並授掉 1小時。滴入環丙胺（0.10ml)，並再攪拌一夜。將反應液分 落於乙酸乙酯及飽和碳酸氫鈉水溶液中，將有機層用水及 飽和食鹽水洗淨及用無水硫酸鈉乾燥。餾去溶媒，然後付 諸於矽凝膠管柱層析（溶出液：乙酸乙酯），將包含目的物 之溶出部分濃縮，懸浮於乙酸乙醋中，將其用己烷稀釋及 濾取結晶，藉由通風乾燥，得到為淡黃色結晶之標題化合 *(6l.6mg，0.118nim(^，53.5%)。 lH-NMR 光譜（DMSO-d6)5(PPm)·· 0·42 (2H，m)，〇.65 (2H，m)， 0.96 (6H, VJ=7.2 Hz), 2.42-2.67 (7H) m), 3.95 (1H, m), 4.2/ (1H，m)，4·30 (1H，m)，4.91 (1H，m)，6.57 (1H，d，J=5.2 Hz)， _____- 505 - 本紙張尺度適用國國家標準(CMS) A4規格(210 x 297公釐)-------- A7 B7 1304061 五、發明説明（500) 7.19 (1H，d，J=2.8 Hz)，7.25 (1H，dd，J=2.8，9.2 Hz)，7.50 (1H，d，J=2.8 Hz)，7.61 (1H，s)，7·98 (1H，s)，8.27 (1H，d， J = 9.2 Hz)，8.70 (1H，s)，8.72 (1H, d，J=5.2 Hz) 〇 如下述合成起始物質。 华造例429- 1 (心（4」胺羞.-3.-氯苯氧某）-6-氨某-7-K2R)-環敷L烷-2-基） 甲氧;r奎淋 藉由與實施例7同樣之手法，從4- (4-胺基-3 -氯苯氧基）-6-氰基-7-羥基喳啉粗生成物（l.OOg，3.21 mmol)及4-甲基-1 -苯磺酸[(2R) ·環氧乙烷-2-基甲基]酯，得到為淡褐色結 晶之標題化合物（198 mg，0.53 8 mmol，16·8%)。 1H-NMR光譜（CDCl3.)(5(pPm): 2·93 (1H，m)，2·98 (1H，m)， 3·50 (1H，m)，4·12 (2H，m)，4.24 (1H，dd，J=5.2，11.2 Hz), 4.49 (1H，dd，J=2.8，11·2 Hz)，6·49 (1H，d，J=5.2 Hz)，6.86 (1H，d，J=8.8 Hz)，6·93 (1H，dd3 J=2.8, 8.8 Hz)，7.14 (1H，d， J=2.8 Hz)，7·48 (1H，s)，8.66-8.68 (2H，m)。 製造例429-2 4-(4-胺基-3-氯笨氣基）-6-氰基- 7-f二乙脖基 2-羥基丙基）氣喊 將（4-(4-胺基-3-氯苯氧基）-6-氰基- 7-((2R) -環氧乙燒· 2-基）甲氧峻琳（96 mg ’ 0.261 mmol)於氮蒙氣下溶於四氫 呋喃（2.6 ml)，加入二乙胺（0·5 ml)，並於50°C攪摔5日。將 反應液減壓·濃縮.，然後付諸於矽凝膠管柱層析（溶出液：乙 酸乙醋），將包含目的物之溶出部分濃縮，懸浮於乙酸乙酷 -506 - 本紙張尺度適用中國國家標毕(CNS) A4規格（210 X 297公釐） 13〇4〇61Example 426 Hydrogen-4-((3⁄4) 琮 ) ) 篡 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) The ester will be 4-((4-(4-amino-3-chlorophenoxy)-6-cyano-7-quinolinyl)oxy)ethyl)-1-hexafluoropyridine The ester (486.5 mg, 0.930 mmol) was dissolved in dimethyl hydrazine (5 ml) under nitrogen atmosphere, then pyridine (0.170 ml, 2.09 mmol) and phenyl chlorophenyl phthalate (0.175 ml, 1·34 mmol) and disturbed for 1 hour. The cyclopropane mill (0.322 ml, 4.65 mmol) was added dropwise and the mixture was further stirred overnight. The reaction mixture was dissolved in ethyl acetate and aq. The solvent was distilled off, and then subjected to column chromatography on a gel column (eluent: ethyl acetate), and the fractions containing the desired product were concentrated, suspended in ethyl acetate, and diluted and filtered. The title compound (343 mg, 〇·566 mmol, 60.8%) was obtained as pale yellow crystals. _ - 502 - Zhang scale applicable Chinese National Standard (CNS) A4 specification (210X297 mm) 1304061 A7, B7 V. Description of invention (497) 1H-NMR spectrum (CDCl3) 5 (ppm): 0.80 (2H, m), 0·95 (2H,m), 1.2 Bu 1.28 (3H,m),1·47 (9H,s),1·77 (2H,m),1·89 (2H,m), 2.67 (1H,m ), 2·75 (2H, m), 4, 12 (2H, m), 4.28 (2H, m), 4.97 (1H, s), 6.50 (1H, d, J = 5.2 Hz), 7.12 (1H, Dd, J=2.8, 8,8 Hz), 7·25 (1H, d, J=2.8 Hz), 7·45 (1H, s), 7·72 (1H, s), 8.44 (1H, d, J=8:8 Hz), 8.66 (1H, s), 8.68 (1H, d, J = 5.2 Hz). The starting material e is synthesized as follows. _Example 426-1 4-(2-((4-Amino-3-chlorophenoxy)-6-amino ♦ 某) 气) hexyl)-1-hexafluorene Crude product of 4-(4-amino-3-chlorophenoxy)-6-cyano-7-hydroxyporphyrin (742 mg) by the same procedure as in Example 7 The title compound (492·6 mg, 0.942 mmol, 39.6%) was obtained as pale brown crystals. iH-NMR spectrum (CDCl3) 5 (ppm): Ml-1.31 (4H, m), 1.46 (9H, s), 1·77 (2H, m), 1·90 (2H, m), 2·52, 2·56 (3H,m),4·11 (2H, m),4·27 (2H,m)5 6·48 (1H,d,J=5.2 Hz), 6.86 (1H,d, 9.2 Hz ), 6.93 (1H, dd, J = 2.8, 9.2 Hz), 7, 14 (1H, d, J = 2.8 Hz), 7.44 (1H, s), 8.66-8.68 (2H, m). Example 427 chlorocyano-7-(2-(4-hexa-hydro ton acetamidine), a compound of the formula (N)-N'-cyclopropyl-monthly urine at '(((4:3) -Chloro-4-((cyclopropylamino)carbonyl)aminophenoxy b 6•cyano-a.5&quot;Quinylyl)oxy)ethyl)-lxhydrogen 1^ than the acid Purpose (343 mg , _____ - 503 - National Standard for Paper Size (CNS) A4 specification (21〇χ 297 mm ^ ' —-:- A7 B7 498 &gt; 1304061 V. Inventive Note (0.5 66 mmol), Trifluoroacetic acid (3 〇ml) was added at room temperature and stirred for 1 hour. The reaction solution was cooled in an ice water bath, diluted with water (4 mL), sodium hydrogen hydride (4.0 g) was slowly added and neutralized, and used The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the mixture was suspended in ethyl acetate. The title compound (286 mg, 0.566 mmol, quantitative). mp NMR (CDCl3) 5 (ppm): 0.78 (2H, m), 0·95 (2H, m), 1.63 (2H ,m), 1.96-2.05 (5H,m), 2.66 (1H,m), 2.90 (2H,m), 3.41 (2H,m), 4.27-4.30 (3H,m),5.10 (1H,s), 6.50 (1H,d, J=5.2 Hz),7·12 (1H,dd, J=2.8,8·8 Hz), 7.27 (1H,d,J=2.8 Hz), 7.46 (1H, s), 7.73 (1H, s), 8.44 (1H, d, J= 8.8 Hz), 8.66 (1H, s), 8.68 (1H, d, J = 5.2 Hz). Example 428 (2-Chloro-j-((6-cyano-7-(2-) -Methyl-4-hexafluor is a bite base) B) Base) -4〃奎〃基) Oxygen) Stupid)-N, cyclopropyl monthly urine will be N-(2-lact-4-(( 6-sayyl-7-(2-(4-ττ Hydrogen p-decyloxyquinolyl)oxy)phenyl)-Ν·-cyclopropyl monthly urine (286 mg, 0.566 mmol) dissolved in tetrahydrofuran ( After 5 ml)-methanol (5 ml), add 37% aqueous formaldehyde (0.5 ml), acetic acid (0.065 ml, 1.13 mmol) and cyanoborohydride (7 lmg, 1 · 13 mmol) and stir at room temperature. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is distilled off, suspended in ethyl acetate, diluted with hexane, and crystallized by filtration, and then air-dried to obtain a pale yellow-504 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm). 13〇4〇61 _ , A7 ------ B7 V. Inventive Note (4) The title compound of the color crystal (2 18.2 mg, 0.420 mmol, 74.1%). iH-NMR spectrum (DMSO-d6) &lt; 5 (ppm): 0.41 (2H, m), 0·65 (2H, m), 1.23 (2 Η, m), 1.50 (1 Η, m), 1.71-1.88 ( 6Η,m),2.15 (3Η,s), 2.56 (1H,m),2.75 (2H,m),4·33 (2H,t,J=6.4 Hz),6.58 (1H, d,J=5.2 Hz ), 7.20 (1H, d, J = 2.8 Hz), 7.26 (1H, dd, J = 2.8, 9.2 H2), 7·50 (1H, d, J = 2.8 Hz), 7.62 (1H, s) , 8·00 (1H, s), 8.28 (1H, d, J = 9.2 Hz), 8.73-8.75 (2H, m). Exemption Example 4 29 chloro-4-((6-cyano-7-((2R)-3-(diethylamine)-2-oxanium I, gas 4-4 phenyl)hydro)) a)-N, cyproteril (4-(4-amino-3-chlorophenoxy)-6-cyano-7-((2R)-3-(diethylamino)-2- Hydroxypropyl)oxy)quinoline) (96.9 mg, 0.22 mmol) was dissolved in dimethylformamide (1 ml) under nitrogen atmosphere, then pyridine (〇〇27 '0.33 mmol) And phenyl chloroformate (〇. 〇 35 ml, 〇·28 mmol) was given for 1 hour. Cyclopropylamine (0.10 ml) was added dropwise and stirred overnight. The reaction was partitioned between ethyl acetate and saturated sodium hydrogen carbonate. In an aqueous solution, the organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and then applied to a gel column chromatography (eluent: ethyl acetate) to dissolve the desired product. Partially concentrated, suspended in ethyl acetate, diluted with hexanes and filtered to give crystals which were crystallized to give the title compound as pale yellow crystals (6l.6mg, 0.118nim (^, 53.5%). -NMR spectrum (DMSO-d6) 5 (PPm)·································· ), 2.42-2.67 (7H) m), 3.95 (1H, m), 4.2/ (1H, m), 4·30 (1H, m), 4.91 (1H, m), 6.57 (1H, d, J= 5.2 Hz), _____- 505 - This paper size applies to national standards (CMS) A4 size (210 x 297 mm) -------- A7 B7 1304061 V. Description of invention (500) 7.19 (1H,d , J=2.8 Hz), 7.25 (1H, dd, J=2.8, 9.2 Hz), 7.50 (1H, d, J=2.8 Hz), 7.61 (1H, s), 7·98 (1H, s), 8.27 (1H, d, J = 9.2 Hz), 8.70 (1H, s), 8.72 (1H, d, J = 5.2 Hz) The starting material is synthesized as follows: Manufacture Example 429-1 (Heart (4) Amine .-3.-chlorophenoxy)-6-ammonia-7-K2R)-cyclic L-alkyl-2-yl)methoxy; r-quinone by the same method as in Example 7, from 4-( Crude product of 4-amino-3-chlorophenoxy)-6-cyano-7-hydroxyporphyrin (1.00 g, 3.21 mmol) and 4-methyl-1-benzenesulfonic acid [(2R) The title compound (198 mg, 0.53 8 mmol, 16.8%) was obtained as pale brown crystals. 1H-NMR spectrum (CDCl3.) (5(pPm): 2·93 (1H, m), 2·98 (1H, m), 3·50 (1H, m), 4·12 (2H, m), 4.24 (1H, dd, J=5.2, 11.2 Hz), 4.49 (1H, dd, J=2.8, 11·2 Hz), 6.49 (1H, d, J=5.2 Hz), 6.86 (1H, d, J=8.8 Hz), 6.93 (1H, dd3 J=2.8, 8.8 Hz), 7.14 (1H, d, J=2.8 Hz), 7·48 (1H, s), 8.66-8.68 (2H, m) Production Example 429-2 4-(4-Amino-3-chloro-phenyl)-6-cyano-7-f-diethyl 2-hydroxypropyl) (4-(4-amine) 3-chlorophenoxy)-6-cyano-7-((2R)-epoxyethylidene-2-yl)methoxyproline (96 mg '0.261 mmol) dissolved in tetrahydrofuran under nitrogen (2.6 ml), add diethylamine (0.5 ml), and stir for 5 days at 50 ° C. The reaction solution was depressurized and concentrated. Then it was applied to a gel column chromatography (eluate: Ethyl acetate), concentrates the dissolved fraction containing the target substance, and suspends it in ethyl acetate - 506 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 13〇4〇61

A7 B7 五、發明説明（ 501 中，將其用己烷稀釋及濾取結晶，藉由通風乾燥，得到為 淡黃色結晶之標題化合物（96.9 mg，〇 220 mmol , 84·20/〇)。 iH-NMR 光譜（〇〇(：13)5咖111):1.09(61*1，1]^7.21^)，2.57- 2·74 (8H，m)，4·12 (2H，m)，4·25 (2H，d，J=4.8 ΗΖ)，6·48 (1H， d，J=5.2 Hz)，6·85 (1H，d，J=8.8 Hz)，6.93 (1H，dd，J=2.8, 8.8 Hz), 7.14 (1H5 d3 J=2.8 Hz), 7.49 (1H, s)3 8.66-8.68 (2H5 m) 〇 ±Jlil430_ 氰基-7-(((2S)-3-(二乙—蕤基丙某） 惠奎啉基）氣）笨某）-N、環丙脲 將4-(4-胺基-3-氣冬氧基）-6-氨基- 7-(((2S)-3-(二乙胺 基）-2-羥基丙基）氧）喹咻（78.6 mg，〇18 mm〇1)於氮蒙氣下 落於二甲基甲酿胺（丨mI)，然後於室溫滴入吡啶（〇 〇22 ml ’ 0.27 mmol)及氯甲酸苯酯（0.028ml，〇 22 _〇1)並攪拌 1小時。滴入環丙胺（〇.l〇ml)，並再攪拌一夜。將反應液分 吟於乙酸乙酯及飽和碳酸氫鈉水溶液中，將有機層用水及 飽和食鹽水洗淨及用無水硫酸鈉乾燥。餘去溶媒，然後付 諸於矽凝膠管柱層析（溶出液：乙酸乙酯），將包含目的物 之/谷出部分濃縮，懸浮於乙酸乙酯中，將其用己烷稀釋及 濾取結晶，藉由通風乾燥，得到為淡黃色結晶之標題化合 物（37.8 mg，〇·〇72 mmol，40.5〇/〇)。 藉由下述·方法合成起始物質。A7 B7 5. Inventive Description (In 501, the title compound (96.9 mg, 〇220 mmol, 84·20/〇) was obtained as a pale yellow crystal. -NMR spectrum (〇〇(:13)5咖111): 1.09 (61*1,1]^7.21^), 2.57- 2.74 (8H, m), 4·12 (2H, m), 4· 25 (2H,d,J=4.8 ΗΖ),6·48 (1H, d,J=5.2 Hz), 6.85 (1H,d,J=8.8 Hz), 6.93 (1H,dd,J=2.8, 8.8 Hz), 7.14 (1H5 d3 J=2.8 Hz), 7.49 (1H, s)3 8.66-8.68 (2H5 m) 〇±Jlil430_ Cyano-7-(((2S)-3-(diethyl-fluorenyl)乙) 惠奎里奥基)气)), N, cyprodione 4-(4-amino-3-oxaxyloxy)-6-amino-7-((2S)-3- (Diethylamino)-2-hydroxypropyl)oxy)quinoline (78.6 mg, 〇18 mm〇1) was added to dimethylamine (丨mI) in a nitrogen atmosphere and then added dropwise at room temperature. Pyridine (〇〇22 ml '0.27 mmol) and phenyl chloroformate (0.028 ml, 〇22 _〇1) and stirred for 1 hour. Cyclopropylamine (〇.l〇ml) was added dropwise and stirred for another night. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed, and then applied to a gel column chromatography (eluent: ethyl acetate), and the fractions containing the desired product were concentrated, suspended in ethyl acetate, diluted with hexane and filtered. The title compound (37.8 mg, 〇·〇 72 mmol, 40.5 〇/〇) was obtained as pale yellow crystals. The starting material was synthesized by the following method.

製造创430- L _________- 507 - 本紙張尺度適用中國國家標準(CNS) Α4規^釐) 502 &gt; 1304061 A7 B7 五、發明説明（ 環氣乙烷·2·基） 甲氣口奎g林 藉由與實施例7同樣之手法，從4-(4-胺基-3-氯苯氧基）-6-氰基-7-羥基喹啉粗生成物（1〇〇g , 3 21 mm〇1)&amp;4•甲基_ 1- 苯磺酸[(2S)-環氧乙烷基甲基]酯，得到為淡褐色結 晶之標題化合物（147 mg，0.400 mmol，12.5%)。 製造例4 3 0 - 2 阵基:J·-氯苯氧茱）_6_氨盖-7_((725丫-3々二Λ眩某卜 2- 羥基丙某）氲V杏嗾 將4-(4-胺基-3-氯苯氧基）-6-氰基-7-((2S)-環氧乙烷-2-基）甲氧喹淋（72 mg，0.196 mmol)於氮蒙氣下溶於四氫呋 喃（2.0 ml),加入二乙胺（0·4 ml)，並於5〇π攪掉5日。將反 應液減壓濃縮，然後付諸於矽凝膠管柱層析（溶出液：乙酸 乙酯），將包含目的物之溶出部分濃縮，懸浮於乙酸乙酯 中，將其用己烷稀釋及濾取結晶，藉由通風乾燥，得到為 淡百色結晶之標題化合物（78.6 mg，0.178 mmol， 91·1%) 〇 實施例4 3 1 1^(2-氪-4-((6-氨某-7-(((210-2-羥某-3彳1-吡咯啶某&gt;)雨 羞_)氧）-4-4啉基）氣）笨某W-環丙脲 將4-(4-胺基-3-氯苯氧基）-6-氰基- 7-(((2R)-2-羥基- 3-(1 -咐洛淀）丙基）氧）4 17林（95 · 1 mg ’ 0·2 17 mmol)於氮蒙氣 下溶於二T基甲醯胺（1 ml)，然後於室溫滴入吡啶（〇〇26 ml，〇·3 3 mmol)及氯甲酸苯醋（0.034 ml，0.27 mmol)並授 __ _- 508 - 本紙張尺度適用中國國家標準(CNS) A4规格(210 χ 297公釐） A7 B7创创430- L _________- 507 - This paper scale applies to China National Standard (CNS) Α4 regulations ^ PCT) 502 &gt; 1304061 A7 B7 V. Description of invention (cyclohexane ethane · 2 · base) From the same procedure as in Example 7, crude product of 4-(4-amino-3-chlorophenoxy)-6-cyano-7-hydroxyquinoline (1 〇〇g, 3 21 mm 〇1) &lt;4&lt;4&gt;-Methyl-1-benzenesulfonic acid [(2S)-oxiranylmethyl] ester gave the title compound (147 mg, 0.400 mmol, 12.5%). Production Example 4 3 0 - 2 Array: J·-chlorophenoxypurine) _6_Ammonia -7_((725丫-3々二ΛΛ一卜2- hydroxypropyl) 氲V apricot will be 4-( 4-Amino-3-chlorophenoxy)-6-cyano-7-((2S)-oxiran-2-yl)methoxyquinone (72 mg, 0.196 mmol) under nitrogen Dissolved in tetrahydrofuran (2.0 ml), added with diethylamine (0.4 ml), and stirred for 5 days at 5 〇π. The reaction solution was concentrated under reduced pressure and then applied to a gel column chromatography (eluent) : (ethyl acetate), the title compound (78.6 mg, EtOAc, EtOAc) 0.178 mmol, 91·1%) 〇 Example 4 3 1 1^(2-氪-4-((6-Ammonia-7-(((210-2-hydroxy--3彳1-pyrrolidine)&gt ;) rain shy _) oxygen)-4-4 porphyrin) gas) stupid W-cyclopropionine 4-(4-amino-3-chlorophenoxy)-6-cyano-7-(( (2R)-2-hydroxy-3-(1-pyrrolidine)propyl)oxy)4 17-lin (95 · 1 mg '0·2 17 mmol) dissolved in di-T-methylformamide under nitrogen (1 ml), then add pyridine (〇〇26 ml, 〇·3 3 mmol) at room temperature Vinegar phenyl chloroformate (0.034 ml, 0.27 mmol) and grant __ _ 508-- This applies China National Standard Paper Scale (CNS) A4 size (210 χ 297 mm) A7 B7

1304061 五、發明説明（503) 拌1小時。滴入環丙胺（0.10 ml)，並再攪拌一夜。將反應液 分溶於乙酸乙酯及飽和碳酸氫鈉水溶液中，將有機声$水^ 及飽和食鹽水洗淨及用無水硫酸鈉乾燥。餘去溶媒，然後 付諸於矽凝膠管柱層析（溶出液：乙酸乙酯），將包含目的 物之溶出部分濃縮，懸浮於乙酸乙酯中，將其用己燒稀釋 及濾取結晶，藉由通風乾燥，得到為淡黃色結晶之標題化 合物（40·3 mg，0.077 mmol，35.6%)。 iH-NMR光譜（DMSO-d6) 5 (ppm): 0·44 (2H，m)，0.68 (2H，m) 1·69 (4H，b〇5 2.50-2.75 (7H，m)，4·02 (1H，m)，4.22 (1H，dd J=5.6, 1〇·4 Hz)，4·31 (1H，dd，J=3.6, 10.4 Hz)，5.04 (1H，m) 6.59 (1H, d, J=5.2 Hz), 7.21 (1H, d, J=2.8 Hz), 7.27 (1H dd 3=2·8, 9·2 Ηζ)，7·52 (1H，d，J=2.8 Hz)，7·63 (1H，s)，7.99 (1H，s)，8,29 (1H，d，J=9.2 Hz)，8·72·8·74 (2H，m)。 製造例431- 1 4-..(4-胺基-3 -氣苯氧基）-6-氰基-7- ((72R) - 2 -旄早-3_ (外卜 咯被基）丙基）氣V套啉 將4-(4-胺基-3-氯苯氧基）-6-氰基- 7-(( 2R) -環氧乙燒-2-基）甲氧喹啉（96 mg，0.261 mmol)於氮蒙氣下溶於四氫吱 喃（2.0 ml)，加入吡哈啶（0.2 ml)，並於室溫攪拌5日。將反 應液減壓濃縮，然後付諸於矽凝膠管柱層析（溶出液··乙酸 乙酯）’將包含目的物之溶出部分濃縮，懸浮於乙酸乙醋 中’將其用己燒稀釋及;慮取結晶，藉由通風乾澡，得到為 淡叉色結晶之標題化合物（95·5 mg，0.218 mmol， 83.4%) 〇 _____- 509 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（504 ) iH-NMR 光譜（CDCl3)5(ppm): 1·26 (2H，m)，1·82 (4H，br) 2·58-2.76 (5Η，m)，2·94 (1Η，m)，4.11 (2Η，m)，4·2〇、4,45 (2H, m), 6.48 (1H, d, J=5.2 Hz), 6.85 (1H, d, J=8.8 Hz), 6.93 (1H, dd, J=2.8, 8.8 Hz), 7.14 (1H, d, J=2.8 Hz), 7.49 (1H3 s) 8.66-8.68 (2H, m) 〇 膏施例432 N_(2-氣'4-((6_亂基_7-(((28)-2_ 子罕基- ι·?比啥淀 某）氧）-4 2奎啉基）氣）茉基V N ’ -環丙胧 將4-(4-胺基-3-氯苯氧基）-6-氰基-7-(((2R)-2-羥基 (卜吡哈啶基）丙基）氧）峻淋（82.0 mg，〇· 187 mmol)於氮蒙 氣下溶於二曱基甲醯胺（1 ml)，然後於室溫滴入吡啶（0〇23 ml，0.28 mmol)及氯甲酸苯酯（〇·〇29χη1，〇·23 mmol)並擾拌 1小時，滴入環丙胺（〇· 1 〇 ml)並攪摔一晚。將反應液分溶於 乙酸乙酯及飽和碳酸氫鈉水溶液中，將有機層用水及飽和 食鹽水洗淨及用無水硫酸鈉乾燥。餾去溶媒，然後付諸於 矽凝膠管柱層析（溶出液：乙酸乙酯），將包含目的物之溶 出部分濃縮，懸浮於乙酸乙酯中，將其用己烷稀釋及濾取 結晶，藉由通風乾燥，得到為淡黃色結晶之標題化合物 (25·0 mg，0.048 mmol，25.6%)。 型造例432-1 4-(4-胺基-3-氯笨氫某6-氰某-7“ (7 2S)-2- _其-3 - Π -吡 哈咬基）丙基）氧）_成 將4-(4 -脖基-3-氣冬乳基）-6 -果基- 7- ((2S)-環氧乙燒-2. 基）甲氧4啉（72 mg，0.196 mmol)於氮蒙氣下溶於四氫呋 -510 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（5〇5) 喃（1·5 ml)，加入π比哈症（〇.15 ml)，並於室溫授拌5曰。將 反應液減壓濃縮，然後付諸於矽凝膠管柱層析（溶出液：乙 酸乙醋），將包含目的物之溶出部分濃縮，懸浮於乙酸乙酯 中，將其用己燒稀釋及濾取結晶，藉由通風乾燥，得到為 淡只色結晶之標題化合物（“.Ο mg，0.187 mmol， 95.4%) 〇 實施例433 · . _ 基）幾棊）（甲基j胺某）茇氪其U7_甲f芊- 6-2奎啉鮝酸甲酯 藉由與實施例10同樣之手法，從7·甲氧基甲胺基） 苯氧基）喹啉羧酸甲酯（828 mg , 2.45 mmol)及異氰酸4_氟 苯酯，得到為白色結晶之標題化合物（1〇78 g , 2 27 mmol，92.6%) 〇 H-NMR光譖（DMSO-d6)5(ppm): 3.39 (3H，s)，3.98 (3H，s)， 4.06 (3H，s)，6·20 (1H，s)，6.57 (1H，d，J=5.2 Ηζ)，6·97 (2H， m)，7.24-7.34 (4H，m)，7·46 (2H，m)，7,52 (1H，s)，8·71 (1H， d，J=5.2 Hz)，8.78 (1H，s)。 ’ 藉由下述方法合成起始物質。 製造例433- 1 D氧棊甲胺氧基）_6·呤啉藉酸甲酯 將甲胺基酚（1·1 1 g , 9 〇〇 mm〇i)溶於二甲基亞颯（ ml),然後於室溫慢加入氫化鈉（36〇 mg , 9 〇〇 並 攪摔20分鐘。加入藉由公知方法得到之肛氯_ 7·甲氧基_心 甲氧羰基4啉（1.51 g，6.〇〇 mm〇丨），並於1〇(Γ(：加熱攪拌二 511 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇 297公釐） 1304061 五、發明説明（ 506) A7 B71304061 V. INSTRUCTIONS (503) Mix for 1 hour. Cyclopropylamine (0.10 ml) was added dropwise and stirred for another night. The reaction mixture was dissolved in ethyl acetate and saturated aqueous sodium hydrogen sulfate. After the solvent was removed, it was applied to a gel column chromatography (eluent: ethyl acetate), and the fractions containing the desired product were concentrated, suspended in ethyl acetate, diluted with hexane and filtered to crystallize. The title compound (40·3 mg, 0.077 mmol, 35.6%) was obtained as pale yellow crystals. iH-NMR spectrum (DMSO-d6) 5 (ppm): 0·44 (2H, m), 0.68 (2H, m) 1·69 (4H, b〇5 2.50-2.75 (7H, m), 4·02 (1H,m), 4.22 (1H, dd J=5.6, 1〇·4 Hz), 4·31 (1H, dd, J=3.6, 10.4 Hz), 5.04 (1H, m) 6.59 (1H, d, J=5.2 Hz), 7.21 (1H, d, J=2.8 Hz), 7.27 (1H dd 3=2·8, 9·2 Ηζ), 7·52 (1H, d, J=2.8 Hz), 7· 63 (1H, s), 7.99 (1H, s), 8, 29 (1H, d, J = 9.2 Hz), 8·72·8·74 (2H, m). Manufacturing Example 431- 1 4-.. (4-Amino-3- gasphenoxy)-6-cyano-7-((72R)-2-pyrene--3-(exo-pyrrolyl)propyl) gas V-sulphonium 4-( 4-Amino-3-chlorophenoxy)-6-cyano-7-((2R)-epoxythiazol-2-yl)methoxyquinoline (96 mg, 0.261 mmol) under nitrogen Dissolved in tetrahydrofuran (2.0 ml), added with pyridine (0.2 ml), and stirred at room temperature for 5 days. The reaction was concentrated under reduced pressure and then applied to a gel column chromatography (eluent) · Ethyl acetate) 'Concentrate the fraction containing the target substance, suspend it in ethyl acetate vinegar', dilute it with hexane; take out the crystals, and dry it in a ventilated air to obtain the title compound of the pale-clear crystal. (95·5 mg, 0.218 mmol, 83.4%) 〇_____- 509 - This paper scale applies to China National Standard (CNS) Α4 size (210 x 297 mm) 1304061 A7 B7 V. Inventions (504) iH-NMR Spectrum (CDCl3) 5 (ppm): 1·26 (2H, m), 1·82 (4H, br) 2·58-2.76 (5Η, m), 2·94 (1Η, m), 4.11 (2Η, m),4·2〇, 4,45 (2H, m), 6.48 (1H, d, J=5.2 Hz), 6.85 (1H, d, J=8.8 Hz), 6.93 (1H, dd, J=2.8 , 8.8 Hz), 7.14 (1H, d, J=2.8 Hz), 7.49 (1H3 s) 8.66-8.68 (2H, m) 〇 施 Example 432 N_(2-气'4-((6_乱基基_ 7-(((28)-2_子子基- ι·? 啥 啥)) Oxygen)-4 2 quinolinyl) gas) jasmine VN '-cyclopropene 4- 4-(4-amino-3 -Chlorophenoxy)-6-cyano-7-(((2R)-2-hydroxy(pyridinyl)propyl)oxy)) (82.0 mg, 187·187 mmol) in nitrogen Dissolved in dimercaptocarhamamine (1 ml), then add pyridine (0 〇 23 ml, 0.28 mmol) and phenyl chloroformate (〇·〇29χη1, 〇·23 mmol) and scramble 1 at room temperature. Hour, add cyclopropylamine (〇·1 〇ml) and stir for one night. The reaction mixture was dissolved in EtOAc EtOAc (EtOAc)EtOAc. The solvent was distilled off, and then subjected to column chromatography on a gel column (eluent: ethyl acetate), and the fractions containing the desired material were concentrated, suspended in ethyl acetate, diluted with hexane and filtered to crystallize. The title compound (25·0 mg, 0.048 mmol, 25.6%) was obtained as pale yellow crystals. Type of Example 432-1 4-(4-Amino-3-chlorophenyl hydrogen 6-cyanyl-7"(7 2S)-2- _3 - Π-pyridyl)propyl)oxy )__ 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- Mmmol) dissolved in tetrahydrofuran-510 under nitrogen atmosphere - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (5〇5) 5 ml), adding π-ha-ha (〇.15 ml), and mixing 5 于 at room temperature. The reaction solution was concentrated under reduced pressure, and then applied to a gel column chromatography (eluent: ethyl acetate) The title compound containing the target substance is concentrated, suspended in ethyl acetate, diluted with hexane and filtered to crystallize, and dried to give the title compound as light color crystals (". Ο mg, 0.187 Ment, 95.4%) 〇 Example 433 · · _ base) several 棊) (methyl j amine) 茇氪 its U7_甲f芊-6-2 quinolinate methyl ester by the same as in Example 10 Mice from 7-methoxymethylamino)phenoxy)quinolinecarboxylic acid methyl ester (828 mg, 2.45 mmol) and 4-fluorophenyl isocyanate The title compound (1〇78 g, 2 27 mmol, 92.6%) was obtained as white crystals. 〇H-NMR 谮 (DMSO-d6) 5 (ppm): 3.39 (3H, s), 3.98 (3H, s) , 4.06 (3H, s), 6·20 (1H, s), 6.57 (1H, d, J = 5.2 Ηζ), 6.97 (2H, m), 7.24-7.34 (4H, m), 7.46 (2H, m), 7, 52 (1H, s), 8.71 (1H, d, J = 5.2 Hz), 8.78 (1H, s). The starting material was synthesized by the following method. Production Example 433-1 D-Methoxymethylamino) 6-porphyrin Methylaminophenol (1·1 1 g , 9 〇〇mm〇i) was dissolved in dimethyl hydrazine (ml) Then, sodium hydride (36 〇 mg, 9 〇〇 was added slowly at room temperature and stirred for 20 minutes. Anal chloride _ 7·methoxy-cardiomethoxycarbonyl 4 phenyl group (1.51 g, 6) obtained by a known method was added. .〇〇mm〇丨), and at 1〇(Γ(:heating and stirring 2511 - this paper scale applies to China National Standard (CNS) A4 specification (21〇297 mm) 1304061 V. Invention description (506) A7 B7

小時。放冷至室溫，將反應液分溶於乙酸乙酯及水中，將 有機層用水及飽和食鹽水洗淨及用無水硫酸鈉乾燥。餾去 溶媒，然後付諸於矽凝膠管柱層析（溶出液：乙酸乙酯）， 將包含目的物之溶出部分濃縮，懸浮於乙酸乙酯中，將其 用己烷稀釋及濾取結晶，藉由通風乾燥，得到為淡黃色钟 晶之標題化合物（ 830 mg，2.45 mmol，40.9%)。j-NMR 光譜（CDCl3)5(ppm): 2.88 (3H，s)，3.83 (1H br) 3·97 (3H，s)，4,04 (3H，s)，6.42 (1H，d，J=5.2 Hz)，6.68 (2H d，J=8.8 H2)，7·01 (2H，d，J=8.8 H2)，7.45 (1H，s)，8.6〇 (1H d，J=5.2 Hz)，8·84 (1H，s)。 實施例434 4-(4-(((4-氟苯胺 6_ 口奎淋致酸 在4-(4-(((4-氟苯胺基）羰基）（甲基）胺基）苯氧基）_7_甲 氧基-6-奎啉羧酸曱酯（1·〇42 g，2·19 mm〇i)中，加入甲醇 (20 ml)及2當量氫氧化鈉水溶液（5 ml)，並於室溫授摔3小 時。在反應液中加入2當量鹽酸及中和後，減壓餘去甲酵， 遽取析出之白色結晶及於70°C乾燥，得到標題化合物（1 〇1 g，2· 19 mmol，定量的）。 iH-NMR 光譜（DMSO-d6)5(Ppm): 3·29 (3H，s)，3 96 (3H，s) 6.64 (1H，d，J=5.2 Ηζ)，7·06 (2H，t，J=8.8 Hz)，7 33 (2H d J=8.8 Hz)，7.42-7.50 (5H，m)，8·23 (1H，s)，8 54 (1H，s) 8.70 (1H，d，· J=5:2 Hz)，13.09 (1H，br)。 ’ 實施例435hour. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and then subjected to column chromatography on a gel column (eluent: ethyl acetate), and the fractions containing the desired material were concentrated, suspended in ethyl acetate, diluted with hexane and filtered to crystals. The title compound (830 mg, 2.45 mmol, 40.9%) was obtained as pale yellow crystals. j-NMR spectrum (CDCl3) 5 (ppm): 2.88 (3H, s), 3.83 (1H br) 3·97 (3H, s), 4,04 (3H, s), 6.42 (1H, d, J = 5.2 Hz), 6.68 (2H d, J=8.8 H2), 7·01 (2H, d, J=8.8 H2), 7.45 (1H, s), 8.6〇 (1H d, J=5.2 Hz), 8· 84 (1H, s). Example 434 4-(4-(((4-(4-(4-(4-(4-(4-(4-(4-(((((((((((((((((((((((((((((((((((((((( _Methoxy-6-quinoline carboxylic acid oxime ester (1·〇42 g, 2·19 mm〇i), adding methanol (20 ml) and 2 equivalents of aqueous sodium hydroxide solution (5 ml), and in the room The temperature was dropped for 3 hours. After adding 2 equivalents of hydrochloric acid to the reaction mixture and neutralizing, the residue was dehydrated and the white crystals were taken out and dried at 70 ° C to give the title compound (1 〇1 g, 2· 19 mmol, quantitative). iH-NMR spectrum (DMSO-d6) 5 (Ppm): 3·29 (3H, s), 3 96 (3H, s) 6.64 (1H, d, J = 5.2 Ηζ), 7 ·06 (2H,t,J=8.8 Hz), 7 33 (2H d J=8.8 Hz), 7.42-7.50 (5H,m),8·23 (1H,s),8 54 (1H,s) 8.70 (1H, d, · J=5: 2 Hz), 13.09 (1H, br). 'Example 435

_- 512 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公爱） -----_- 512 - This paper size applies to China National Standard (CNS) A4 specification (21〇x 297 public) -----

裝 訂Binding

線 1304061Line 1304061

θ·6·-環丙基：4-(4-(((4· 胺某）璣某κ甲某）胺甚、芊声 基）-7二甲氧基-6-峻淋# 脸 將4-(4-(((4-氟苯胺基）羰基）（甲基）胺基）苯氧基）_7_甲 氧基奎啉羧酸（115 mg，〇·25 mmol)於氮蒙氣下溶於二 甲基甲醒胺（2 ml)，然後於室溫依次加入三乙胺（〇 2❿丨）， (111-1;2,3-苯并三唑-1-基氧）（三（二甲胺基））鱗六氟磷酸鹽 (221 mg，0.50 mmol)及環丙胺（010 ml)後並攪拌一夜。將 反應液分溶於乙酸乙酯及水中，將有機層用水及飽和食鹽 水洗淨及用典水硫酸納乾燥。鶴去溶媒，然後藉由碎凝膠 管柱層析（溶出液：乙酸乙酯）而精製，將包含目的物之溶 出部分減壓濃縮後’懸浮於乙酸乙g旨中，將其用己燒稀釋 及濾取結晶，藉由通風乾燥，得到為白色結晶之標題化合 物（78.7 mg，0.157 mmol，63.1%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 〇·57 (2H，m)，0·70 (2H，m)， 2.86 (1H, m), 3.29 (3H, s), 3.98 (3H, s), 6.64 (1H, d, J=5.2 Hz), 7.06 (2H, t, J=8.8 Hz), 7.31 (2H, d, J=8.8 Hz), 7.42- 7.49 (5H，m)，8.23 (1H，s)，8·34 (1H，d，J=4.0 Hz)，8.43 (1H， s)，8·68 (1H，d，J=5.2 Hz)。 實施例436 N6-(2-甲氧乙基）-4-(4-(α_4二氟笨胺某）蕤某U甲某）胺某） 笨氣基V7-甲氣基套啉藉醯胺 藉由與實施例435同樣之方法，從4-(4-(((4-氟苯胺基）羰 基）（甲基）胺基）苯氧基）-7_甲氧基-6-峻淋竣酸（1 15 mg， 0.25 mmol)及2-甲氧基乙胺’得到為白色結晶之標題化合 -513 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x297公#)θ·6·-cyclopropyl: 4-(4-((4. amine)) 玑 a κ甲) amine, 芊 基)))))))) -(4-(((4-fluoroanilinyl)carbonyl))(methyl)amino)phenoxy)-7-methoxyquinolinecarboxylic acid (115 mg, 〇·25 mmol) dissolved under nitrogen In dimethyl amide (2 ml), then triethylamine (〇2❿丨), (111-1; 2,3-benzotriazol-1-yloxy) (three (two) Methylamino)) squamous hexafluorophosphate (221 mg, 0.50 mmol) and cyclopropylamine (010 ml), and stirred overnight. The reaction solution was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine. The mixture is dried and dried with sodium sulphate. The crane is desolved in a solvent, and then purified by a gel column chromatography (eluent: ethyl acetate), and the dissolved fraction containing the desired substance is concentrated under reduced pressure and then suspended in acetic acid. The title compound (78.7 mg, 0.157 mmol, 63.1%) was obtained as white crystals. MH-NMR spectrum (DMSO-d6) 5 (ppm) ): 〇·57 (2H,m), 0·70 (2H,m), 2.86 (1H, m), 3.29 (3H, s), 3.98 (3H, s), 6.64 (1H, d, J=5.2 Hz), 7.06 (2H, t, J=8.8 Hz), 7.31 (2H, d, J=8.8 Hz), 7.42- 7.49 ( 5H, m), 8.23 (1H, s), 8.34 (1H, d, J = 4.0 Hz), 8.43 (1H, s), 8.68 (1H, d, J = 5.2 Hz). N6-(2-methoxyethyl)-4-(4-(α_4 difluoromethaneamine) 蕤 a U A certain amine) a stupid base V7-methyl sulphonate Example 435, in the same manner, from 4-(4-((4-fluoroanilinyl)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-furanic acid (1 15 Mg, 0.25 mmol) and 2-methoxyethylamine 'obtained as the title of white crystal -513 - This paper scale applies to China National Standard (CNS) A4 specification (21〇x297 public#)

裝 訂Binding

1304061 ' A7 B7 五、發明説明（508) 物（97.0 mg，〇·187 mmol，75_1〇/〇) 0 iH-NMR 光譜（DMSO-d6)5(ppm): 3·29 (3H，s)，3·30 (3H，s)， 3·48 (4Η，br)，4·02 (3Η，s)，6·65 (1Η，d，J=5.2 Ηζ)，7.06 (2Η， t，J=8.8 Hz)，7.32 (2H，d，J=8.8 Hz)，7.43-7.48 (4H，m)，7.52 (1H，s)，8.23 (1H，s)，8.45 C1H，br)，8·62 (1H，s)，8·69 (1H，d， J=5.2 Hz) 〇 實施例437 N6-甲氫某-4-(4-(((4-氣笨胺基）羰基K甲基）胺基）苯氧 基）-7-曱氣某-6- 4啉藉醯胺 藉由與實施例435同樣之手法，從4-(4-(((4-氟苯胺基）羰 基）（甲基）胺基）苯氧基）-7-曱氧基-6-喹啉羧酸（115 mg’ 0.25 mmol)及甲氧胺鹽酸鹽，得到為白色結晶之標題化合 物（79·2 mg，0.161 mmol，64.8%)。 W-NMR 光譜（DMS〇-d6)5(ppm): 3·29 (3H，s)，3·73 (3H，s)， 3.98 (3Η, s), 6.65 (1H, d, J=5.2 Hz), 7.06 (2H, t, J=8.8 Hz), 7.32 (2H, d, J=8.8 Hz), 7.42-7.50 (5H, m), 8.23 (1H, s), 8.44 (1H，s)，8·69 (1H，d，J=5.2 Hz)，11.45 (1H，s) 〇 實施例43 8 N6-(2-乙乳乙基）-4-(3 -氣-4-(((¾丙胺基）裁基）胺基）笨氧 基）-7-曱氳基-6-崦啉#醯胺 將4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧基）-7-甲氧 基-6- 4淋幾酸（86 mg，0.20 mmol)於氮蒙氣下溶於二甲基 甲酿胺（2·ιη1)，·然後於室溫依次加入2-乙氧基乙胺（0.042 ml，0.40 mmol)，三乙胺（0.2 ml)及（（1Η-1，2,3 -苯并三吐- 514 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 1304061 ' · A71304061 ' A7 B7 V. Description of the invention (508) (97.0 mg, 〇·187 mmol, 75 〇/〇) 0 iH-NMR spectrum (DMSO-d6) 5 (ppm): 3·29 (3H, s), 3·30 (3H, s), 3·48 (4Η, br), 4·02 (3Η, s), 6·65 (1Η, d, J=5.2 Ηζ), 7.06 (2Η, t, J=8.8 Hz), 7.32 (2H, d, J = 8.8 Hz), 7.43-7.48 (4H, m), 7.52 (1H, s), 8.23 (1H, s), 8.45 C1H, br), 8.62 (1H, s), 8.69 (1H, d, J = 5.2 Hz) 〇 Example 437 N6-methylhydrogen-4-(4-(((4-(4-(phenylamino))carbonyl)methyl)amino)benzene Oxy)-7-helium a certain 6- 4 oxanol amide was obtained from 4-(4-((4-fluoroanilino)carbonyl)(methyl)amino group by the same procedure as in Example 435. Phenoxy)-7-decyloxy-6-quinolinecarboxylic acid (115 mg 0.25 mmol) and methoxyamine hydrochloride afforded the title compound as white crystals (79·2 mg, 0.161 mmol, 64.8 %). W-NMR spectrum (DMS〇-d6) 5 (ppm): 3·29 (3H, s), 3·73 (3H, s), 3.98 (3Η, s), 6.65 (1H, d, J=5.2 Hz ), 7.06 (2H, t, J=8.8 Hz), 7.32 (2H, d, J=8.8 Hz), 7.42-7.50 (5H, m), 8.23 (1H, s), 8.44 (1H, s), 8 · 69 (1H, d, J = 5.2 Hz), 11.45 (1H, s) 〇 Example 43 8 N6-(2-Ethylethyl)-4-(3- gas-4-(((3⁄4 propylamino) ) base) amino) stupidoxy)-7-mercapto-6-carboline# decylamine 4-(3-chloro-4-(((cyclopropylamino)carbonyl))amino)phenoxy ) 7-methoxy-6- 4 leuco acid (86 mg, 0.20 mmol) was dissolved in dimethyl ketoamine (2·ιη1) under nitrogen atmosphere, and then 2-B was added sequentially at room temperature. Oxyethylamine (0.042 ml, 0.40 mmol), triethylamine (0.2 ml) and ((1Η-1,2,3-benzotrix-514 - this paper scale applies to Chinese National Standard (CNS) Α4 specifications ( 210X297 mm) 1304061 ' · A7

1-基氧）（二（二甲胺基））銹六氟磷酸鹽）（133 mg, 〇2〇 後並攪拌一夜。將反應液分溶於乙酸乙酯及水中，將有機 層用水及飽和食鹽水洗淨及用無水硫酸鈉乾燥。餘去溶 媒’懸浮於乙酸乙酯中，將其用己烷稀釋及濾取結晶，藉 由通風乾躁，得到為白色結晶之標題化合物（87.7 ， 0.176 mmol，87.9%) 〇 H-NMR光 if(DMSO-d6)5(ppm): 0·42 (2H，m)，0.64 (2H，m) 1·13 (3H，t，J=6.8 Hz)，2·56 (1H, m)，3.44-3.53 (6H，m)，4·〇2 (3Ή，s)，6.52 (1H，d，J=5.2 Hz)，7·18 (1H，d，J=2.8 Hz)，7.22 (1H，dd，J=2.8, 9.2 Hz)，7.48 (1H，d，J=2.8 Hz)，7·52 (1H，s)， 7·97 (1H，s)，8.25 (1H，s)，8·26 (1H，dd，J=2.83 9.2 Hz)，8.46 (1H，m)，8.62 (1H，s)，8·66 (1H，d，J=5.2 Hz)。 實施例4 3 9 Μ-(2-(2-丙氣某）乙基3-氣-心以（環丙胺某）蕤某、胺 基）苯氣基）-7-甲氣基-6-0奎淋教酿胺 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（86 mg，0.20 mmol)及2-(2-丙氧基）乙胺，得到為白色結晶之標題化合物 (90.0 mg，0.175 mmol，87.7%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm)·· 0·42 (2H，m)，0.65 (2H，m)， 1.11 (6H，d，J=6.4 Hz)，2.56 (1H，m)，3.43-3.53 (4H，m)， 3.60 (1H，m)，4.02 (3H，s)，6·52 (1H，d，J=5.2 Hz)，7,18 (1H， d，J=2.8 Hz)，7:22 (1H, dd，J=2.8，8.8 Hz)，7·47 (1H，d， J=2,8 Hz)，7.52 (1H，s)，7·97 (1H，s)，8·26 (1H，d，J=8.8 Hz)， -515 - 本紙張尺度適用中國國家標準(CMS) A4規格(21〇x 297公釐)1-yloxy)(di(dimethylamino)) rust hexafluorophosphate) (133 mg, 〇2〇, and stirred overnight. The reaction solution was dissolved in ethyl acetate and water, and the organic layer was saturated with water. The title compound (87.7, 0.176) was obtained as white crystals eluted eluted eluted eluted M, H, H, H, H, H, H, H, H, H 2·56 (1H, m), 3.44-3.53 (6H, m), 4·〇2 (3Ή, s), 6.52 (1H, d, J=5.2 Hz), 7·18 (1H, d, J= 2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7·52 (1H, s), 7·97 (1H, s), 8.25 ( 1H, s), 8.26 (1H, dd, J = 2.83 9.2 Hz), 8.46 (1H, m), 8.62 (1H, s), 8.66 (1H, d, J = 5.2 Hz). 4 3 9 Μ-(2-(2-propenyl)ethyl 3- gas-heart to (cyclopropylamine) 蕤, amine) benzene group)-7-methyl group-6-0 quinine Teach the amine by the same procedure as in Example 438, from 4-(3-chloro-4-(((cyclopropane) Carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (86 mg, 0.20 mmol) and 2-(2-propoxy)ethylamine Compound (90.0 mg, 0.175 mmol, 87.7%) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm)·· 0·42 (2H, m), 0.65 (2H, m), 1.11 (6H, d, J =6.4 Hz), 2.56 (1H, m), 3.43-3.53 (4H, m), 3.60 (1H, m), 4.02 (3H, s), 6.52 (1H, d, J = 5.2 Hz), 7 ,18 (1H, d, J=2.8 Hz), 7:22 (1H, dd, J=2.8, 8.8 Hz), 7·47 (1H, d, J=2, 8 Hz), 7.52 (1H, s ),7·97 (1H,s),8·26 (1H,d,J=8.8 Hz), -515 - This paper scale applies to Chinese National Standard (CMS) A4 specification (21〇x 297 mm)

裝 訂Binding

線 1304061 A7 B7 51Cl· 五、發明説明（ 8.43 (1H，m)，8.46 (1H，s)，8·66 (1H，d，J=5.2 Hz)。 實施例440 · N6-(互氰基乙棊1^-(3-氯-4-((^環丙胺基）蕤甚1胺某）茉氫 基）-7」二吧__氧基-6- α杏毗淼眩 藉由與實施例438同樣之手法，從4-(3-氯-4_(((環丙胺基） 羰基）_胺基）苯氧基）-7-甲氧基·6-喹啉羧酸mg , 〇 2〇 mmol)及3-胺基丙腈，得到為白色結晶之標題化合物（738 mg，0·154 mmol，76.5%) 〇 j-NMR 光譜（DMSO-d6)(5(ppm): 0.42 (2H，m)，0.65 (2H，m)， 2·56 (1H，m)，2.81 (2H，m)，3.56 (2H，m)，4.02 (3H，s) 6 53 (1H，d，J=5.2 Hz)，7.20 (1H，d，J=2.8 Hz)，7·24 (1H，dd， J=2.8，8·8 Hz)，7·49 (1H，d，J=2.8 Hz)，7.53 (1H，s)，7·99 (1H，s)，8·27 (1H，d，J=8.8 Hz)，8·61 (1H，s)，8.67 (ih d J=5.2 Hz)，8.74 (1H，m)。 實施例44 1 基甲基-4_(3-氣-4-(((環邑^基）蕤某）胺某」^氣某 7-甲氧基-6-4琳#醯胺 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙胺基） 幾基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（86 mg , 0.20 mmol)及2-胺基乙腈鹽酸鹽’得到為白色結晶之標題化合物 (82.7 mg，0.178 mmol，88.8%)。 W-NMR 光譜（DMS〇-d6)&lt;5(ppm)·· 0.42 (2H，m)，0·65 (2H m) 2.56 (1Η，m)，4·05 (3Η，s)，4·35 (2Η，d，J=5.6 Ηζ)，6·54 (1Η d，J=5.2 Hz)，7.20 (1H，d，J=2.8 Hz)，7.25 (1H，dd，J=2 8 -516 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）Line 1304061 A7 B7 51Cl· V. Description of the invention ( 8.43 (1H, m), 8.46 (1H, s), 8.66 (1H, d, J = 5.2 Hz). Example 440 · N6-(M-cyano B棊1^-(3-chloro-4-((cyclopropylamino) 蕤1 amine) jasmonyl)-7" 二吧__oxy-6-α apricot 淼 藉 藉 与 实施 实施 实施 实施438, in the same manner, from 4-(3-chloro-4-(((cyclopropylamino)carbonyl)))amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid mg, 〇2〇mmol And 3-aminopropionitrile, the title compound (738 mg, 0·154 mmol, 76.5%) </ br> </ br> NMR spectrum (DMSO-d6) (5 (ppm): 0.42 (2H, m) , 0.65 (2H, m), 2·56 (1H, m), 2.81 (2H, m), 3.56 (2H, m), 4.02 (3H, s) 6 53 (1H, d, J = 5.2 Hz), 7.20 (1H,d,J=2.8 Hz), 7·24 (1H, dd, J=2.8, 8·8 Hz), 7·49 (1H, d, J=2.8 Hz), 7.53 (1H, s) , 7·99 (1H, s), 8.27 (1H, d, J = 8.8 Hz), 8.61 (1H, s), 8.67 (ih d J = 5.2 Hz), 8.74 (1H, m). Example 44 1 methyl 4-(3-carb-4-(((cyclo))))) Example 438 the same method, from 4-(3 -Chloro-4-((cyclopropylamino) benzyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (86 mg, 0.20 mmol) and 2-aminoacetonitrile hydrochloride The title compound (82.7 mg, 0.178 mmol, 88.8%) was obtained as white crystals. W-NMR spectrum (DMS 〇-d6) &lt;5 (ppm)·· 0.42 (2H, m), 0·65 (2H m) 2.56 (1Η,m),4·05 (3Η,s),4·35 (2Η,d,J=5.6 Ηζ),6·54 (1Η d,J=5.2 Hz), 7.20 (1H,d , J=2.8 Hz), 7.25 (1H, dd, J=2 8 -516 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm)

裝 訂Binding

13040611304061

9.2 Ηζ)，7·50 (1H，d，JN2.8 Hz)，7,56 (1H，s)，7·99 (1H，s)， 8·28 (1H，d，J=9.2 Hz)，8·69 (1H，d，J=5.2 Hz)，8.71 (1H s) 9.05 (1H，m)。 ’ ’ 實施例442 甲基二氯環丙胺μ複基）胺某）茇氰乇）·7_曱 氧基-纟-4：琳藉醯脖 藉由與貫施例438同樣之手法，從4_(3_氯_4_(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6_喹啉羧酸（43 mg , 〇1〇 mmol)及40%曱胺（甲醇溶液），得到為白色結晶之標題化合 物（31.6 mg，〇·〇72 mmo卜 71.7%)。 iH-NMR光譜（DMSO-d6)5(ppm): 〇·42 (2H，m)，〇·65 (2H，m)， 2.56 (1H，m)，2·82 (3H，d，J=4.8 Hz)，4.00 (3H，s)，6·51 (1H， d，J=5.2 Hz)，7.18 (1H，d，J=2.8 Hz)，7.22 (1H，dd，&gt;2.8, 9.2 Hz)，7.47 (1H，d，J=2.8 Hz)，7.50 (1H，s)，7·96 (1H，s)， 8.26 (1H，d，J=9.2 Hz)，8·34 (1H，m)，8.57 (1H，s)，8,65 d，J=5.2 Hz)。 ’ 實施例4439.2 Ηζ), 7·50 (1H, d, JN2.8 Hz), 7, 56 (1H, s), 7·99 (1H, s), 8·28 (1H, d, J = 9.2 Hz), 8·69 (1H, d, J = 5.2 Hz), 8.71 (1H s) 9.05 (1H, m). ' 'Example 442 Methyldichlorocyclopropylamine μ complex base) Amine 茇 茇 茇 乇 · · · · · : : : : : : : : : : : : : : : : : : : : : : : 藉 藉 藉 藉 藉 藉 藉 藉 藉 藉 藉(3_Chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6_quinolinecarboxylic acid (43 mg, 1 mmol) and 40% decylamine ( The title compound (31.6 mg, 〇·〇 72 mmo, 71.7%) was obtained as white crystals. iH-NMR spectrum (DMSO-d6) 5 (ppm): 〇·42 (2H, m), 〇·65 (2H, m), 2.56 (1H, m), 2·82 (3H, d, J=4.8 Hz), 4.00 (3H, s), 6·51 (1H, d, J = 5.2 Hz), 7.18 (1H, d, J = 2.8 Hz), 7.22 (1H, dd, &gt; 2.8, 9.2 Hz), 7.47 (1H, d, J = 2.8 Hz), 7.50 (1H, s), 7.96 (1H, s), 8.26 (1H, d, J = 9.2 Hz), 8.34 (1H, m), 8.57 (1H, s), 8, 65 d, J = 5.2 Hz).例 Example 443

Mr胃乙基-4-(3-氣-4-(((環雨fe其^^齡：某 氧基-6· 4：琳#酿胺 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喳啉羧酸（43 mg , 〇1〇 mmol)及2.0M乙胺（四氫呋喃溶液），得到為白色結晶之標 題化合物（29·6 mg，0.065 mmol，65.1%)。 lH-NMR 光譜（DMS〇-d6)5(ppm): 〇·42 (2H，m)，0.65 (2H，m) __- 517 - 本戒張反度通用中國國家標準(CMS) A4規格(210 x 297公釐） 1304061 〜 A7 ___ B7 五、發明説明（~~) ~~ 1.13 (3H, t, J=7.2 Hz), 2.56 (1H, m)3 3.25-3.35 (2H, m), 4.00 (3H，s)，6·51 (1H，d，J=5.2 Hz)，7·18 (1H，d，J=2.8 Hz)，7.21 (1H，dd, J=2.8, 9.2 Hz)，7.46 (1H，d，J=2.8 Hz)，7.49 (1H，s)， 7.96 (1H，s)，8,25 (1H，d，Hz)，8·37 (1H，m)，8.52 (1H， s)，8·64 (1H，d，J=5.2 Hz)。 實施例444 丙基-i(3-蠢瑷丙胺基）羰基）胺基）笨甲 氧基-6-7奎味券醯 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7_甲氧基- 6-0奎淋幾酸（43 mg，0.10 mmol)及丙胺，得到為白色結晶之標題化合物（2丨6 mg， 0.046 mmol , 46.1%) ° W-NMR 光譜（DMSO-d6)5(ppm): 0.42 (2H, m)，〇·65 (2H，m)， 0·90 (3H，t，J=7.2 Hz)，1.54 (2H，m)，2·56 (1H，m)，3.22-3.28 (2H，m)，4.00 (3H，s)，6.51 (1H，d，J=5.2 Hz)，7·18 (1H，d， J=2.8 Hz)，7.21 (1H，dd，J=2.8, 9.2 Hz)，7·46 (1H，d，J=2.8 Hz)，7.49 (1H，s)，7.97 (1H，s)，8·27 (1H，d，J=9.2 Hz)，8.35 (1H，m)，8·49 (1H，s)，8.64 (1H，d，J=5.2 Hz)。 實施例445 丙炔基-4-(3-氯-4-(((環丙胺某）蕤基）胺基）茉氧基）-7-甲氧基-6-崦啉卷si胺 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（43 mg，〇.1〇 mmol)及丙炔胺，得到為白色粉末之標題化合物（25.4 mg， -518 - 本紙張尺度適用中國國家標準(CMS) A4規格(210 X 297公釐) 1304061 〜 A7 _ B7_ 五、發明説明（~~) &quot; &quot; 0.055 mmol，54·6%) 〇 W-NMR光譜（DMSO-d6)5(ppm): 0.42 (2H，m)，0.65 (2H，m)， 2·56 (1H，m)，3·13 (1H，m)，4.00 (3H，s)，4·10 (2H，m)，6·53 (1H，d，J=5.2 Hz)，7.19 (1H，d，J=2.8 Hz)，7·24 (1H，dd， J=2.8，9.2 Hz)，7.49 (1H，d，J=2.8 Hz)，7.53 (1H，s)，7·99 (1H，s)，8·27 (1H，d5 J=9.2 Hz)，8.59 (1H，s)，8·67 (1H，d， J=5.2 Hz), 8.79 (1H, m) ° 實施例446 N6-環丙曱基-4-(3-氯瓖丙胺基）羰基）胺基）差氣某）-1-甲氧某-6-4啉#醯胺 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（43 mg，0β10 mmol)及（胺甲基）環丙烷鹽酸鹽，得到為白色結晶之標題化 合物（25·6 mg，0.053 mmol，53.2%)。 !H-NMR 光譜（DMSO-d6)5(ppm): 0·26 (2H，m)，〇·41-〇 47 (4Η，m)，0.65 (2Η，m)，1·06 (1Η，m)，2.56 (1Η，m)，3·22 (2Η m)，4.03 (3H，s)，6.53 (1H，d，J=5.2 Hz)，7·19 (1H，d，J=2.8 Hz)，7·24 (1H，dd，J=2.8, 9·2 Hz)，7.48 (1H，d，j=2 8 Hz)， 7.52 (1H，s)，7.98 (1H，s)，8·27 (1H，d，J=9.2 HZ)，8.45 (1H， m)，8·56 (1H，s)，8.67 (1H，d，J=5.2 Hz)。 實施例447 HP -(順式氣環丙基）-4-(3 -氯- 環丙胺革」^塗基）胺著） 甲某-6-4啉羧醯胺 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙胺基） ____- 519 -_ 本紙張尺度適用中國國家標準(CNS) A4規格（210X297公釐） ' --- 1304061 〜· A7 __B7 五、發明説明（~^ 羰基）胺基）苯氧基）-7-甲氧基- 6-0奎淋複酸（43 mg，0.10 mmol)及順式-2-氟環丙胺甲苯橫酸鹽，得到為白色結晶之 標題化合物（38.4 mg，0.079 mmol，79.2%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 0·42 (2H，m)，0·65 (2H，m)， 1·03-1·17 (2H，m)，2·56 (1H，m)，2·91 (1H, m)，4·00 (3H，s)， 4.79 (1H, m), 6.51 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.24 (1H, dd5 J=2.8, 8.8 Hz), 7.47 (1H, d, J=2.8 Hz), 7.51 (1H，s)，.7.98 (1H，s)，8·26 (1H，d，J=8.8 Hz), 8·45 (1H，m)， 8.50 (1H，s)，8.65 (1H，d，J=5.2 Hz) 〇 實施例448 Ιϋ(3-甲氧丙基卜—㈠-氯-心以丨環丙胺某^羰某^脖其^节氣 基）-7-甲氣基-6-p奎淋卷醯胺 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙胺基） 致基）胺基）苯氧基）-7-甲氧基- 6-0奎淋幾酸（43 mg , 〇 1〇 mmol)及3-甲氧丙胺，得到為白色結晶之標題化合物（3〇.3 mg，0.061 mmol，60.7%) 〇 ΐΗ·ΝΜΙΙ 光譜（DMSO-d6)(5(ppm): 0,42 (2H，m)，0.65 (2H，m)， 1.77 (2H，m)，2·56 (1H，m)，3.24 (3H，s)，3·34-3·42 (4H，m)， 4.00 (3H，s)，6.51 (1H，d，J=5.2 Hz)，7·20 (1H, d，J=2.8 Hz) 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H3 d, J-2.8 Hz), 7.5〇Mr. stomach ethyl-4-(3-gas-4-(((环环fefe^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ (3-Chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-carbolinecarboxylic acid (43 mg, 〇1〇mmol) and 2.0M ethylamine The title compound (29·6 mg, 0.065 mmol, 65.1%) was obtained as white crystals. lH-NMR spectrum (DMS 〇-d6) 5 (ppm): 〇·42 (2H, m), 0.65 (2H,m) __- 517 - This is the general Chinese national standard (CMS) A4 specification (210 x 297 mm) 1304061 ~ A7 ___ B7 V. Invention description (~~) ~~ 1.13 (3H, t , J=7.2 Hz), 2.56 (1H, m)3 3.25-3.35 (2H, m), 4.00 (3H, s), 6·51 (1H, d, J=5.2 Hz), 7·18 (1H, d, J = 2.8 Hz), 7.21 (1H, dd, J = 2.8, 9.2 Hz), 7.46 (1H, d, J = 2.8 Hz), 7.49 (1H, s), 7.96 (1H, s), 8, 25 (1H, d, Hz), 8.37 (1H, m), 8.52 (1H, s), 8.64 (1H, d, J = 5.2 Hz). Example 444 propyl-i (3- stupid a propylamino)carbonyl)amino)phenylidene-6-7 quinone oxime by the same procedure as in Example 438, from 4-(3-chloro-4-((( Amino) carbonyl)amino)phenoxy)-7-methoxy- 6-0 quinuconic acid (43 mg, 0.10 mmol) eluted M, 46.1%) ° W-NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H, m), 〇·65 (2H, m), 0·90 (3H, t, J = 7.2 Hz), 1.54 (2H, m), 2·56 (1H, m), 3.22-3.28 (2H, m), 4.00 (3H, s), 6.51 (1H, d, J = 5.2 Hz), 7·18 (1H, d, J = 2.8 Hz), 7.21 (1H, dd, J = 2.8, 9.2 Hz), 7.46 (1H, d, J = 2.8 Hz), 7.49 (1H, s), 7.97 (1H, s), 8·27 (1H, d, J=9.2 Hz), 8.35 (1H, m), 8.49 (1H, s), 8.64 (1H, d, J = 5.2 Hz). Example 445 Propynyl-4-(3-chloro-4-(((cyclopropylamine)) sulfhydryl)) yloxy)-7-methoxy-6-carboline vol. Example 438, in the same manner, from 4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (43 mg, 〇.1〇mmol) and propargylamine, the title compound is obtained as a white powder (25.4 mg, -518 - the paper size applies to the Chinese National Standard (CMS) A4 size (210 X 297 mm) 1304061 ~ A7 _ B7_ , invention description (~~) &quot;&quot; 0.055 mmol, 54.6%) 〇W-NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H, m), 0.65 (2H, m), 2· 56 (1H,m),3·13 (1H,m), 4.00 (3H,s),4·10 (2H,m),6·53 (1H,d,J=5.2 Hz), 7.19 (1H, d, J = 2.8 Hz), 7·24 (1H, dd, J = 2.8, 9.2 Hz), 7.49 (1H, d, J = 2.8 Hz), 7.53 (1H, s), 7·99 (1H, s ), 8·27 (1H, d5 J=9.2 Hz), 8.59 (1H, s), 8.67 (1H, d, J = 5.2 Hz), 8.79 (1H, m) ° Example 446 N6-Cyclopropyl Mercapto-4-(3-chloroindolyl)carbonyl)amino)methane)-1-methoxy--6-4 phenyl #醯 amine by the same as Example 438 a method from 4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (43 mg, 0β10 mmol) The title compound (25. 6 mg, 0.053 mmol, 53.2%) was obtained as white crystals. !H-NMR spectrum (DMSO-d6) 5 (ppm): 0·26 (2H, m), 〇·41-〇47 (4Η, m), 0.65 (2Η, m), 1·06 (1Η, m ), 2.56 (1Η, m), 3.22 (2Η m), 4.03 (3H, s), 6.53 (1H, d, J = 5.2 Hz), 7·19 (1H, d, J = 2.8 Hz), 7·24 (1H, dd, J=2.8, 9·2 Hz), 7.48 (1H, d, j=2 8 Hz), 7.52 (1H, s), 7.98 (1H, s), 8.27 (1H , d, J = 9.2 HZ), 8.45 (1H, m), 8.56 (1H, s), 8.67 (1H, d, J = 5.2 Hz). Example 447 HP-(cis-gascyclopropyl)-4-(3-chloro-cyclopropylamine)- amide-based amide-methyl-carboxamide was obtained in the same manner as in Example 438. Manipulation, from 4-(3-chloro-4-(((cyclopropylamino))- 519-_) This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) ' --- 1304061 ~· A7 __B7 V. INSTRUCTION DESCRIPTION (~^ carbonyl)amino)phenoxy)-7-methoxy- 6-0 quinonic acid (43 mg, 0.10 mmol) and cis-2-fluorocyclopropylamine toluene The title compound (38.4 mg, 0.079 mmol, 79.2%) was obtained as white crystals. iH-NMR spectrum (DMSO-d6) 5 (ppm): 0·42 (2H, m), 0·65 (2H, m) , 1·03-1·17 (2H,m),2·56 (1H,m),2·91 (1H, m),4·00 (3H,s), 4.79 (1H, m), 6.51 ( 1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.24 (1H, dd5 J=2.8, 8.8 Hz), 7.47 (1H, d, J=2.8 Hz), 7.51 (1H ,s),.7.98 (1H,s),8·26 (1H,d,J=8.8 Hz), 8·45 (1H,m), 8.50 (1H,s),8.65 (1H,d,J= 5.2 Hz) 〇Example 448 Ιϋ(3-methoxypropylbu-(a)-chloro-heart to 丨cyclopropylamine ^ carbonyl some ^ neck its ^ throttle base) - 7 - A The group of 6-p-quinone-co-amine was obtained from 4-(3-chloro-4-(((cyclopropylamino)))amino)phenoxy)-7- by the same procedure as Example 438. Methoxy- 6-0 quinolate acid (43 mg, 〇1 mmol) and 3-methoxypropylamine gave the title compound as white crystals (3 〇.3 mg, 0.061 mmol, 60.7%) 〇ΐΗ· ΝΜΙΙ Spectrum (DMSO-d6) (5 (ppm): 0,42 (2H, m), 0.65 (2H, m), 1.77 (2H, m), 2·56 (1H, m), 3.24 (3H, s ),3·34-3·42 (4H,m), 4.00 (3H,s),6.51 (1H,d,J=5.2 Hz),7·20 (1H, d,J=2.8 Hz) 7.24 (1H , dd, J=2.8, 9.2 Hz), 7.47 (1H3 d, J-2.8 Hz), 7.5〇

(1H，s)，7.96 (1H，s)，8.27 (1H，dd，J=2.8，9.2 Hz)，8 41 (1H m)，8·54 (1H，s)，8.65 (1H，d，J=5.2 Hz)。 實施例449 ' · 迎_-(2·胺基酮基乙基）-4-(3-氯-仝（（（環丙哼羰某）脖 -520 - 衣紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7(1H, s), 7.96 (1H, s), 8.27 (1H, dd, J = 2.8, 9.2 Hz), 8 41 (1H m), 8·54 (1H, s), 8.65 (1H, d, J =5.2 Hz). Example 449 '· 迎_-(2·Amino ketoethyl)-4-(3-chloro-iso(((cyclopropene carbonyl)) neck-520 - clothing paper scale applicable to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304061 A7 B7

五、發明説明（515 基）茉氫某）-7-甲氲基-6-崦啉#醯胺 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喳啉羧酸（43 mg , 〇.10 mmol)及甘胺酿胺鹽酸鹽，得到為白色結晶之標題化合物 (37·4 mg，0.077 mmol，77.3%) 〇 W-NMR 光譜（DMSO-d6)5(Ppm): 0·42 (2H，m)，0·65 (2H，m)， 2·56 (1Η，m)，3·94 (2Η，d，J=5.6 Ηζ)，4·07 (3Η，s)，6·53 (1Η， d，J=5.2 Hz)，7.14 (1H，s)，7·20 (1Η，d，J=2.8 Hz)，7,24 (1H， dd, J=2.8, 9.2 Hz), 7.44 (1H, s), 7.50 (1H, d, J=2.8 Hz), 7.56 (1H，s)，7.99 (1H，s)，8·27 (1H，d，J二9.2 Hz)，8·67,8·71 (2H， m)，8.77 (1H，s)。 實施例450 N6-((2R)四lL-2-咭喃甲基V4-(3-氯r_4-(((i丙l4)羰某） 胺基）笨氣基）-7-甲氣基-6-4啉教醯藶· 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-唛啉羧酸（43 mg，0·10 mmol)及R-四氫糠基胺，得到為白色粉末之標題化合物 (31.8 mg，0.062 mmol，62.2%)。 iH-NMR光譜（DMS〇-d6)5(ppm): 0·42 (2H，m)，0·65 (2H，m)， 1·62 (1Η，m)，1.78-1.93 (3Η，m)，2·57 (1Η，m)，3·38 (2Η，m)， 3·64 (1H，dd，J=3.6, 14.0 Hz)，3·79 (1H，dd，J=4.〇, 14.0 Hz)， 3·99 (1H，m)，4.02 (3H，s)，6.51 (1H，d，J=5.2 HZ)，7.18 (1H， s)，7·23 (l.H，dd，J=2.8, 8.8 Hz)，7.47 (1H，d，J=2.8 Hz)，7.52 (1H，s)，7·97 (1H，s)，8·26 (1H，d，卜8.8 Hz)，8.41 (ih，m)， -521 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 1304061 、 … A7 ____B7 五、發明説明(~~) ' ~' 8.59 (1H，s)，8·65 (1H，d，J=5.2 Hz)。 實施例451 N6-((2j丄四¾l-2-呋喃甲基）-4-η-氰-4-(((環丙胺蕞)羰某&gt;l 胺基）苯氧基）_ 7 -曱氫基-6 - 4淋# g忘脖 藉由與實施例43 8同樣之手法，從4-(3-氯-4-(((環丙胺基） 談基）胺基）尽氧基）-7-甲氧基-6-咬琳幾酸（43 mg，〇 1〇 mmol)及S-四氫糠基胺，得到為白色粉末之標題化合物 (36·4 mg，0.071 mmol，71.2%)。 實施例452 士 1基-7-幾基-4- 4淋基）氣笨某）-Nf - (4-蠢.苯某、啤 將&gt;1-(4-(7-宇氧基）-6-氰基-4-0奎琳基）氧苯基卜]^-(4-氟 苯基）脲（6.20g，12·3 mmol)於氮蒙氣下溶解於三氟乙酸（6〇 ml)及硫代苯甲醚（3.6 ml，30.7 mmol)後，於60 °C授拌一 夜。將反應液減壓濃縮，在得到之殘餘物中加入水（1 〇〇 後，加入碳酸氫鈉使之中和，然後再加入乙醚（2〇〇 mi)並 攪拌，濾取析出之結晶，用水及乙醚洗淨，於70°C乾燥， 得到為黃色結晶之標題化合物（4.816 g，11.6 mmol， 94.8%)。 iH-NMR 光譜（DMSO-dJc^ppm): 6.42 (1H，d，J=5.2 Hz)， 7.11 (2H，m), 7.22 (2H，m)，7.41 (1H，s)，7·46 (2H，m)，7·58 (2H，m)，8·64 (1H，d，J=5.2 Hz)，8.67 (1H，s)，8.73 (1H，s)， 8·82 (1H，s)。 實施例453 · · N- 4- ( 6-氨基-7- ((2R)-環氣乙燒-2-基）甲最，某-4- g奎g林基）氧 ____ - 522 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 … 、 A7 -----B7__ 五、發明説明（517) 蓋Αΐτ&gt;Γ-(4-Ιί.苽某 藉由與實施例7同樣之手法，從Ν-(4-(6-氰基-7-羥基-4-口奎σ林基）氧苯基）-Ν’-(4-氟苯基）·(1·24 g，3.0 mmol)及4-甲基-1-苯磺酸[(2R)-環氧乙烷-2-基甲基]酯，得到為淡黃 色結晶之標題化合物（713 mg，1.52 mmol，50.5%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 2.81 (1H，m)，2·92 (1H，m)， 3.46 (1Η，m)，4·17 (1Η，dd，J=6.8，11·6 Ηζ)，4·71 (1Η，dd， J==2.4，11.6 Hz)，6.53 (1H，d，J=5.2 Hz)，7·12 (2Η，m)，7.24 (2H，m)，7·46 (2H，m)，7·58 (2H，m)，7·63 (1H，s)，8.7卜8.73 (2H，m)，8·78 (1H，s)，8.83 (1H，s)。 f施例454 氰基-7-((72R)-2- # 某-3-Π-毗咯啶某）丙某） 奎啉基）氫）H ) - Ν· - (4-氟茉基）脲 將N-(4-(6-氰基-7-((2R)-環氧乙烷-2-基）甲氧基-4-喹啉 基）氧苯基氟苯基）脲（200 mg，0.425 mmol)於氮蒙 氣下溶解於四氫呋喃（5·0 ml)中，加入吡咯啶（〇.5ml)並於 室溫攪掉一夜。將反應液減壓濃縮，付諸於矽凝膠管柱層 析（溶出液：乙酸乙酯-甲醇=9 ·· 1),將包含目的物之溶出 部分漢縮，加入甲醇（5 ml)並使之結晶，濾取結晶並藉由 通風乾燥，得到為淡黃色結晶之標題化合物（157 7 , 0.291 mmol，68.5%) 〇 iH-NMR 光譜（DMSO-d6) 5 (ppm): 1·67 (4H，br)，2.47-2.52 (5Η, m), 2.69 (1Ή, m), 4.01 (1H, m)5 4.20 ( 1H, dd, J=5.6 10.8 Hz), 4.30 (1H, dd, J=3.6, 10.8 Hz), 5.02 (1H, d, J=4.4 ___- 523 -_ 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) *&quot; &quot; ' 1304061 A7 B7 五、發明説明（518)V. Description of the Invention (515-based) hydrazine-hydrogen)-7-carboxylidene-6-carboline # guanamine The same procedure as in Example 438, from 4-(3-chloro-4-((() Propylamino) carbonyl)amino)phenoxy)-7-methoxy-6-carbolinecarboxylic acid (43 mg, 〇.10 mmol) and glycine amine hydrochloride afforded the title compound as white crystal (37·4 mg, 0.077 mmol, 77.3%) 〇W-NMR spectrum (DMSO-d6) 5 (Ppm): 0·42 (2H, m), 0·65 (2H, m), 2·56 (1Η ,m),3·94 (2Η,d,J=5.6 Ηζ),4·07 (3Η,s),6·53 (1Η, d,J=5.2 Hz), 7.14 (1H, s), 7· 20 (1Η, d, J=2.8 Hz), 7, 24 (1H, dd, J=2.8, 9.2 Hz), 7.44 (1H, s), 7.50 (1H, d, J=2.8 Hz), 7.56 (1H , s), 7.99 (1H, s), 8.27 (1H, d, J 9.2 Hz), 8.67, 8.71 (2H, m), 8.77 (1H, s). Example 450 N6-((2R)tetralL-2-indolylmethyl V4-(3-chloror_4-(((i)l4)carbonyl)amino) stupid)-7-methyl- 6-4 啉 醯苈 醯苈 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- The title compound (31.8 mg, 0.062 mmol, 62.2%) was obtained as a white powder. </RTI> <RTIgt; </RTI> <RTIgt; </RTI> </RTI> <RTIgt; -d6)5(ppm): 0·42 (2H,m),0·65 (2H,m), 1·62 (1Η,m), 1.78-1.93 (3Η,m),2·57 (1Η, m),3·38 (2Η,m), 3·64 (1H,dd,J=3.6, 14.0 Hz),3·79 (1H,dd,J=4.〇, 14.0 Hz), 3·99 ( 1H,m),4.02 (3H,s),6.51 (1H,d,J=5.2 HZ), 7.18 (1H, s),7·23 (lH,dd,J=2.8, 8.8 Hz),7.47 (1H ,d,J=2.8 Hz),7.52 (1H,s),7·97 (1H,s),8·26 (1H,d,b 8.8 Hz),8.41 (ih,m), -521 Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061, ... A7 ____B7 V. Invention description (~~) ' ~' 8.59 (1H, s), 8·65 (1H, d, J=5.2 Hz). Example 45 1 N6-((2j丄4 3⁄4l-2-furylmethyl)-4-η-cyano-4-(((cyclopropylamine)carbonyl)&gt;l amino)phenoxy)-7-hydrazine -6 - 4 淋# g Forgot neck by the same procedure as in Example 43 8 from 4-(3-chloro-4-(((cyclopropylamino)))))))) The title compound (36·4 mg, 0.071 mmol, 71.2%) was obtained as a white powder. mp </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 452 士士1基-7-几基-4- 4 底基)气笨某)-Nf - (4- stupid. Benzene, beer will be > 1-(4-(7-decyl)-6- Cyano-4-0 quinolinyloxyphenyl]-(4-fluorophenyl)urea (6.20 g, 12.3 mmol) was dissolved in trifluoroacetic acid (6 〇ml) under nitrogen atmosphere and After thioanisole (3.6 ml, 30.7 mmol), it was mixed overnight at 60 °C. The reaction solution was concentrated under reduced pressure, and water (1 EtOAc) The title compound (4.816 g, 11.6 mmol, 94.8%) was obtained. Hz), 7.11 (2H,m), 7.22 (2H,m), 7.41 (1H,s),7·46 (2H,m),7·58 (2H,m),8·64 (1H,d, J = 5.2 Hz), 8.67 (1H, s), 8.73 (1H, s), 8·82 (1H, s). Example 453 · · N- 4-(6-Amino-7-((2R)-环气乙乙-2-基)甲最,一-4-g奎克林基) Oxygen ____ - 522 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ... A7 -----B7__ V. Description of Invention (517) Cover Αΐτ> Γ-(4-Ιί.苽 by the same method as in Example 7, from Ν-(4-(6-cyano-7-) Hydroxy-4-hydroxyl-infraline)oxyphenyl)-indole-(4-fluorophenyl)·(1·24 g, 3.0 mmol) and 4-methyl-1-benzenesulfonic acid [(2R) -oxiran-2-ylmethyl]ester, obtained as The title compound (713 mg, 1.52 mmol, 50.5%) of pale yellow crystals. iH-NMR spectrum (DMSO-d6) 5 (ppm): 2.81 (1H, m), 2·92 (1H, m), 3.46 (1Η , m), 4·17 (1Η, dd, J=6.8, 11·6 Ηζ), 4·71 (1Η, dd, J==2.4, 11.6 Hz), 6.53 (1H, d, J=5.2 Hz) ,7·12 (2Η,m), 7.24 (2H,m),7·46 (2H,m),7·58 (2H,m),7·63 (1H,s),8.7 8.73 (2H, m),8·78 (1H,s),8.83 (1H,s). f Example 454 Cyano-7-((72R)-2-# -3- Π---pyrrolidine)) Quinolinyl)hydrogen)H)-Ν·-(4-fluoromethyl)urea will be N-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxy) Base-4-quinolinyl)oxyphenylfluorophenyl)urea (200 mg, 0.425 mmol) was dissolved in tetrahydrofuran (5.0 mL) under nitrogen atmosphere, and pyrrolidine (〇.5 ml) was added to the chamber. The temperature was stirred up overnight. The reaction solution was concentrated under reduced pressure, and applied to a gel column chromatography (eluent: ethyl acetate-methanol=9··1), and the fractions containing the desired substance were condensed and added to methanol (5 ml). The title compound (157 7 , 0.291 mmol, 68.5%) was obtained as a pale yellow crystal. </i>iH-NMR spectrum (DMSO-d6) 5 (ppm): 1·67 ( 4H, br), 2.47-2.52 (5Η, m), 2.69 (1Ή, m), 4.01 (1H, m)5 4.20 ( 1H, dd, J=5.6 10.8 Hz), 4.30 (1H, dd, J=3.6 , 10.8 Hz), 5.02 (1H, d, J=4.4 ___- 523 -_ This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) *&quot;&quot;&quot; '1304061 A7 B7 V. Invention Description ( 518)

Hz), 6.51 (1H, d? J=5.2 Hz), 7.11 (2H, m), 7.23 (2H, m), 7.46 (2H，m)，7.57-7.61 (3H，m)，8.70-8.75 (3H，m)，8.83 (1H，s)。 實施例455 坠（4-((6-胺基-7-(((2R)-3-(二乙胺某）-2-衮丙某）畲、土 喹啉基氣）茉某氣茉某 將Ν-(4-(6-氰基-7-((2R)-環氧乙烷-2-基）甲氧基-4-喹琳 基）氧苯基）-Ν·-(4-氟苯基）脲（200 mg，0.425 mmol)於氮蒙 氣下溶解於四氫呋喃（5.0 ml)，加入二乙胺（lo ml)並於60 C擾拌一夜。將反應液減壓濃縮，付諸於碎凝膠管柱層析 (✓谷出液·乙乙醋-曱醇=9· 1)，將包含目的物之溶出部 分濃縮，加入甲醇（5 ml)並使之結晶，濾取結晶並藉由通 風乾燥’传到為淡黃色結晶之標題化合物（12 6.4 m g，0.2 3 3 mmol，54.7%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): 0·96 (6H，t，J=7.2 Hz)， 2.42-2.57 (5H，m)，2·64 (1H，m)，3·95 (1H，m)，4.21 (1H，dd， J=5.6，10.4 Hz)，4.30 (1H，dd，J=3.6，10.4 Hz)，4.91 (1H，d， J=4.4 Hz)，6·51 (1H，d，J=5.2 Hz)，7·11 (2H，m)，7.23 (2H， m)，7.46 (2H，m)，7.56-7.60 (3H，m)，8·70-8·75 (3H，m)，8.82 (lH，s)〇 實施例456 仏丄4-((6-氨某羥基-3-Π-六氤吡啶某）丙某） 里奎也某）氩）茉基）-N· - (4-氣茉某 將N-(4-(6 -说基- 7- ((2R)-環乳乙燒-2-基）甲氧基-4 -口奎17林 1_____- 524 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 一 、 A7 _____ B7 五、發明説明（519) 基）氧苯基）-N，-(4-氟苯基）脲（200 mg，0.425 mmol)於氮蒙 氣下溶解於四氫呋喃（5.0 ml)，加入六氩吡啶（〇 5 ml)並於 60C攪掉一夜。將反應液減壓濃縮，付諸於碎凝膠管柱層 析（ί谷出液：乙酸乙S旨-甲醉=9· 1) ’將包含目的物之溶出 部分濃縮，加入曱醇（5 ml)並使之結晶，濾取結晶並藉由 通風乾燥’得到為淡黃巴結晶之標題化合物（16 9.8 m g， 0.306 mmol » 71.9%) ° h-NMR 光譜（DMSO-d6)5(ppm): 1·36 (2H，m)，1·47 (4H，m)， 2.34-2.51 (6Η，m)，4.02 (1Η，m)，4·20 (1Η，dd，J=5.6，10.4 Hz)，4·30 (1H，dd，J=3.2，10.4 Hz)，4.93 (1H，d，J=4.4 Hz)， 6.51 (1H，d，J=5.2 Hz)，7·11 (2H，m)，7.23 (2H，m)，7·46 (2H， m)，7.57-7.62 (3Ή，m)，8·70-8·75 (3H，m)，8·83 (1H，s)。 實施例457 7-(芊氣基）-4-(3-氣-(4-((環丙胺基）羰某）胺某）笨氣某）-6〃奎啉羧酸甲酯 將4-(4-胺基-3-氯苯氧基）-7-(芊氧基）-6-喹啉羧酸曱酯 (3.938 g，9·06 mmol)於氮蒙氣下溶於二甲基甲醯胺（40 ml)，然後於室溫滴入吡啶（1·1〇 ml，13.6 mmol)及氯曱酸 苯酯（1.70 ml，13.6 mmol)並授拌卜時。滴入環丙胺（1.88 ml，27.2 mmol)，再攪捽一夜。將反應液分溶於乙酸乙酯 (400 ml)及水（200 ml)中，將有機層用水洗淨後’減壓濃 縮，加入乙酸乙酯（40 ml)及濾取析出之結晶，藉由通風乾 燥，得到為淡褐色結晶之標題化合物（2.225 g ’ 4·3〇 mmol，47·4%) 〇 -525 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五 發明説明（ 52(l· H-NMR 光譜（DMSO-d6)5(Ppm): 〇 42 、 ^ 2 (2H，m)，0.65 (2H，m)， 2·56 (1H，m)，3·87 (3H，s)，5·39 … s), 6.51 (in d J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.24 (iH ，， ，i UH&gt; dd3 J=2.8, 9.2 Hz), 7.32 (1H, m), 7.41 (2H, m), 7.49 fm h t 、 、 ⑽，d，卜2.8 Hz)，7·54 (2H， m)，7.61 (1H，s)，7·97 (1H，s)，8·26 ( (1H, s)5 8.67 (1H3 d5 J=5.2 Hz) 〇 ’ ’ * Hz), 8.60 藉下述方法合成起始物質。 製造例4.57-1 ^(((2,2-一甲基-4,6- 一嗣某- -亞-发、闽 ~ 圜-5-其、甲冀、 歷基）-2-衮基芊酸甲酯 T泰〉 在為公知化合物之4-胺基-2-與其^ # 丄 ^ 工卷卞故甲酯（7·59 g，45·4 mmol)中加入酸（7 ·2 g，50 mmol)，居田於一 1 上 原甲鉍三乙酯（50 ml)及 2-丙醉（50 ml)，並於10(TC攪拌1小時。 r 、、 于放冷至1：溫，濾取 析出之結晶’用乙鍵洗淨及通風乾怪 取乾Μ ’得到為白色結晶之 標題化合物（13·98 g，43.5 mmol，95 8%)。 W-NMR 光譜（CDCl3mppm): L76 (^，°s) Μ? (3h s) 6.75 (IH, dd, 1=2.4, 8.8 Hz), 6.83 (1H, d, J=2.4 Hz)&gt; ； 9 ' (1H，d，J=8.8 Hz)，8.65 (1H，m)，U.〇 (1H，s)，u 2〇 (ih， m) 〇 ， 製造例457-2 HJ7 氧基）-4ϋ2,2-二甲基•亞二i六圚· k基）甲某）胺基）芊酸甲酯 在氮蒙氣及室溫下，將4-(((2,2-二甲基-4,6-二酮基 亞一氧六圜-5-基）甲基）胺基）-2 -#雙基；酸曱酉旨（H975 g， -526 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐）Hz), 6.51 (1H, d? J=5.2 Hz), 7.11 (2H, m), 7.23 (2H, m), 7.46 (2H, m), 7.57-7.61 (3H, m), 8.70-8.75 (3H , m), 8.83 (1H, s). Example 455 ((4-((6-Amino-7-((2R)-3-(diethylamine))))), quinolinyl-based gas) Ν-(4-(6-Cyano-7-((2R)-oxiran-2-yl)methoxy-4-quinolinyl)oxyphenyl)-indole-(4-fluoro Phenyl)urea (200 mg, 0.425 mmol) was dissolved in tetrahydrofuran (5.0 ml) under nitrogen atmosphere, and diethylamine (li ml) was added and the mixture was stirred overnight at 60 C. Fragmentation of gel column chromatography (✓, effluent, ethyl acetate, decyl alcohol = 9.1), concentration of the fractions containing the target, addition of methanol (5 ml) and crystallization, filtration and crystallization The title compound (12 6.4 mg, 0.23 3 mmol, 54.7%) was obtained as a light yellow crystal. 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 0·96 (6H, t, J =7.2 Hz), 2.42-2.57 (5H, m), 2·64 (1H, m), 3·95 (1H, m), 4.21 (1H, dd, J=5.6, 10.4 Hz), 4.30 (1H, Dd, J = 3.6, 10.4 Hz), 4.91 (1H, d, J = 4.4 Hz), 6·51 (1H, d, J = 5.2 Hz), 7·11 (2H, m), 7.23 (2H, m ), 7.46 (2H, m), 7.56-7.60 (3H, m), 8·70-8·75 (3H, m), 8.82 (lH, s)〇 Example 456 仏丄4-((6-Ammonia hydroxy-3-indole-hexafluoropyridinyl) propyl) 里奎也) argon) 茉基)-N· - (4-气茉一N- (4-(6-sayyl-7-((2R)-cyclolacyl-2-yl)methoxy-4 - 口奎17林1_____- 524 - This paper scale applies to Chinese National Standard (CNS) A4 Specification (210 X 297 mm) 1304061 I. A7 _____ B7 V. Description of the invention (519) oxyphenyl)-N,-(4-fluorophenyl)urea (200 mg, 0.425 mmol) in nitrogen Dissolved in tetrahydrofuran (5.0 ml), added with hexafluoropyridine (〇5 ml) and stirred overnight at 60 C. The reaction mixture was concentrated under reduced pressure and applied to a gel column column chromatography. S-------- 1) 1) 'Concentrate the fractions containing the target, add sterol (5 ml) and crystallize it, filter the crystals and dry by airing to give the title compound as pale yellow crystal (16 9.8 mg, 0.306 mmol » 71.9%) ° h-NMR spectrum (DMSO-d6) 5 (ppm): 1·36 (2H, m), 1·47 (4H, m), 2.34-2.51 (6Η, m), 4.02 (1Η, m), 4·20 (1Η, dd, J=5.6, 10.4 Hz), 4·30 (1H, dd, J=3.2, 10.4 Hz), 4.93 (1 H, d, J = 4.4 Hz), 6.51 (1H, d, J = 5.2 Hz), 7·11 (2H, m), 7.23 (2H, m), 7·46 (2H, m), 7.57-7.62 (3Ή, m), 8·70-8·75 (3H, m), 8·83 (1H, s). Example 457 7-(Indolyl)-4-(3-gas-(4-((cyclopropylamino)carbonyl)amine)) Something )-6〃Minyl carboxylic acid methyl ester 4-( 4-Amino-3-chlorophenoxy)-7-(decyloxy)-6-quinolinecarboxylic acid oxime ester (3.938 g, 9.06 mmol) was dissolved in dimethylformamide under nitrogen atmosphere. Amine (40 ml) was then added dropwise pyridine (1·1 〇ml, 13.6 mmol) and phenyl chlorophenyl phthalate (1.70 ml, 13.6 mmol) at room temperature. Cyclopropylamine (1.88 ml, 27.2 mmol) was added dropwise and stirred overnight. The reaction mixture was dissolved in ethyl acetate (400 ml) and water (200 ml), and the organic layer was washed with water and then concentrated under reduced pressure, ethyl acetate (40 ml) was added and the crystals were separated by filtration. Air-dried to give the title compound (2.225 g '4·3〇mmol, 47.4%) 〇-525 - This paper size applies to Chinese National Standard (CNS) A4 size (210X 297 mm) 1304061 A7 B7 Five inventions description (52 (l·H-NMR spectrum (DMSO-d6) 5 (Ppm): 〇42, ^ 2 (2H, m), 0.65 (2H, m), 2·56 (1H, m), 3·87 (3H, s), 5·39 ... s), 6.51 (in d J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.24 (iH , , , i UH&gt; dd3 J= 2.8, 9.2 Hz), 7.32 (1H, m), 7.41 (2H, m), 7.49 fm ht , , (10), d, 2.8 Hz), 7·54 (2H, m), 7.61 (1H, s), 7·97 (1H, s), 8.26 ((1H, s)5 8.67 (1H3 d5 J=5.2 Hz) 〇' ' * Hz), 8.60 The starting material was synthesized by the following method. Production Example 4.57-1 ^(((2,2-Methyl-4,6- 一嗣一--亚-发,闽~ 圜-5-其,甲冀, 历基)-2-衮基芊Acid methyl ester T Thai> Add acid (7 · 2 g, 50) to 4-amino-2- and its known compound methyl ester (7·59 g, 45·4 mmol). Mum), 居田在一1 上原甲铋三酯 (50 ml) and 2- propyl drunk (50 ml), and stirred at 10 (TC for 1 hour. r,, and allowed to cool to 1: temperature, filter The precipitated crystals were washed with hexanes and dried to give the title compound (13·98 g, 43.5 mmol, 95 8%) as white crystals. W-NMR spectrum (CDCl3mppm): L76 (^, °s) Μ? (3h s) 6.75 (IH, dd, 1=2.4, 8.8 Hz), 6.83 (1H, d, J=2.4 Hz)&gt;; 9 ' (1H,d,J=8.8 Hz), 8.65 (1H,m), U.〇(1H,s),u 2〇(ih, m) 〇, Manufacturing Example 457-2 HJ7 oxy)-4ϋ2,2-dimethyl•Asian II 圚· K-based) methyl amide) methyl decanoate 4-(((2,2-dimethyl-4,6-dione)-oxo-6--5 in nitrogen atmosphere and room temperature -yl)methyl)amino)-2 -# double base; acid hydrazine (H975 g, -526 - suitable for paper size Chinese National Standard (CNS) A4 size (210 X 297 mm)

裝 訂Binding

線 1304061 '、〜 - - ' * A7 _______ B7 五、發明説明（521) 43.5 mmol)懸浮於二甲基甲酿胺（14〇 ml)中，並慢慢加入氫 化納（1.87 g，46.8 mmol)。.1_5小時後，滴入芊基溴化物 (5.7 ml，47·9 mmol)並攪摔2曰。將反應液用水（700 ml)稀 釋’攪拌一夜後，濾取析出之結晶，用乙醚洗淨，藉由於 7〇°C乾燥，得到為白色結晶之標題化合物（15 477 g，37 6 mmol ; 86.5%)。 iH-NMR 光譜（CDCl3)5(ppm): ι·76 (6H，s)5 3.91 (3H，s)， 5.23 (2H，s)，6·83 (1H，s)，6·88 (1H，m)，7.26-7.54 (5H，m)， 7·95 (1H，m)，8.62 (1H，m)，11.24 (1H，m)。 製造例457·^ 芊氳基）-4-酮基-1,4-二1-6- g套淋教酸甲酯 在2-(芊氧基）-4-(((2,2-二甲基- 4,6-二酮基-1，3-亞二氧 六圜_5-基）甲基）胺基）苄酸甲酯（15.477 g，37.6 mmol)中加 入Dowtherm A(160 ml)，並於200°C攪拌1小時。放冷至室 溫，濾取析出之結晶，用乙醚洗淨，藉由通風乾燥得到標 題化合物（7.19 g，23.2 mmol，61.8%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 3.81 (3H，s)，5·26 (2H，s)， 5.97 (1H, d, J=7.6 Hz), 7.09 (1H, s), 7.30-7.53 (5H, m), 7.84 (1H，m)，8·46 (1H，s)，11.69 (1H，m) 〇 製造例457-4 2二（芊氧基）-4-氯-6-4啉藉酸甲酯 在7-(芊氧基）-4-酮基-1，4-二氫-6-喹啉瘦酸甲酯（7.19g， 23 ·2 mmol)中，加入硫酿氯（70 ml)及觸媒量之二甲基甲酿 胺，在攪拌下加熱回流3小時。將反應液減壓濃縮，慢慢加 _- 527 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7Line 1304061 ', ~ - - ' * A7 ____ B7 V. Description of the invention (521) 43.5 mmol) suspended in dimethyl ketoamine (14 〇 ml) and slowly added sodium hydride (1.87 g, 46.8 mmol) . After .1_5 hours, decyl bromide (5.7 ml, 47·9 mmol) was added dropwise and stirred for 2 曰. The reaction mixture was diluted with EtOAc (EtOAc). %). iH-NMR spectrum (CDCl3) 5 (ppm): ι·76 (6H, s) 5 3.91 (3H, s), 5.23 (2H, s), 6·83 (1H, s), 6·88 (1H, m), 7.26-7.54 (5H, m), 7.95 (1H, m), 8.62 (1H, m), 11.24 (1H, m). Production Example 457·^ ))-4-keto-1,4-di1-6-g sets of methyl ester of methyl ester in 2-(decyloxy)-4-(((2,2-) Add methyl Dowtherm A (160 ml) to methyl 4-,6-dione-1,3-dioxahexamethylene-5-yl)methyl)amino)benzylate (15.477 g, 37.6 mmol) And stirred at 200 ° C for 1 hour. The mixture was allowed to cool to room temperature. crystals crystals crystals crystals eluted eluted with diethyl ether. iH-NMR spectrum (DMSO-d6) 5 (ppm): 3.81 (3H, s), 5·26 (2H, s), 5.97 (1H, d, J = 7.6 Hz), 7.09 (1H, s), 7.30 -7.53 (5H, m), 7.84 (1H, m), 8.46 (1H, s), 11.69 (1H, m) 〇Production Example 457-4 2 bis(decyloxy)-4-chloro-6- Adding sulfur to chlorine by adding methyl ester to methyl 4-(decyloxy)-4-keto-1,4-dihydro-6-quinoline methyl ester (7.19g, 23 · 2 mmol) (70 ml) and the amount of catalyst dimethyl ketoamine were heated under reflux for 3 hours with stirring. The reaction solution is concentrated under reduced pressure and slowly added _- 527 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7

五、發明説明 入2 ί !'風氧化制溶液中和後’用乙酸乙g旨萃取，將有楼芦 用水及飽和食鹽水洗淨，以及用無水硫酸鈉乾燥。餘去溶 媒，加入乙醚使之結晶化，濾取結晶及通風乾燥，得到為 淡褐巴結晶之標題化合物（4 · 0 6 7 g，12 · 4 mm ο 1)。 iH-NMR 光譜（CDCl3)5(pPm): 4.00 (3H，s)，5.33 (2H，s) 7.3 卜7'58 (7H，m)，8·66 (1H，s)，8·75 (1H，d，卜5.2 Hz)。 I造例457-1 4-(4 -胺基-j-氣表氧基）-7-(卞氧基杏淋择酸甲酷 將4 -胺基-3-乳紛（2.22 g ’ 15.45 mmol)溶於二甲基亞石風 (4〇 ml) ’ 於室溫下fefe 加入氫化 #3(618 mg，15 45 mmol) 並攪拌30分鐘。加入7-(芊氧基）-4-氯-6-喳啉幾酸曱酉旨 (4·05 g ’ 12.36 mmol)，並於100°C及攪掉下加熱2小時。放 冷至室溫，將反應液分溶於乙酸乙酯與水中，將有機声用 水及飽和食鹽水洗淨及用無水硫酸鈉乾燥。餘去溶媒，然 後付諸於矽凝膠管柱層析（溶出液：乙酸乙酯），將包本目 的物之;谷出部分濃縮’懸浮於乙酸乙g旨中，將其用己、燒稀 釋及濾取結晶，藉由通風乾燥，得到為淡褐色結晶之標題 化合物（3.938 g，9.06 mmol，73.3%)。 lH-NMR 光譜（CDC13) 5 (ppm): 3.98 (3H，s)，4.11 (2H m) 5·34 (2H，s)，6·43 (1H，d，&gt;5·2 Hz)，6·85 (1H，d，J=8.8 Hz) 6·93 (1H，dd，J=2.8，8.8 Hz)，7.14 (1H，d，J=2.8 Hz) 7 30· 7·57 (6H，m)，8·62 (1H，d，J=5.2 Hz)，8·82 (1H，s)。’ 膏施例458 · N 6 - (j -氣乙基）.4-(4-((環丙胺基）幾胺華- I.甲基笨氣 -528 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 〜 -- A7 _____B7 _ _ 五、發明説明（523) 基）-7-甲氣甚-6-4^株# gjfe脖 將4-(4-胺基-3-甲基苯氧基）-7-甲氧基-6-喹啉羧酸甲酯 (30 mg ’ 0.0736 mmol)溶於N，N-二甲基甲酿胺（1·4 ml)，加 入三乙胺（0.071 ml)，苯并三唑-1-基參（二甲胺基）銹六氟 嶙酸鹽（63 mg)，在其中加入2-氟乙胺鹽酸鹽（14 mg)，並 在室溫攪拌5小時。在反應溶液中加入水，用乙酸乙酯·四 氫呋喃萃取，用飽和食鹽水洗淨，用無水硫酸鎂乾燥以及 將濾液減壓餾去。將得到之結晶懸浮於乙醇中，用乙醚稀 釋後濾取結晶，用乙醚洗淨結晶及吸引乾燥後，得到為淡 只色結晶之標題化合物（22 mg，0.0486 mmol，66.03%) 0 H-NMR *if(DMSO-d6)(5(ppm):0.41-0.45(2H，m)，（K63-0.69 (2H，m)，2.22 (3H，s)，2·52-2·60 (1H，m)，3.61 (1H，q， J=5.2 Hz)5 3.67 (1H, q, J=5.2 Hz), 4.03 (3H, s)5 4.52 (1H, t? J=5.2 Hz)，4·64 (1H，t，J=5.2 Hz)，6·47 (1H，d, JN5.0 Hz)， 6.78 (1H，m)，7·05 (1H，dd，J=2.8 Hz，8.8 Hz)，7.11 (1H，d， &gt;2.8 Hz)，7.52 (1H，s)5 7·63 (1H，s)，7.94 (1H，d，J=8.8 Hz)， 8.59-8.62 (2H，m)，8·66 (1H，d，J=5.0 Hz)。 如下述合成起始原料。 製造例458- 1 甲杲苯氣某）-7-甲氫某-6-4味盡酸甲醋 使用WO 〇〇5 0405記載之4-氯-7-甲氧基-6-峻淋複酸甲酯 (1.5 g，5.9127 mmol)及 4-胺基-3-甲酚（1.46 g，1 1.8254 mmol)，藉由與製造例395-ι同樣之方法，得到為褐色結晶 之標 4 化合物（158 mg，0.4669 mmol，7.90%)。 _______· 529 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇χ297公釐） 1304061 A7 B7V. INTRODUCTION OF THE INVENTION Into 2 !! After the neutralization of the air-oxidizing solution, the mixture was extracted with acetic acid, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was crystallized from crystals, crystals, crystals, and dried to give the title compound (4·0 6 7 g, 12 · 4 mm ο 1 ). iH-NMR spectrum (CDCl3) 5 (pPm): 4.00 (3H, s), 5.33 (2H, s) 7.3 Bu 7'58 (7H, m), 8.66 (1H, s), 8.75 (1H , d, 5.2 Hz). I. 例 457-1 4-(4-Amino-j-gasooxy)-7-(卞 杏 杏 淋 择 酸 将 将 4 4 4 4 4 4 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 Soluble in dimethyl sapphire (4 〇 ml) ' Add hydrogenation #3 (618 mg, 15 45 mmol) at room temperature and stir for 30 minutes. Add 7-(decyloxy)-4-chloro- 6-porphyrin acid (4.05 g ' 12.36 mmol), and heated at 100 ° C for 2 hours with stirring. Allow to cool to room temperature and dissolve the reaction in ethyl acetate and water. The organic sound is washed with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent is removed, and then applied to a gel column chromatography (eluent: ethyl acetate) to coat the desired product; The title compound (3.938 g, 9.06 mmol, 73.3%) was obtained as a pale brown crystals. Spectrum (CDC13) 5 (ppm): 3.98 (3H, s), 4.11 (2H m) 5·34 (2H, s), 6·43 (1H, d, &gt; 5·2 Hz), 6.85 ( 1H,d,J=8.8 Hz) 6.93 (1H, dd, J=2.8, 8.8 Hz), 7.14 (1H, d, J=2.8 Hz) 7 30· 7·57 (6H m),8·62 (1H,d,J=5.2 Hz),8·82 (1H,s).' Paste application 458 · N 6 - (j - gas ethyl). 4-(4-(( Cyclopropylamino)amine-I.methyl stupid-528 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ~ -- A7 _____B7 _ _ V. Invention description (523 Methyl 4-(4-amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxylic acid methyl ester (30 mg '0.0736 mmol) dissolved in N,N-dimethylcaraamine (1.4 ml), added with triethylamine (0.071 ml), benzotriazol-1-yl ginyl (dimethylamino) Rust hexafluoroantimonate (63 mg), which was added with 2-fluoroethylamine hydrochloride (14 mg), and stirred at room temperature for 5 hours. Water was added to the reaction solution and extracted with ethyl acetate·tetrahydrofuran. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the filtrate was evaporated to dryness. The crystals were evaporated in ethanol, and the crystals were diluted with diethyl ether, and the crystals were filtered, washed with diethyl ether and dried. The title compound (22 mg, 0.0486 mmol, 66.03%) mp. -0.45(2H,m),(K63-0.69 (2H,m), 2.22 (3H,s),2·52-2·60 (1H,m),3.61 (1H,q, J=5.2 Hz)5 3.67 (1H, q, J=5.2 Hz), 4.03 (3H, s)5 4.52 (1H, t? J=5.2 Hz), 4·64 (1H, t, J=5.2 Hz), 6·47 (1H ,d, JN5.0 Hz), 6.78 (1H,m),7·05 (1H,dd,J=2.8 Hz,8.8 Hz), 7.11 (1H,d, &gt;2.8 Hz),7.52 (1H,s ) 5 7·63 (1H, s), 7.94 (1H, d, J = 8.8 Hz), 8.59-8.62 (2H, m), 8.66 (1H, d, J = 5.0 Hz). The starting materials were synthesized as described below. Production Example 458- 1 formazan benzene gas) -7-methylhydrogen-6-4 flavor acid vinegar using 4-chloro-7-methoxy-6-furanic acid as described in WO 〇〇5 0405 The methyl ester (1.5 g, 5.9127 mmol) and 4-amino-3- cresol (1.46 g, 1 1.8254 mmol) were obtained as a brown crystal of compound 4 (158). Mg, 0.4669 mmol, 7.90%). _______· 529 - This paper size applies to China National Standard (CNS) A4 specification (21〇χ297 mm) 1304061 A7 B7

W-NMR光譜（DMSO-d6)5(PPm): 2.06 (3H, s)，3 84 (3H s) 3-95 (3H, s), 4.93 (2H, s), 6.40 (1H, d, J=5.0 Hz), 6.69 d，J=8.4 Hz), 6.82 (1H, d, J=8.4 Hz), 6.86 (1H, s), 7.47 (1H S)，8.56 (1H，s)，8·62 (1H，d，J=5.〇 Hz)。 ’ ’W-NMR spectrum (DMSO-d6) 5 (PPm): 2.06 (3H, s), 3 84 (3H s) 3-95 (3H, s), 4.93 (2H, s), 6.40 (1H, d, J =5.0 Hz), 6.69 d, J=8.4 Hz), 6.82 (1H, d, J=8.4 Hz), 6.86 (1H, s), 7.47 (1H S), 8.56 (1H, s), 8.62 ( 1H, d, J = 5. 〇 Hz). ’ ’

製造例45 SOManufacturing Example 45 SO

Hldl環丙胺棊）幾棊）胺某-3-U苯氣某 喳啉#酸甲酯 使用4.-(4-胺基-3-甲基苯氧基）-7-甲氧基甲氧羰基喳 啉（158 mg，0.4669 mmol),藉由與製造例17同樣之操作將 其胺基甲酸苯酯化，然後在未精製下藉由與實施例u同樣 之操作使環丙胺作用，得到為淡褐色結晶之標題化合物 (Π3 mg，0.4105 mmol，87·92〇/〇)。 iH-NMR 光譜（DMSO-d6) 5 (ppm): 0.40-0.43 (2Η，m) 0 61 0.66 (2H, m), 2.20 (3H, s), 2.52-2.57 (1H, m), 3.85 (3H, s), 3.96 (3H, s), 6.45 (1H, d, J=5.4 Hz), 6.75 (1H, s)5 7.04 〇h! dd，J=2.4 Hz，8.8 Hz)，7.10 (1H，d，J=2.4 Hz)，7.51 (1H，s)， 7.60 (1H，s)，7·92 (1H，d, J=8.8 Hz)，8·57 (1H，s)，8.66 (1H， d，J=5.4 Hz)。 製造例45 8-3 生二（4-((環丙臉基）羰基）胺基-3-甲某笨氣某&gt;&gt;·7_甲氣某-4 g林#酸 將N-環丙基- N·- [ 2-甲基-4- (6-幾基-7-甲氧基-4-峻淋基） 氧苯基]賊（173 mg，0.3972 mmol)溶於甲酵（3 ml)中，加入 2N氫氧化鈉水溶液（1 ml)，並於60°C加熱攪拌45分鐘。減 -530 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 - A7 ____ B7 五、發明説明（525) 壓餾去溶媒，將析出之結晶再溶於甲醇，在其中加入IN鹽 酸，直至pH為4，然後在其中加入飽和食鹽水。用乙酸乙 酯·四氫呋喃萃取，用飽和食鹽水洗淨，用無水硫酸鎂乾 燥以及將溶媒減壓餾去。將得到之結晶懸浮於丙酮·乙醚 中，濾取結晶及吸引乾燥，得到為褐色結晶之標題化合物 (95 mg ’ 0.2332 mmol，56.80%)。 iH-NMR光譜（DMSO-d6) 5(ppm): 0·42 (2H，m)，〇·66 (2H，m)， 2·25 (3Η，s)，2·57 (1Η，m)，3·51(1Η，br s)，4.05 (3Η，s)，6.84 (1H，d，J=6.8 Hz)，7.12 (1H，br s)，7·16 (1H，dd，J=2.4 Hz， 8.8 Hz)，7.21 (1H，br s)，7.74 (1H，s)，7·92 (1H，s)，8.06 (1H， d，J=8.8 Hz)，8.70 (1H，s)，8·95 (1H，d，J=6.8 Hz)。 實施例4 5 9 N6-(2-甲氧乙基）-4-(4-((環丙胺某）羰基）胺基-3-甲基茉氣 某）-7-甲氣基-6-株藉gj胺 使用4-(4-((環丙胺基）羰基）胺基-3-甲基苯氧基）-7-甲氧 基-6-喹啉羧酸（30 mg，0.0736 mmol)及2-甲氧基乙胺 (0.0123 ml)，進行與實施例458同樣之反應，然後藉由NH 矽凝膠管柱層析（乙酸乙酯：甲醇= 10: 1)精製，將得到之結 晶懸浮於丙酮：乙醚=1 : 5中，濾取，用乙醚洗淨結晶及吸 引乾燥後，得到為淡黃色結晶之標題化合物（17 mg， 0.0366 mmol , 49.73%) ° iH-NMR 光譜（01^3046)5(??111):0.41-0.45(211，111)，0.63-0.69 (2H，m)，2:22 (3H，s)，2.54-2.60 (1H，s)，3·30 (3H，s)， 3.50 (4H，m)，4.04 (3H，s)，6.47 (1H，d，J=5.0 Ηζ)，6·78 (1H， _ - 531 - _ 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 〜 … A7 __ _ B7 五、發明説明（526 ) m)5 7.05 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.12 (1H, d5 J=2.4 Hz), 7.52 (1H, s), 7.63 (1H5 s), 7.94 (1H, d, J=8.4 Hz), 8.45 (1H, br s)，8·63 (1H，s)，8.66 (1H，d，J=5.0 Hz)。 豐施例460 環丙胺某）蕤某）胺基-3-甲其y氣某V7-甲乳基-6 -邊淋瘦酿胺 使用4-(心（（環丙胺基）羰基）胺基-3-曱基苯氧基）-7_曱氧 基-6-喹啉羧酸（3〇 mg，〇·〇736 mmol)及甲氧胺鹽酸鹽 (〇·〇123 ml)進行與實施例458同樣之反應，然後用NH型麥 凝膠層析（乙酸乙酯：曱醇=10 :丨）精製，將得到之結晶懸 浮於乙醇中及用己烷稀釋，濾取，然後用己烷洗淨結晶及 吸引乾燥後，得到為淡黃色結晶之標題化合物（7 mg， 0.0160 mmo卜 21.74%)。 iH-NMR 光譜卩^^0-(16)5(??111):0.40-0.45 (21*1，111)，0.63- 0.68 (2H, m)5 2.21 (3H, s), 2.51 (3H, s), 2.53-2.59 (1H, m), 3.94 (3H，s)，6·46 (1H，d，J=5.0 Hz)，6.79 (1H，s)，7.04 (1H， d, J=8.4 Hz), 7.09 (1H, s), 7.43 (1H, s), 7.63 (1H, s), 7.92 (1H, d5 J=8.4 Hz), 8.04 (1H, s), 8.62 (1H, d, J=5.0 Hz), 9.86 (1H，s)。 實施例461 環丙基-3H-咮唑# f4.5-bl吡啶-4-某）氣茉某卜Ν' (4-氟茉某）服 將2-環丙基-7-(4-胺基苯氧基）-3Η-咪唑并[4,5-b]吡啶 130 mg，異氰酸對氟苯酯0·06 ml，四氫呋喃5 ml及二甲基 _- 532 -____ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 … Λ,. -- ------B7 五、發明説明^ 一'' -- 甲酿胺0.5 ml於室溫下攪摔35分鐘。在反應液中加anh型 石夕凝膠’然後減壓餾去溶媒以使反應生成物吸著於矽凝膠 上。將遠s夕凝膠饋入充填有Nh型矽凝膠之乾燥管柱中，然 後進行管柱精製（乙酸乙酯，繼而乙酸乙酯：甲醇=1〇: 1)。將得到之殘餘物從乙酸乙酯-甲醇-己烷中固體化，得 到為灰色固體之目的物38 mg。 H-NMR (DMSO-d6) 5 (ppm): 1.02-1.12 (4H，m)，2.04-2.14 (1H，m)·，6.34 (0.75H，d，J=5.6 Ηζ)，6·35 (0·25Η，d，J=5.6Hldl cyclopropylamine 棊)) a certain amine -3- benzene gas porphyrin # acid methyl ester using 4.-(4-amino-3-methylphenoxy)-7-methoxymethoxycarbonyl The porphyrin (158 mg, 0.4669 mmol) was subjected to the same procedure as in Production Example 17 to give the phenylamine carbazate, and then, under the same procedure as in Example u, the cyclopropylamine was allowed to act as a light. The title compound (Π3 mg, 0.4105 mmol, 87·92 〇/〇) of brown crystals. iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.40-0.43 (2Η,m) 0 61 0.66 (2H, m), 2.20 (3H, s), 2.52-2.57 (1H, m), 3.85 (3H , s), 3.96 (3H, s), 6.45 (1H, d, J=5.4 Hz), 6.75 (1H, s)5 7.04 〇h! dd, J=2.4 Hz, 8.8 Hz), 7.10 (1H, d , J=2.4 Hz), 7.51 (1H, s), 7.60 (1H, s), 7.92 (1H, d, J = 8.8 Hz), 8.57 (1H, s), 8.66 (1H, d, J = 5.4 Hz). Production Example 45 8-3 Raw bis(4-((cyclopropyl)carbonyl)amino-3-methyl a stupid gas&gt;&gt;·7_A gas a-4 glin#acid N-ring Propyl-N--[2-methyl-4-(6-methyl-7-methoxy-4-yronyl)oxyphenyl] thief (173 mg, 0.3972 mmol) dissolved in formazan (3 In ml), add 2N aqueous sodium hydroxide solution (1 ml) and heat and stir at 60 ° C for 45 minutes. minus -530 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 - A7 ____ B7 V. Inventive Note (525) The solvent is distilled off, the precipitated crystals are redissolved in methanol, and 1% hydrochloric acid is added thereto until the pH is 4, and then saturated brine is added thereto, and extracted with ethyl acetate·tetrahydrofuran. The title compound (95 mg of the title compound) was obtained as a brown crystals. 0.2332 mmol, 56.80%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 0·42 (2H, m), 〇·66 (2H, m), 2·25 (3Η, s), 2· 57 (1Η,m),3·51(1Η,br s),4.05 (3Η,s) , 6.84 (1H, d, J = 6.8 Hz), 7.12 (1H, br s), 7·16 (1H, dd, J = 2.4 Hz, 8.8 Hz), 7.21 (1H, br s), 7.74 (1H, s), 7.92 (1H, s), 8.06 (1H, d, J = 8.8 Hz), 8.70 (1H, s), 8.95 (1H, d, J = 6.8 Hz). Example 4 5 9 N6-(2-methoxyethyl)-4-(4-((cyclopropylamine)carbonyl)amino-3-methyl-methane)-7-methyl--6-strain is used by gjamine 4 -(4-((Cyclopropylamino)carbonyl)amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxylic acid (30 mg, 0.0736 mmol) and 2-methoxy The amine (0.0123 ml) was reacted in the same manner as in Example 458, and then purified by column chromatography (ethyl acetate:methanol = 10:1). The title compound (17 mg, 0.0366 mmol, 49.73%) was obtained as the pale yellow crystals (yield: &lt;RTI ID=0.0&gt; ): 0.41-0.45 (211,111), 0.63-0.69 (2H,m), 2:22 (3H,s), 2.54-2.60 (1H,s),3·30 (3H,s), 3.50 (4H ,m),4.04 (3H,s),6.47 (1H,d,J=5.0 Ηζ),6·78 (1H, _ - 53 1 - _ This paper scale applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) 1304061 ~ ... A7 __ _ B7 V. Invention description (526) m)5 7.05 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.12 (1H, d5 J=2.4 Hz), 7.52 (1H, s), 7.63 (1H5 s), 7.94 (1H, d, J=8.4 Hz), 8.45 (1H, br s), 8· 63 (1H, s), 8.66 (1H, d, J = 5.0 Hz). Example 460 Cyclopropylamine 蕤 ) ) ) ) ) ) ) ) ) ) 胺 胺 胺 胺 胺 某 某 某 某 某 某 某 某 某 某 某 某 某 某 某 某 某 某 某 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 3-mercaptophenoxy)-7-decyloxy-6-quinolinecarboxylic acid (3 〇mg, 〇·〇 736 mmol) and methoxyamine hydrochloride (〇·〇123 ml) were carried out and examples 458, the same reaction, and then purified by NH-type gel chromatography (ethyl acetate: decyl alcohol = 10: hydrazine), and the obtained crystals were suspended in ethanol and diluted with hexane, filtered, and then washed with hexane. The title compound (7 mg, 0.0160 mmo, 21.74%) was obtained as pale yellow crystals. iH-NMR spectrum 卩^^0-(16)5(??111): 0.40-0.45 (21*1,111), 0.63-0.68 (2H, m)5 2.21 (3H, s), 2.51 (3H, s), 2.53-2.59 (1H, m), 3.94 (3H, s), 6.46 (1H, d, J = 5.0 Hz), 6.79 (1H, s), 7.04 (1H, d, J = 8.4 Hz) ), 7.09 (1H, s), 7.43 (1H, s), 7.63 (1H, s), 7.92 (1H, d5 J=8.4 Hz), 8.04 (1H, s), 8.62 (1H, d, J=5.0 Hz), 9.86 (1H, s). Example 461 cyclopropyl-3H-carbazole #f4.5-blpyridine-4-() 气莫某卜Ν' (4-fluoromosa) serving 2-cyclopropyl-7-(4-amine Phenyloxy)-3Η-imidazo[4,5-b]pyridine 130 mg, p-fluorophenyl isocyanate 0.06 ml, tetrahydrofuran 5 ml and dimethyl_- 532 -____ This paper size applies to China National Standard (CNS) A4 Specification (210 X 297 mm) 1304061 ... Λ,. -- ------B7 V. Description of the Invention ^ One'' -- A brewing amine 0.5 ml is stirred at room temperature 35 minute. Anh-type gelatin gel was added to the reaction solution, and then the solvent was distilled off under reduced pressure to adsorb the reaction product onto the ruthenium gel. The far-day gel was fed into a dry column packed with a Nh-type ruthenium gel, and then subjected to column purification (ethyl acetate, followed by ethyl acetate:methanol = 1 〇: 1). The residue obtained was solidified from ethyl acetate-methanol-hexane toieldield, H-NMR (DMSO-d6) 5 (ppm): 1.02-1.12 (4H, m), 2.04-2.14 (1H, m)·, 6.34 (0.75H, d, J = 5.6 Ηζ), 6.35 (0) ·25Η, d, J=5.6

Hz), 7.05-7.18 (4H, m), 7.40-7.55 (4H, m), 7.98 (0.75H, d, J=5.6 Hz), 8.07 (0.25H, d, J=5.6 Hz), 8.69 (0.75H, s)5 8.70 (0.25H，s)，8·73 (0.75H，s)，8.76 (0.25H，s)。 如下述得到原料。 製造例461- 1 里-丙基-7-(心胺某I氣某）_ 3H-咪唑并「4.5- bl毗诠 將4-氯-2-硝基胺基吡啶9.3 g每次以少許量加至濃硫酸6〇 ml中。加入終了後立刻除去冷浴並於室溫攪拌2 5小時。將 反應溶液展開在冰上，加入濃氨水以使pH值成為5。濾取析 出之固體’於60。(：風乾，得到黃色之固體11·2 g。將如此得 到之固體11.2 g加至對硝基酚ι〇·8 g，修尼鹼17瓜丨及^甲 基-2-吡咯啶酮34 ml之混合物中並於120 °C加熱授摔3小 時。回到室溫後加入水50 ml，以及;慮取析出之固體。於6〇 C風乾仔到4·77 g固體。將該固體4.77 g溶於四氫啥喃1〇〇 ml，加入鈀/碳(Pd-C(10%，濕重））2·0 g並於常壓下還原24 小時。濾去Pd-C後，減壓餾去溶媒，得到為紅褐色油狀物 -533 - 本紙張尺度適用中國國家標準(CMS) A4規格(210 X 297公釐) 1304061 〜 -- AT ' . _ ____ B7 五、發明説明（528 ) 5·2 g。將該油狀物5.2 g加至環丙烷羧酸4.6 g與磷酸5〇⑴丨之 混合物中並於1 60 C加熱攪掉5小時。將反應溶液展開在冰 上’加入5N氫氧化鋼水溶液及中和，然後用乙酸乙酯萃 取。將萃取液用硫酸鎂乾燥，繼而減壓餾去溶媒。將得到 之殘餘物用NH型矽凝膠（氯仿：甲醇=1〇:丨）精製。減壓餘 去溶媒，將得到之殘餘物溶於少量乙酸乙酯中及放置，濾 取析出之固體’得到為目的物之黑紫色固體13〇 mg。 ^-NMR (DMSO-d6) (5 (ppm)； i.〇〇.L12 (4H? m), 2.05-2.14 (1H，m)，5.08 (2H，bs)，6.23 (1H，d，J=5.6 Hz), 6.61 (2H, d， J=8.8 Hz), 6.83 (1.5H, d, J=8.8 Hz), 6.90 (0.5H, d, J=8.8 Hz), 7.92 (0·75Η，d，J=5.6 Hz)，8.01 (〇.25H，d，J=5.6 Hz)，12.75 (0.75H，s)，12.85 (0.25H，s) 〇 實施例462 (2-環丁燒幾胺某· 基）氫笨基1 - N，- Γ 4-氯茇甚&gt;&gt; m 在N-[4-(2-胺基吡啶基）氧苯，“心氟苯基）脲1〇〇 mg，三乙胺〇·12 ml及四氫呋喃1〇 mi於室溫攪拌之溶液中， 加入環丁烷羰基氯70 mg並攪拌15分鐘。在反應溶液中加入 NH型矽凝膠，減壓餾去溶媒，以使反應生成物吸著於矽凝 膠上。將該矽凝膠饋入充填有NH型矽凝膠之乾燥管柱中， 然後進行管柱精製（氯仿··甲醇=4〇 ··丨）。將得到之殘餘物 從乙酸乙酯-甲醇-己烷中固體化，得到為白色固體之目的 物 64 mg 〇 (H-NMR (DMSO-d6) 5 (ppm): 1.68-1,78 (1H，m)，1·80·1·92 l紙張尺度適财S S家鮮(CNSTX^(⑽χ 297公#) 1304061 〜 ' - A7 j__—___B7 五、發明説明（529 ) (1H, m), 1.95-2.18 (4H, m), 3.24-3.34 (4H, m), 6.63 (1H, dd, J=5.6 Hz, J-2.4 Hz), 7.05-7.15 (4H5 m)r 7.42-7.49 (2H, m), 7.52 (2H, d, J=8.8 Hz), 7.66 (1H, d, J=2.4 Hz)5 8.13 (1H, d, j=5.6 Hz)，8.71 (1H，s)，8·77 (1H，s)，10.29 (1H，s)。 如下述得到原料。 遨i告例462-1 2-胺基-4二(4'硝基苽氫某）毗咗 將2-胺基-4-氯吡啶15.88 g，對-硝基酚34.5 g，修尼鹼52 ml及卜甲基-2-吡咯啶酮1〇〇 mis16〇t攪拌15小時。加入 水，用乙酸乙酯萃取及於減壓下餾去溶媒。將得到之殘餘 物以使用NH型矽凝膠之管柱層析（己烷··乙酸乙酯=1 : u 精製，得到為淡黃色固體之目的物3.24g。 ^-NMR (DMSO-d6) 5 (ppm): 6.04 (1H, d, J=2.4 Hz), 6.12 (2H, br s), 6.26 (1H, dd, J=6.0 Hz, J=2.4 Hz), 7.32 (2H, d5 J=8.8 Hz)，7·92 (1H，d，J=6.0 Hz)，8.31 (2H, d, J=8.8 Hz)。 製造例462-2 2二胺基-4- (4-胺基茉氫某、毗θ 將2-胺基-4-( 4-硝基苯氧基）吡啶1 g加至鐵粉2.0 g，氯化 銨4.0 g，乙醇30 ml，二甲基甲醯胺30 ml及水15 ml之混合 物中，以及於1 〇〇°C劇烈攪拌1 〇分鐘。將反應液經矽藻土過 濾，減壓餾去溶媒，得到為固體之目的物0.53 g。 ^-NMR (DMSO-d6) δ (ppm): 5.04 (2H, bs), 5.72 (1H, d3 J=1.6 Hz)； 5.81(2H, br s), 6.05 (1H, dd, J=5.6 Hz, J=1.6 H2), 6.57 (2H, d, J=8.8 Hz), 6.75 (2H, d, J=8.8 Hz), 7.70 (1H, d, _ - 535 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 x 297公釐) ： · 1304061Hz), 7.05-7.18 (4H, m), 7.40-7.55 (4H, m), 7.98 (0.75H, d, J=5.6 Hz), 8.07 (0.25H, d, J=5.6 Hz), 8.69 (0.75 H, s) 5 8.70 (0.25H, s), 8.73 (0.75H, s), 8.76 (0.25H, s). The raw materials were obtained as follows. Production Example 461-1 里-propyl-7-(Heartamine A gas) _ 3H-imidazole and "4.5- bl contiguous 4-chloro-2-nitroaminopyridine 9.3 g each time in a small amount Add to 6 〇ml of concentrated sulfuric acid. Immediately after the end of the addition, remove the cold bath and stir at room temperature for 25 hours. The reaction solution is spread on ice, and concentrated ammonia is added to bring the pH to 5. The precipitated solid is filtered. 60. (: air-dried to obtain a yellow solid 11.2 g. 11.2 g of the solid thus obtained was added to p-nitrophenol oxime · 8 g, nicotinic base 17 melon and ^ methyl-2-pyrrolidone In a mixture of 34 ml and heated at 120 °C for 3 hours, return to room temperature, add 50 ml of water, and; take out the precipitated solids. Air dry at 6 ° C to 4.77 g solids. 4.77 g was dissolved in 1 〇〇ml of tetrahydrofuran, and palladium/carbon (Pd-C (10%, wet weight)) 2·0 g was added and reduced under normal pressure for 24 hours. After filtering off Pd-C, subtract Distillation to the solvent to obtain a reddish brown oil -533 - This paper scale applies to the Chinese National Standard (CMS) A4 specification (210 X 297 mm) 1304061 ~ -- AT ' . _ ____ B7 V. Description of invention (528 ) 5·2 g. Add 5.2 g of this oil to cyclopropane The mixture of 4.6 g of carboxylic acid and 5 ruthenium (1) ruthenium phosphate was stirred and heated at 1600 C for 5 hours. The reaction solution was developed on ice and added to a 5N aqueous solution of hydrogen hydroxide and neutralized, and then extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was purified eluting with EtOAc ( chloroform:methanol = hexane: hexane). A small amount of ethyl acetate was placed and placed, and the precipitated solid was collected by filtration to give the desired product as a dark purple solid 13 </ RTI> </ RTI> NMR (DMSO-d6) (5 (ppm); i. 〇〇.L12 (4H? m ), 2.05-2.14 (1H,m),5.08 (2H,bs),6.23 (1H,d,J=5.6 Hz), 6.61 (2H, d, J=8.8 Hz), 6.83 (1.5H, d, J =8.8 Hz), 6.90 (0.5H, d, J=8.8 Hz), 7.92 (0·75Η, d, J=5.6 Hz), 8.01 (〇.25H, d, J=5.6 Hz), 12.75 (0.75H) , s), 12.85 (0.25H, s) 〇 Example 462 (2-cyclobutanthineamine)-hydrogen stupyl 1 - N,- Γ 4-chloroindole &gt;&gt; m in N-[ 4-(2-Aminopyridyl)oxybenzene, "heart fluorophenyl" urea 1 〇〇 mg, triethylamine 〇 · 12 ml and tetrahydrofuran 1 〇mi dissolved at room temperature To the solution, 70 mg of cyclobutanecarbonyl chloride was added and stirred for 15 minutes. An NH type hydrazine gel was added to the reaction solution, and the solvent was distilled off under reduced pressure to cause the reaction product to be adsorbed on the ruthenium gel. The ruthenium gel was fed into a drying column packed with an NH type ruthenium gel, and then subjected to column purification (chloroform·methanol = 4 〇 ··丨). The residue obtained was solidified from ethyl acetate-methanol-hexane (hexanes: hexanes: hexanes: m),1·80·1·92 l paper scale suitable for wealth SS fresh (CNSTX^((10)χ 297 public#) 1304061 ~ ' - A7 j______B7 V. Description of invention (529 ) (1H, m), 1.95- 2.18 (4H, m), 3.24-3.34 (4H, m), 6.63 (1H, dd, J=5.6 Hz, J-2.4 Hz), 7.05-7.15 (4H5 m)r 7.42-7.49 (2H, m), 7.52 (2H, d, J=8.8 Hz), 7.66 (1H, d, J=2.4 Hz)5 8.13 (1H, d, j=5.6 Hz), 8.71 (1H, s), 8.77 (1H, s ), 10.29 (1H, s). The starting material is obtained as follows. 遨i 例例462-1 2-Amino-4 bis(4'nitroindole hydrogen) 咗 咗 2-amino-4-chloropyridine 15.88 g, p-nitrophenol 34.5 g, sulphonic acid 52 ml and benzyl-2-pyrrolidone 1 〇〇mis16 〇t were stirred for 15 hours, water was added, extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue obtained was purified by column chromatography (hexane··········· 5 (ppm): 6.04 (1H, d, J=2.4 Hz), 6.12 (2H, br s), 6.26 (1H, dd, J=6.0 Hz, J=2.4 Hz), 7.32 (2H, d5 J=8.8 Hz), 7.92 (1H, d, J=6.0 Hz), 8.31 (2H, d, J = 8.8 Hz). Production Example 462-2 2Diamino-4-(4-aminomethylhydrogen, θ θ 2-amino-4-(4-nitrophenoxy) 1 g of pyridine was added to a mixture of 2.0 g of iron powder, 4.0 g of ammonium chloride, 30 ml of ethanol, 30 ml of dimethylformamide and 15 ml of water, and vigorously stirred at 1 ° C for 1 Torr. The reaction mixture was filtered through EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj =1.6 Hz); 5.81(2H, br s), 6.05 (1H, dd, J=5.6 Hz, J=1.6 H2), 6.57 (2H, d, J=8.8 Hz), 6.75 (2H, d, J= 8.8 Hz), 7.70 (1H, d, _ - 535 - This paper size applies to Chinese National Standard (CNS) A4 size (210 x 297 mm): · 1304061

J=5.6 Hz)。 £..jt .^1462^ 氣笨基卜Ν’&quot;4-氣茉某 將2-胺基·4-(4_胺基苯氧基）吡啶0.53 g溶於四氫咬喃2〇 ml及二甲基甲醯胺1〇 ml之混合溶媒中，然後於室溫下加入 異氰酸對-氟苯酯〇·36 ml並攪拌丨小時。在反應溶液中加入 NH 土碎&amp;疋膠，減壓餘去溶媒，以使反應生成物吸著於碎凝 膠上。鮮該矽凝膠饋入充填有NH型矽凝膠之乾燥管柱中， 然後進行管柱精製（氯仿：甲醇=20 : 1，繼而1〇 :丨）。減壓 館去溶媒，得到為白色粉末之目的物61〇 mg。 ^-NMR (DMSO-d6)(5(ppm)： 5.78 (1H, s), 5.87 (1H3 s), 5.89 (1H，s)，6·09-6·13 (1H，m)，7.00-7.15 (4H，m)，7·42-7·52 (4H， m), 7.77 (1H, dd, J=6.0 Hz, J=1.6 Hz), 8.69 (1H, s), 8.73 (1H, s) o 進行與實施例462同樣之操作，合成以下之檢體。 貫施例463 ΚιΙ·4-(2· 丁鵰胺棊吡啶·4·基）氲茉基l-N’-M-氣y.某）服— H-NMR (DMSO-d6) 5 (ppm): 0·85 (3H，t，J=7.2 Hz) 1 52 (2H，tq，J=7.2 Hz，J=7.2 Hz)，2.30 (2H，t，J=7.2 Hz)，6·63 (1H, dd, J=5.6 Hz, J=2.0 Hz), 7.06-7.16 (4H, m), 7.42-7.50 (2H，m)，7.52 (2H，d，J=8.8 Hz)，7·65 (1H，d，J=2.0 Hz)，8.14 (1H，d，J=5.6 Hz)，8·72 (1H，s)，8·77 (1H，s)，10.45 (1H，。 實施例464 * 土丄4- f 2-(4-乙氧魏某丁酿基）胺某tz比咬-4-某1氧笨某丨_ ]sj&gt; - -536 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 五、發明説明（ 531 A7 B7J = 5.6 Hz). £..jt .^1462^ 笨笨基卜Ν'&quot;4-气茉一2-Amino 4-(4-aminophenoxy)pyridine 0.53 g dissolved in tetrahydroethylene 2 〇ml And a mixed solvent of dimethylformamide 1 〇 ml, then 36 ml of p-fluorophenyl phthalate is added at room temperature and stirred for a few hours. NH soil crushing &amp; gum was added to the reaction solution, and the solvent was removed under reduced pressure to cause the reaction product to be adsorbed on the gel. Freshly, the ruthenium gel was fed into a drying column packed with an NH type ruthenium gel, and then subjected to column purification (chloroform: methanol = 20: 1, and then 1 〇: 丨). The solvent was decompressed to obtain a target of 61 〇 mg as a white powder. ^-NMR (DMSO-d6) (5 (ppm): 5.78 (1H, s), 5.87 (1H3 s), 5.89 (1H, s), 6·09-6·13 (1H, m), 7.00-7.15 (4H,m),7·42-7·52 (4H, m), 7.77 (1H, dd, J=6.0 Hz, J=1.6 Hz), 8.69 (1H, s), 8.73 (1H, s) o The same procedure as in Example 462 was carried out to synthesize the following samples. Example 463 ΚιΙ·4-(2·丁丁胺棊pyridine·4·yl)氲茉基l-N'-M-qi y. ) - H-NMR (DMSO-d6) 5 (ppm): 0·85 (3H, t, J = 7.2 Hz) 1 52 (2H, tq, J = 7.2 Hz, J = 7.2 Hz), 2.30 (2H ,t,J=7.2 Hz),6·63 (1H, dd, J=5.6 Hz, J=2.0 Hz), 7.06-7.16 (4H, m), 7.42-7.50 (2H,m),7.52 (2H, d, J = 8.8 Hz), 7·65 (1H, d, J = 2.0 Hz), 8.14 (1H, d, J = 5.6 Hz), 8.72 (1H, s), 8.77 (1H, s ), 10.45 (1H,. Example 464 * Bandit 4-f 2-(4-Ethoxydibutyryl)amine A certain tz than bite-4- some 1 oxygen stupid _]sj&gt; - -536 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 V. Description of the invention ( 531 A7 B7

(4-乱苯基）牌 iH-NMR (DMSO-d6) 5 (ppm): 1·14 (3H，t，J=7.2 Hz) 1 74 (2H, tt, J—7.2 Hz, J—7.2 Hz), 2.26 (2H, t, J=7.2 Hz) 2 35 (2H3 t, J=7.2 Hz)5 4.01 (2H, q, j=7.2 Hz), 6.62 (1H, dd J=6.0 Hz，J=2.4 Hz)，7.05-7.14 (4H，m)，7·41-7·49 (2H m)’ 7·51 (2H，d，J=8.8 Hz)，7.62 (1H，d，J=2.4 Hz)，8·14 (ih d J=6.0 Hz)，8·70 (1H，s)，8·76 (1H，s)。 ’ ’ 實施例465 以_二丄心（2'於鹼醯胺基ϋ -心基）氧笨某1- N，- (4_蠢苯葚 lH-NMR (DMSO-d6) 5 (ppm): 6.75 (1H, dd5 J=5.6 Hz J=2 4 Hz)5 7.06-7.18 (4H, m), 7.42-7,58 (5H, m), 7.75 (1H, 2.4 Hz) 8·22 (2H，m)，8.72 (2H，br s)，8·78 (1H，s)，9·〇6 (1H s)。 實施例466 Ν'丨4- f 2-(4- #基丁醯基）胺基吡啶-4-基1氧笨甚丨·(j· 氟笨基）脲 將N-{4-[2-(4-乙氧談基丁酿基）胺基p比咬-4-基]氧苯 基卜Ν，-(4-氟苯基）腺22 mg，2N氫氧化銷水溶液1 mi，甲 醇2 ml及二甲基甲醯胺1 ml於80 °C攪拌20分鐘。回到室溫 後，加入5N鹽酸水溶液0.4 ml，濾取析出之固體，得到為 白色固體之目的物16 mg。 lH-NMR (DMSO-d6) (5 (ppm): 1.72 (2H, tt, J=7.2 Hz, J=7.2 Hz), 2.20 (2H, t, J=7.2 Hz), 2.36 (2H, t, J=7.2 Hz), 6.62 (1H, dd, J=6.0 Hz, J=2.0 Hz), 7.05-7.15 (4H, m)5 7.41-7.49 (2H, m), 7.52 (2H, d, J=8.8 Hz), 7.63 (1H, d, J=2.0 Hz), 8.14 (1H, 537 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 x 297公釐）(4- disordered phenyl) brand iH-NMR (DMSO-d6) 5 (ppm): 1·14 (3H, t, J = 7.2 Hz) 1 74 (2H, tt, J-7.2 Hz, J-7.2 Hz ), 2.26 (2H, t, J=7.2 Hz) 2 35 (2H3 t, J=7.2 Hz) 5 4.01 (2H, q, j=7.2 Hz), 6.62 (1H, dd J=6.0 Hz, J=2.4 Hz),7.05-7.14 (4H,m),7·41-7·49 (2H m)' 7·51 (2H,d,J=8.8 Hz), 7.62 (1H,d,J=2.4 Hz), 8·14 (ih d J=6.0 Hz), 8·70 (1H, s), 8.76 (1H, s). Example 465 _二丄心(2' in the base 醯 ϋ ϋ - 心 )) oxy azo 1 - N, - (4 _ benzoquinone lH-NMR (DMSO-d6) 5 (ppm): 6.75 (1H, dd5 J=5.6 Hz J=2 4 Hz)5 7.06-7.18 (4H, m), 7.42-7,58 (5H, m), 7.75 (1H, 2.4 Hz) 8·22 (2H,m ), 8.72 (2H, br s), 8 · 78 (1H, s), 9 · 〇 6 (1H s). Example 466 Ν '丨 4- f 2-(4- #基丁醯基) Aminopyridine - 4-yl 1 oxo 丨 丨 · (j· fluoro phenyl) urea N-{4-[2-(4-ethoxyxyl aryl) amino group p is more than -4-yl] oxyphenyl Dicholine, -(4-fluorophenyl) gland 22 mg, 2N aqueous solution of hydrogen peroxide 1 mi, 2 ml of methanol and 1 ml of dimethylformamide were stirred at 80 ° C for 20 minutes. After returning to room temperature, add 0.4 ml of a 5N aqueous solution of hydrochloric acid, and the precipitated solid was collected by filtration to afford 16 mg as a white solid. lH-NMR (DMSO-d6) (5 (ppm): 1.72 (2H, tt, J=7.2 Hz, J=7.2 Hz), 2.20 (2H, t, J=7.2 Hz), 2.36 (2H, t, J=7.2 Hz), 6.62 (1H, dd, J=6.0 Hz, J=2.0 Hz), 7.05-7.15 (4H, m)5 7.41-7.49 (2H, m), 7.52 (2H, d, J=8.8 Hz), 7.63 (1H, d, J=2.0 Hz), 8.14 (1H, 537 - This paper scale applies to Chinese national standards ( CNS) A4 Specifications 210 x 297 mm)

訂Order

絲 1304061 A7 B7 五、發明説明（ 532&gt; d5 J=6.0 Hz), 8.71 (1H, s), 8.76 (1H, s)3 10.46 (1H, s), 12.03(1H，s) 〇 實施例467N- f (盘丙曱基）胺羧基p比咬-4_某}氣茉某）·Ν，* (心氣笨基）脲 將4-(4-胺基苯氧基）_2-[(環丙基曱基）胺羰基]吡啶ι〇〇 mg溶於四氫呋喃5 nd，然後於室溫下加入異氰酸對-氟苯酯 0·075 ml並授拌1小時。在反應溶液中加入nh型矽凝膠，減 壓餾去溶媒，以使反應生成物吸著於矽凝膠上。將該矽凝 膠饋入充填有NH型矽凝膠之乾燥管柱中，然後進行管柱精 製（己烷：乙酸乙酯=1: 1，繼而乙酸乙酯，繼而乙酸乙 酯：甲醇=10 : 1)。減壓餾去溶媒，在殘餘物中加入乙酸乙 酯及己烷以及濾取析出之固體，得到為淡黃色粉末之目的 物 25 mg。 lH-NMR (DMSO-d6) 5 (ppm): 0.21 (2H, bs), 0.38 (2H, bs), 1·02 (1H，bs)，3.12 (2H，dd，J=6.0 Hz，6.0 Hz)，7·07-7·21 (5H, m), 7.37 (1H, s), 7.43-7.51 (2H, m), 7.56 (2H, d, J=8.0Hz)，8.49 (1H，d，J=5.2 Hz)，8·74 (1H，s)，8·81 (1H，s)，8.83 (1H，t，J=6.0 Hz)。 如下述得到原料。 製造例4 6 7 - 1 4-氣-2-「（環丙甲基）胺羰某Ub啶 將4-氯」2-羧基吡啶2.0 g，（胺甲基）環丙烷鹽酸鹽1.7 g， 1-乙基-3-( 3-二乙胺丙基）碳化二亞胺鹽酸鹽（WSC) 2.9 g , -538 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐） 裝 訂Wire 1304061 A7 B7 V. Description of the invention ( 532 &gt; d5 J = 6.0 Hz), 8.71 (1H, s), 8.76 (1H, s) 3 10.46 (1H, s), 12.03 (1H, s) 〇 Example 467N- f (Phenyl propyl) amine carboxyl p than bite - 4 _ a certain gas 某 ) Ν * * * * * * 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- The mercapto)aminocarbonyl]pyridinium oxime mg was dissolved in tetrahydrofuran 5 nd, then p-fluorophenyl isocyanate 0.075 ml was added at room temperature and allowed to stir for 1 hour. An nh-type ruthenium gel was added to the reaction solution, and the solvent was distilled off under reduced pressure to cause the reaction product to be adsorbed on the ruthenium gel. The ruthenium gel was fed into a dry column packed with NH-type ruthenium gel, and then subjected to column purification (hexane: ethyl acetate = 1: 1, followed by ethyl acetate, then ethyl acetate: methanol = 10) : 1). The solvent was distilled off under reduced pressure, and ethyl acetate and hexane were added to the residue, and the precipitated solid was collected by filtration to afford 25 mg as a pale yellow powder. lH-NMR (DMSO-d6) 5 (ppm): 0.21 (2H, bs), 0.38 (2H, bs), 1·02 (1H, bs), 3.12 (2H, dd, J = 6.0 Hz, 6.0 Hz) ,7·07-7·21 (5H, m), 7.37 (1H, s), 7.43-7.51 (2H, m), 7.56 (2H, d, J=8.0Hz), 8.49 (1H, d, J= 5.2 Hz), 8.74 (1H, s), 8·81 (1H, s), 8.83 (1H, t, J = 6.0 Hz). The raw materials were obtained as follows. Production Example 4 6 7 - 1 4-gas-2-"(cyclopropylmethyl)amine carbonyl A Ub pyridine 2.0 g of 4-chloro"2-carboxypyridine, (aminomethyl)cyclopropane hydrochloride 1.7 g, 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride (WSC) 2.9 g , -538 This paper size applies to Chinese National Standard (CNS) A4 size (210x 297 mm) Binding

線 1304061五、發明説明（ A7 B7 1-經基苯并三唑（Η〇Β〇2·3 g，三乙胺2.1 ml及四氫呋喃30 ml於里溫攪拌2小時。加入水及用乙酸乙酯萃取，繼而將矽 凝膠加至萃取液中及減壓館去溶媒。將該碎凝膠饋入充填 有碎4膠之乾燥管柱中，然後藉由管柱層析（己燒：乙酸乙 醋=4 : 1，繼而2 ·· 1}精製。得到為黃色油狀物之目的物h5 g ° W-NMR (DMS〇-d6) 5 (ppm): 0.19-0.30 (2H，m)，0.36-0.43 (2H，m)，0·99-1·09 (1H，m)，3.15 (2H，dd，J=6.4 Hz, J=6.4 Hz)，7·75 (1H，d，J=5.6 Hz), 8·01 (1H，s)，8.62 (1H，d，J=5.6Hz), 8.90 (1H，t，J=6.4 Hz)。 製造例467-2 _L(環一丙甲U胺羰基1 - 4 - ( 4 -硝某笨氣某、毗# 將4-氣-2-[(環丙甲基）胺羧基]峨咬ι·5 g，對-硝基紛2 〇 g，修尼鹼3·1 ml及1-曱基-2-吡咯啶酮6·2 1111於160它攪拌3 小時。加入水，用乙酸乙酯萃取及於減壓下餾去溶媒。將 得到之殘餘物以使用NH型矽凝膠之管柱層析（己烷：乙酸 乙酯=4 ·· 1，繼而2 : 1)精製，得到為無色油狀物之目的物 0·35 g 〇h-NMR (DMSO-d6)5(ppm): 0·19-0·24 (2H，m)，0·36·〇·41 (2H, τη), 1.02 (1Η, bs), 3.13 (2H, dd, J=6.4 Hz, 1-6.4 Hz) 7.34 (1H, dd, 1=5.6 Hz, J=1.6 Hz), 7.44 (2H, d, J=8.8 Hz), 7·55 (1H，d，J=1.6 Hz), 8·33 (2H，d, J=8.8 Hz)，8.61 (1H, d J=5.6 Hz): 8·90 (1H，t，J=6.4 Hz)。 ’ 製造例467-3 -539 -Line 1304061 V. Description of the invention (A7 B7 1-p-benzotriazole (Η〇Β〇2·3 g, triethylamine 2.1 ml and tetrahydrofuran 30 ml stirred at room temperature for 2 hours. Add water and ethyl acetate) Extraction, and then adding the ruthenium gel to the extract and the decompression chamber to remove the solvent. The crushed gel is fed into a dry column packed with crushed 4 glue, and then subjected to column chromatography (hexane: acetic acid B) Vinegar = 4: 1, and then 2 ·· 1} refined. Obtained the object as a yellow oil. h5 g ° W-NMR (DMS 〇-d6) 5 (ppm): 0.19-0.30 (2H, m), 0.36 -0.43 (2H,m),0·99-1·09 (1H,m),3.15 (2H,dd,J=6.4 Hz, J=6.4 Hz),7·75 (1H,d,J=5.6 Hz ), 8·01 (1H, s), 8.62 (1H, d, J = 5.6 Hz), 8.90 (1H, t, J = 6.4 Hz). Production Example 467-2 _L (cyclo-propenyl U-amine carbonyl 1 - 4 - ( 4 -Nitrate a stupid gas, V. # 4- 4-(2-cyclopropanylmethyl)amine carboxyl group] ι·5 g, p-nitro group 2 〇g, sulphine 3·1 ml and 1-mercapto-2-pyrrolidone 6·2 1111 were stirred for 3 hours at 160. Water was added, extracted with ethyl acetate and the solvent was evaporated under reduced pressure. Column layer of NH type gel The product was purified by chromatography (hexane: ethyl acetate = 4··1, and then 2:1) to give the desired product as a colorless oil: 0·35 g 〇h-NMR (DMSO-d6) 5 (ppm): 0· 19-0·24 (2H,m),0·36·〇·41 (2H, τη), 1.02 (1Η, bs), 3.13 (2H, dd, J=6.4 Hz, 1-6.4 Hz) 7.34 (1H , dd, 1=5.6 Hz, J=1.6 Hz), 7.44 (2H, d, J=8.8 Hz), 7·55 (1H, d, J=1.6 Hz), 8·33 (2H,d, J= 8.8 Hz), 8.61 (1H, d J=5.6 Hz): 8·90 (1H, t, J=6.4 Hz). ' Manufacturing Example 467-3 -539 -

裝 訂 線 1304061 A7 B7 534少 五、發明説明（ 胺基苯氧基）-2vLL^^基）胺諾某Ufck冷 將2-[(環丙甲基）胺羰基卜4-(4-硝基苯氧基)吡啶〇35 g加 至鐵粉0.7g，氯化銨1.4g,乙醇1〇ml，二曱基甲醯胺1〇1111 及水5 ml之混合物中，於1〇(rc劇烈攪拌2〇分鐘。將反應液 經矽藻土過濾，減壓餾去溶媒，得到為淡褐色油狀物之目 的物0:37 g。 ^-NMR (DMSO-d6) 5 (ppm): 0.20-0.30 (2H, m), 0.38-0.44 (2H, m)5 0.99-1.10 (1H, m)5 3.13 (2H, dd5 J=6.4 Hz, J=6.4 Hz), 5.14-5.19 (2H, m), 6.65 (2H, d5 J=8.8 Hz), 6.87 (2H, d, J-8.8 Hz)，7.10 (1H，dd，J=5.6 Hz，J=2.8 Hz)，7·35 (1H，d， J=2.8 Hz), 8.47 (1H, d, J=5.6 Hz), 8.81 (1H, t, J=6.4 Hz) 〇 實施例468 K 4-「2'·(丁醯胺基）吡啶-4-基1氲茇甚n，-環石日早） 將N-{4-[2-(丁醯胺基）吡啶基]氧苯基}胺基甲酸苯酯 〇·116 g，環丙胺0.034 g，三乙胺0·041 ml及四氫呋喃1〇 — 在封管中於ioo°c加熱1小時。在反應溶液中加ANH型矽凝 膠’減壓餾去溶媒，以使反應生成物吸著於矽凝膠上。將 該矽凝膠饋入充填有NH型矽凝膠之乾燥管柱中，然後進行 管柱精製（乙酸乙酯）。減壓餾去溶媒，在殘餘物中加入t 酸乙酯-己烷中以及濾取析出之固體，得到為白色固體之目 的物20 mg。 1H-NMR (DMS〇-d6) 5 (ppm): 0·38-0·45 (2H，m)，〇 61-〇 67 (2Η，m)，.0.86 (3Η，t，J=7.2 Ηζ)，1·54 (2Η，tq，J=7.2 Ηζ J=7.2 Hz)，2.31 (2H，t，J=7.2 Hz)，2.48-2.58 (1H，m)，6 42’ -540 -Gutter 1304061 A7 B7 534 less five, invention description (aminophenoxy)-2vLL ^ base) amino acid Ufck cold 2-[(cyclopropylmethyl)amine carbonyl b 4- (4-nitrobenzene 35 g of oxy)pyridinium was added to a mixture of iron powder 0.7 g, ammonium chloride 1.4 g, ethanol 1 〇 ml, dimercaptocaramine 1 1111 and water 5 ml at 1 〇 (rc vigorously stirred 2 The reaction mixture was filtered through celite, and the solvent was evaporated. 2H, m), 0.38-0.44 (2H, m)5 0.99-1.10 (1H, m)5 3.13 (2H, dd5 J=6.4 Hz, J=6.4 Hz), 5.14-5.19 (2H, m), 6.65 ( 2H, d5 J=8.8 Hz), 6.87 (2H, d, J-8.8 Hz), 7.10 (1H, dd, J=5.6 Hz, J=2.8 Hz), 7·35 (1H, d, J=2.8 Hz) ), 8.47 (1H, d, J = 5.6 Hz), 8.81 (1H, t, J = 6.4 Hz) 〇 Example 468 K 4-"2'·(Budecylamino)pyridin-4-yl 1氲茇Even n,- ring stone early morning) N-{4-[2-(butyryl)pyridyl]oxyphenyl} phenyl carbamate 〇·116 g, cyclopropylamine 0.034 g, triethylamine 0 · 041 ml and tetrahydrofuran 1 〇 - heated in a sealed tube at ioo ° C for 1 hour. Add A to the reaction solution. The NH type ruthenium gel 'reduced the solvent under reduced pressure so that the reaction product is adsorbed on the ruthenium gel. The ruthenium gel is fed into a dry column packed with an NH type ruthenium gel, and then the column is refined. (Ethyl acetate). The solvent was evaporated under reduced pressure, and ethyl acetate-hexane (hexane) was evaporated. 5 (ppm): 0·38-0·45 (2H,m), 〇61-〇67 (2Η,m),.0.86 (3Η,t,J=7.2 Ηζ),1·54 (2Η,tq , J=7.2 Ηζ J=7.2 Hz), 2.31 (2H, t, J=7.2 Hz), 2.48-2.58 (1H, m), 6 42' -540 -

1304061 〜 -- A7 ________ B7 五、發明説明（535) (1H, s), 6.62 (1H, dd, J=5.6 Hz, J=2.0 Hz), 7.05 (2H, d, j-8.8 Hz)3 7.49 (2H, d, J=8.8 Hz), 7.64 (1H? d, J=2.0 Hz), 8.15 (1H，d，J=5.6 Hz)，8.41 (1H，s)，10·82 (1H，s)。 如下述得到原料。 Μ 468- 1 2-二n驢胺·羞-4- 肖基茉氧甚、毗畦 在2-胺基-4-(4-硝基苯氧基）吡啶L0 g，三乙胺L8 ml及 四氫呋喃20 ml之攪掉溶液中，於室溫下滴入丁醯氯0.93 ml。攪拌1小時後，加入水及用乙酸乙酯萃取，用硫酸鎂乾 燥後減壓餾去溶媒。將殘餘物用矽凝膠層析（己烷：乙酸乙 酯=2 : 1)精製，得到為無·色油狀物之目的物〇 6 g。 ^-NMR (CDC13) 5 (ppm): 0.99 (3H, t, J=7.2 Hz), 1.73 (2H, tq, J=7.2 Hz, J=7.2 Hz), 2.36 (2H, t, J=7.2 Hz), 6.72 (1H, dd5 J=5.6 Hz, 2.4 Hz), 7.21 (2H, d, J=8.8 Hz), 7.95 (1H, d, J=2.41304061 ~ -- A7 ________ B7 V. Description of invention (535) (1H, s), 6.62 (1H, dd, J=5.6 Hz, J=2.0 Hz), 7.05 (2H, d, j-8.8 Hz)3 7.49 (2H, d, J=8.8 Hz), 7.64 (1H? d, J=2.0 Hz), 8.15 (1H, d, J=5.6 Hz), 8.41 (1H, s), 10·82 (1H, s) . The raw materials were obtained as follows. 468 468- 1 2-di-n-amine · shy-4- succinyl methoxy oxy, fluorene in 2-amino-4-(4-nitrophenoxy) pyridine L0 g, triethylamine L8 ml and The solution was stirred up in 20 ml of tetrahydrofuran, and 0.93 ml of butyl chloride was added dropwise at room temperature. After stirring for 1 hour, water was added and extracted with ethyl acetate, and dried over magnesium sulfate. The residue was purified by silica gel chromatography (hexane:ethyl acetate = 2:1) ^-NMR (CDC13) 5 (ppm): 0.99 (3H, t, J = 7.2 Hz), 1.73 (2H, tq, J = 7.2 Hz, J = 7.2 Hz), 2.36 (2H, t, J = 7.2 Hz ), 6.72 (1H, dd5 J=5.6 Hz, 2.4 Hz), 7.21 (2H, d, J=8.8 Hz), 7.95 (1H, d, J=2.4

Hz)，8.22 (1H，d，J=5.6 Hz)，8.25 (1H，br s)，8·30 (2H，d， J=8.8 Hz)。 製造例468-2 4-(4 -胺基冬乳基）-2-( 丁酿胺某）p比淀 將2-丁醯胺基-4-(4-硝基苯氧基”比啶〇.6 g，鐵粉1.2 g， 氯化銨2.8g，乙醇10 ml，二甲基甲醯胺1〇 ml及水5 ml之混 合物於100°C劇烈授拌10分鐘。將反應液經矽藻土過濾，減 壓餘去落媒’繼而在;慮液中加入水及用乙酸乙g旨萃取。用 破酸鎂乾燥，繼而減壓餾去溶媒，得到為淡黃色固體之目 的物0.6 g。 I—-—___- 541 _ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061Hz), 8.22 (1H, d, J = 5.6 Hz), 8.25 (1H, br s), 8·30 (2H, d, J = 8.8 Hz). Production Example 468-2 4-(4-Amino-winter-milyl)-2-(butylamine) p-ratio 2-butylideneamino-4-(4-nitrophenoxy)pyridinium .6 g, iron powder 1.2 g, ammonium chloride 2.8 g, ethanol 10 ml, dimethylformamide 1 〇 ml and water 5 ml mixture were vigorously mixed at 100 ° C for 10 minutes. The soil was filtered, and the residue was removed under reduced pressure. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The mixture was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object as a pale yellow solid. I—————___- 541 _ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061

五、發明説明（ 536&gt; !H-NMR (DMSO-d6)5(ppm): 〇.86 (3H，t，J==7 2 Hz)，} 54 (2H, tq, J=7.2 Hz, J=7.2 Hz), 2.30 (2H, t3 1=7.2 Hz), 5.06- 5·15 (2H，m)，6·56 (1H，dd，J=5.6 Hz，J=2.4 Hz)，6.61 (2H，d， hU Hz)，6.81 (2H，d，J=8.8 Hz)，7·61 (lH，J，风4 Hz)， 8·10 (1H，d，J=5.6 Hz)，10.38 (1H，s)。 奋丨j 4 6 8 - 3 2-.(.丁醯胺基）》比淀-4_基^^^^胺某甲醴茉酯 在4-(4-胺基苯氧基）-2-(丁醯胺基）吡啶〇3 g ,三乙胺 0.14 ml及四氫呋喃10 ml之冰冷攪拌溶液中，滴入氯甲酸苯 醋〇.uml。去除冷浴及於室溫下授拌一夜。在反應溶液中 加入轄膠’減㈣去料，以歧應生成物吸著於碎凝 膠上。將該矽凝膠饋入充填有矽凝膠之乾燥管柱中，然後 進行管柱精製（己烷：乙酸乙酯=2 : i，繼 ’' 潑而1 · 1)。減壓餾 去溶媒，得到為無色固體之目的物。 h-NMR (DMSO_d6)(5(ppm): 〇·δ6 (3H，t，j=7 2 Hz)，iμ (扭，％&gt;7.21^=7.2_，2.31(2心，&gt;72_，66心 6.80 (m’ m)，7」6 (2H，d，J=8.8 Hz)，7 22 7 3i (3h，叫， 7.41-7.48 (2H，m)，7.60 (2H，d，J=8.8 Hz), 7·66 (1H，d，J=2 〇V. Inventive Note ( 536 &gt; !H-NMR (DMSO-d6) 5 (ppm): 〇.86 (3H, t, J==7 2 Hz),} 54 (2H, tq, J=7.2 Hz, J =7.2 Hz), 2.30 (2H, t3 1=7.2 Hz), 5.06- 5·15 (2H, m), 6.56 (1H, dd, J=5.6 Hz, J=2.4 Hz), 6.61 (2H, d, hU Hz), 6.81 (2H, d, J = 8.8 Hz), 7.61 (lH, J, wind 4 Hz), 8·10 (1H, d, J = 5.6 Hz), 10.38 (1H, s ). 丨 丨 j 4 6 8 - 3 2-. (. Butyrylamine) 》Precipitate-4_ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ To the ice-cold stirred solution of 2-(butylammonium)pyridinium 3 g, triethylamine 0.14 ml and tetrahydrofuran 10 ml, chloroformic acid phenylacetate.uml was added dropwise, and the cold bath was removed and mixed overnight at room temperature. Adding the rubber to the reaction solution minus (four) to remove the product from the disintegrating product onto the broken gel. The crucible gel is fed into the drying column filled with the crucible gel, and then the column is refined ( Hexane: ethyl acetate = 2: i, followed by '', and 1·1). The solvent was evaporated to give the title compound as a colorless solid. h-NMR (DMSO_d6) (5 (ppm): 〇·δ6 (3H,t,j=7 2 Hz), iμ (twist, %&gt;7.21^=7.2_, 2.31 (2 hearts, &gt ; 72_, 66 hearts 6.80 (m' m), 7" 6 (2H, d, J = 8.8 Hz), 7 22 7 3i (3h, called, 7.41-7.48 (2H, m), 7.60 (2H, d, J=8.8 Hz), 7·66 (1H,d,J=2 〇

Hz)，8.17 (1H，dd，&gt;5.6 Hz，J=2·。Hz)，丨。72 (ih，’s): i〇 % (1H，s) 〇 實施例469 二甲...胺甲基嘧啶其 氧）本基1-(3 -乳笨基）骑 在1-(3-氟苯基）-3-[4-(6-苯基-7H-吡咯并[2,3_d]嘧啶·* 1304061 A7 B7 五、發明説明（537) 基氧）苯基]月尿50 mg中，加入N，N-二甲基亞甲铵琪化物 (Eschenmoser氏鹽）29.5 mg及二甲基甲酿胺1.5 ml，並於 100 °C揽掉整夜後，加入水，及用乙酸乙醋分液萃取。將有 機層濃縮，減壓乾燥及付諸於NH矽凝膠管柱層析（乙酸乙 酯-甲醇），得到標題化合物20 mg。 MS 光譜（ESI): 497(M+1) 1H-NMR * — :(DMS〇-d6)2.26(6H，s)，3.64(2H，s)，6.73-6·80 (1H，m)，6.85 (1H，s)，7·08-7·58 (10H，m)，8·0〇 (1H，d， J=7.7 Hz), 8.26 (1H, d, J=0.9 Hz), 8.82 (1H, s)5 8.92 (1H, s), 12.54 (1H，b'r s) 〇 實施例470 1- {4二「6- (4-字氣基苯基）-7H- 口比♦并f 2·3_(Π 口密哈-4-某資/μ 2 -乱本基} _ 3 _ ;哀丙月尿 將1- {4-[6-(4_芊氧苯基）-7-(2-三甲矽烷乙氧甲基）-7Η-吡咯并[2,3-d]嘧啶-4-基氧]-2-氯苯基卜3-環丙脲38 mg溶 於0.8 ml四氫呋喃中，然後滴下四丁銨氟化物（四氫呋喃1 Μ溶液）0.2 ml並回流2小時。回到室溫後，加入水，用乙酸 乙酯-四氫呋喃分液萃取。將有機層用水及飽和食鹽水洗 淨，濃縮及減壓乾燥，得到標題化合物26 mg。 iH-NMR光譜：（DMSO-d6) 〇·39-〇·44 (2H，m)，0.60-0.70 (2H， m)，2.50-2.60 (1H，m)，5·18 (2H，s)，6.93 (1H，s)，7.09-7.50 (10H，m)，7.89 (2H，d，J=8.1 Hz)，7.92 (1H，s)，8.13 (1H，d， J=8.1 Hz)，8.28 (1H，d，J=l.〇 Hz)，12.60 (1H，br s)。 實施例471 ____- 543 : 本紙張尺度適用中國國家標準(CNS) A4規格（210 x 297公釐） 裝 訂Hz), 8.17 (1H, dd, &gt; 5.6 Hz, J = 2 · Hz), 丨. 72 (ih,'s): i〇% (1H, s) 〇 Example 469 dimethyl...amine methylpyrimidine Oxygen) The base 1-(3-emulsion) rides on 1-(3- Fluorophenyl)-3-[4-(6-phenyl-7H-pyrrolo[2,3_d]pyrimidine·* 1304061 A7 B7 V. Description of the invention (537) oxy)phenyl] monthly urine 50 mg, Add 29.5 mg of N,N-dimethylimidium amide (Eschenmoser's salt) and 1.5 ml of dimethyl ketoamine, and after removing overnight at 100 °C, add water and use ethyl acetate. Liquid extraction. The organic layer was concentrated, dried under reduced pressure and purified eluting elut elut elut elut elut elut elut MS spectroscopy (ESI): 497 (M+1) 1H-NMR (m): (DMS 〇-d6) 2.26 (6H, s), 3.64 (2H, s), 6.73-6.80 (1H, m), 6.85 (1H, s), 7·08-7·58 (10H, m), 8·0〇 (1H, d, J=7.7 Hz), 8.26 (1H, d, J=0.9 Hz), 8.82 (1H, s)5 8.92 (1H, s), 12.54 (1H, b'r s) 〇 Example 470 1- {4 2 "6-(4-word p-phenyl)-7H-port ratio ♦ and f 2· 3_(Π口密哈-4-一资/μ 2 -乱本基} _ 3 _ ; 丙 月 month urine will be 1- {4-[6-(4_芊oxyphenyl)-7-(2- Trimethyl decane ethoxymethyl)-7 Η-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl 3-cyclopropanil 38 mg was dissolved in 0.8 ml of tetrahydrofuran, and then dropped four 0.2 ml of butyl ammonium fluoride (tetrahydrofuran 1 hydrazine solution) and reflux for 2 hours. After returning to room temperature, water was added and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with water and saturated brine, concentrated and reduced. Drying to give the title compound: 26 mg. MH-NMR spectrum: (DMSO-d6) 〇·39-〇·44 (2H, m), 0.60-0.70 (2H, m), 2.50-2.60 (1H, m), 5·18 (2H, s), 6.93 (1H, s), 7.09-7.50 (10H, m), 7.89 (2H, d, J = 8.1 Hz), 7.92 (1H, s), 8.13 (1H, d, J = 8.1 Hz), 8.28 (1H, d, J = l. 〇 Hz), 12.60 (1H, br s). Example 471 ____- 543 : This paper scale applies to the Chinese National Standard (CNS) A4 size (210 x 297 mm) binding

線 j3〇4〇61 、 -- A7 _____B7 玉、發明説明（538) 乳-·4-「6- (4- 苯基）· 7H•说哈并「2 3_ ⑴嘧啶-4-基 苯基丨-3-環丙月^ 在卜{4-[6-(4-苄氧苯基）-7H-吡咯并[2,3-d]嘧啶·4-基 氧]-2-氯苯基}-3-環丙腺24 mg中，加入三氟乙酸2 ml及硫 苯醚0.1 m卜並於45°C攪拌30分鐘。將反應系減壓濃縮後， 加入威和竣酸氫鋼水溶液及調成鹼性後，用乙酸乙酯-四氫 呋喃分液萃取。將有機層用飽和食鹽水洗淨，用無水硫酸 鈉乾燥後，濃縮及減壓乾燥，得到標題化合物丨5 mg。 iH-NMR 光 lf:(DMS〇-d6) 0.39-0.44 (2H，m)，0.60-0.67 (2H， m), 2.52-2.60 (1H, m)3 6.80-6.88 (3H, m), 7.12 (1H, d, J=2.0 Hz), 7.27 (1H, dd, J=9.0 Hz, Jf=2.0 Hz), 7.40 (1H, d5 J=2.0 Hz), 7.76 (2H, d, J=9.0 Hz), 7.91 (1H? s), 8.13 (1H5 d, J=9.〇Line j3〇4〇61 , -- A7 _____B7 jade, invention description (538) milk-·4-"6-(4-phenyl)·7H•说哈和"2 3_ (1) pyrimidin-4-ylphenyl hydrazine -3-cyclopropanol ^ in {4-[6-(4-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl}- 2 ml of 3-cyclopropyl gland, 2 ml of trifluoroacetic acid and 0.1 m of thiophenyl ether were added and stirred at 45 ° C for 30 minutes. After the reaction was concentrated under reduced pressure, the aqueous solution of hydrazine hydrogen hydride was added and adjusted. After the basic layer was extracted with ethyl acetate-tetrahydrofuran, the organic layer was washed with brine, dried over anhydrous sodium sulfate (DMS〇-d6) 0.39-0.44 (2H, m), 0.60-0.67 (2H, m), 2.52-2.60 (1H, m)3 6.80-6.88 (3H, m), 7.12 (1H, d, J= 2.0 Hz), 7.27 (1H, dd, J=9.0 Hz, Jf=2.0 Hz), 7.40 (1H, d5 J=2.0 Hz), 7.76 (2H, d, J=9.0 Hz), 7.91 (1H? s) , 8.13 (1H5 d, J=9.〇

Hz)? 8.25 (1H3 d, J=l.〇 Hz), 9.77 (1H, br s), 12.50 (1H, br s) ° f施例472 h 苄氧幕苯幕UH-吡咯并「2,3-dl盧啶-4-甚氧i 笨基丨-3-(3-氣茉某）月尿 在6-(4- +氧笨基）-4·(4 -硝基苯氧基比哈并[2 3-d] 嘧啶550 mg中，加入鐵粉600 mg，氯化銨1·ι g，乙醇1〇 ml，四氫呋喃20 ml及水1〇 ml，並於80- 8 5 °C擾掉1 5小 時。回到室溫後，經矽藻土過濾，在濾液中加入乙酸乙醋 及水，並分液萃取。將有機層用無水硫酸鈞乾燥，經、纟帛检 過濾及濃縮乾固，得到含胺基體之粗製物493 mg。將該粗 製物490 mg於90 °C溶於甲苯10 ml及乙腈10 nU,然後加入 ______________ - 544 - I紙張尺度適用中國國家標準(CNS) A4規格（210X 297公釐) -- 1304061 〜 、· A7 __— B7 五、發明説明（539) 異氰酸3-氟苯酯0.3 ml並授摔1小時。放置於室溫，滤取析 出之結晶及乾燥，得到標題化合物45〇 mg。 iH-NMR 光瑨：（DMS〇-d6) 5.17 (2H，s)，6.77 (1H，dt，J=2.9, 7·8 Ηζ)，6·88 (1H，d5 J=1.2 ΗΖ)，7.08-7·53 (14H，m)，7.88 (2H, d, J-9.1 Hz), 8.25 (1H, s), 8.75 (1H, s), 8.98 (1H, s), 12.56 (1H, br s) 〇 f施例473 1- ( 3 -礼年皋）-3 - { 4-「6- (4-轉某笨基）-7H-说啤并「2·3 - dl _ 啶-4-基氧1笨某U尿 將卜{心[6-(4-苄氧苯基）-7H-吡咯并[2,3-d]嘧啶-4-基氧] 苯基}-3-(3-氟苯基）踩377 mg溶於三氟乙酸4 ml及硫代苯 ' 甲醚0·4 ml中，然後於45°C攪拌40分鐘。其後，回到室溫， 加入碳酸鉀調成鹼性，用乙酸乙酯-四氫呋喃（5 :丨）混合溶 媒分液萃取。將有機層濃縮乾固，得到標題化合物3工〇 mg 0 W-NMR 光譜：（DMSO-d6) 6.70-6.80 (2H，m)，6·82 (2H，d J=8.3 Hz), 7.10-7.52 (7H, m), 7.75 (2H, d5 J=8.3 Hz), 8.23 (1H，s)，8.85 (1H，s)，8·98 (1H，s)，8·98 (1H，s)，12·48 (1H， br s) o 實施例474 1__-上4二{6-「4-(2-二乙胺基乙乳基）-冬基卜711-叶卜.哈并「213_(^] 嘧咬-4-基氲丨茉某3-氣笨基）脲 將1-(3」氟苯基）-3- {4-[6-(4-羥基苯基）-7H-吡洛并[2 3-d]嘧啶-4-基氧]苯基}脲丨14 mg溶於二甲基甲醯胺2 ml，加 _____- 545 - 本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐） 1304061 〜 -- Λ, . · _ ____B7 五、發明説明Ϊ~&quot; 入2-氯乙基二乙胺鹽酸鹽44 mg(約1當量）及碳酸氫鉀63 mg (2·5當量）’並於50_6〇t攪拌16小時。之後，加入2•氯乙基 二乙胺鹽酸鹽17 mg，碳酸氫鉀20 mg及二甲基甲醯胺j ml，並於同溫度攪摔整夜。之後，回到室溫，加入水，用 乙酸乙酯·四氫呋喃分液萃取。將有機層用水及飽和食鹽 水洗淨，濃縮，付諸於NH型矽凝膠管柱層析（己烷·乙酸乙 醋）。得到包含標題化合物之粗製固體33 mg。將其用乙酸 乙醋洗淨’得到標題化合物5 mg。 MS 光譜（ESI): 555(M+1)， iNMR光譜：（DMS0-d6) 〇·96 (6H，t，J==7 4 Hz)，2 53 (4H，七 J=7.4 Hz)，2·78 (2H，t，J=6.2 Hz)，4.06 (2H，t，J=6.2 Hz)， 6.74-6.88 (2H，m)，7.02 (2H，d，J=9.0 Hz)，7.09-7.54 (7H，m)， 7.86 (2H, d, J=9.0 Hz), 8.25 (1H3 s), 8.83 (1H, br s), 8.96 (1H，br s)，12·50 (1H，br s)。 如下述合成中間體。 製造例474-1 卞氣苯基）-4'(4-硝基基吡咯并f 2,3-dl嘧杏 在4-硝基盼3.09 g中，加入碳酸鉀2·97 g及二甲基甲醯胺 30 ml並於130°C攪拌10分鐘後，加入6_(4•芊氧苯基卜肛氯-7H-吡咯并[2,3-d]嘧啶2.49 g，於13〇。(：攪拌5小時及於135 C擾拌整夜。回到室溫後，加入水，遽取析出之固體，然 後付諸於NH型矽凝膠管柱層析（乙酸乙酯），之後加入乙醚 及乙酸乙酯’以及進行超音波處理。濾取固體，得到標題 化合物1.2 g。 L________ - 546 - 本紙張尺度通用中國國家標準(CNS) A4規格(210 X 297公爱） 1304061 ' - A7 _ __Β7 ______ 五、發明説明（541) h-NMR 光譜：（DMSO-d6) 5.18 (2H，s)，6·99 (1H，d，J=1.7 Hz)，7.08-7.13 (2H，m)，7.28-7.48 (5H，m)，7.53-7.60 (2H， m)，7.88-7.93 (2H，m)，8.30-8.35 (3H，m)，12.71 (1H，br s)。 實施例475 1二（3-氣苯基）-3 - { 4-「6- M- 口比嘻哈-〗-莘苯某）-7H- p比吃并 [一2,3_ dl嘧啶-4_基氯1苽篡}月尿 在4-氯-6-(4-吡嘻啶-1-基苯基）_7!1-吡哈并[2,3-引嘧啶 63 0 mg中，加入4-硝基酚646 mg，竣酸鉀817 mg及二甲基 甲醯胺6.3 ml，並於130 °C攪摔整夜。加入水，用乙酸乙酯 分液萃取，將有機層用水及飽和食鹽水洗淨及濃縮乾固， 得到510 mg固體。在該固體中，加入鐵粉500 mg，氯化銨丄 g，乙醇20 m卜四氫呋喃1〇 ml及水3 m卜並於80°C攪拌2小 時。回到室溫後，經矽藻土過濾，在濾液中加入乙酸乙 醋，四氫呋喃及水，並分液萃取，將有機層用無水硫酸鈞 乾燥’經绵检過〉慮及濃縮乾固，得到3 80 mg之粗製物。在 其中加入甲苯5 m卜乙腈5 ml及四氫呋喃5 ml並於100°C溶 解’然仗加入異夜故3 -氣私§旨〇 · 19 m 1並擾掉1小時。放置於 室溫，濾取析出之結晶，用乙醚洗淨及減壓乾燥，得到標 題化合物40 mg。 MS 光譜（ESI; nega): 509(M+1) iH-NMR 光譜：（DMSO-d6) 1.85-2.02 (4H，m)，3.10-3.32 (4H， m), 6.42 (1H, d5 J=8.2 Hz)5 6.60 (1H, d, J-8.2 Hz), 6.70-6.80 (2H, m), 7.02-7.53 (9H, m), 8.00 (1H, s), 8.99 (1H, s), 9.17 (1H，s)，1 1.81 (1H，br s)。 ___- 547 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）Hz)? 8.25 (1H3 d, J=l.〇Hz), 9.77 (1H, br s), 12.50 (1H, br s) ° f Example 472 h benzylic oxide benzene curtain UH-pyrrole "2,3 -dl pyridine-4-methoxy i 笨 丨-3-(3-气茉) month urine in 6-(4- + oxyphenyl)-4·(4-nitrophenoxybiha [2 3-d] Pyrimidine 550 mg, add iron powder 600 mg, ammonium chloride 1 · ι g, ethanol 1 〇 ml, tetrahydrofuran 20 ml and water 1 〇 ml, and disturb at 80-85 ° C 1 After returning to room temperature, it is filtered through diatomaceous earth, and ethyl acetate and water are added to the filtrate, and the mixture is extracted by liquid separation. The organic layer is dried with anhydrous barium sulfate, filtered, and concentrated to dryness. The crude product containing amide was obtained 493 mg. The crude product 490 mg was dissolved in 10 ml of toluene and 10 nU of acetonitrile at 90 ° C, and then added to the ______________ - 544 - I paper scale for the Chinese National Standard (CNS) A4 specification ( 210X 297 mm) -- 1304061 ~ , · A7 __- B7 V. Inventive Note (539) 3-Fluorophenyl isocyanate 0.3 ml and given for 1 hour. Place at room temperature, filter out the precipitated crystals and dry , the title compound was obtained as 45 〇mg. iH-NMR 瑨: (DMS〇-d6) 5.17 (2H, s), 6.77 (1H , dt, J=2.9, 7·8 Ηζ), 6.88 (1H, d5 J=1.2 ΗΖ), 7.08-7·53 (14H, m), 7.88 (2H, d, J-9.1 Hz), 8.25 (1H, s), 8.75 (1H, s), 8.98 (1H, s), 12.56 (1H, br s) 〇fexample 473 1- (3 - ceremony year)-3 - { 4-"6- (4-turn to a stupid base) - 7H- said beer and "2·3 - dl _ pyridine-4-yloxy 1 stupid U urine will be {heart [6-(4-benzyloxyphenyl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-(3-fluorophenyl) tread 377 mg dissolved in trifluoroacetic acid 4 ml and thiobenzene 'methyl ether 0·4 ml Then, it was stirred at 45 ° C for 40 minutes. Thereafter, it was returned to room temperature, added with potassium carbonate to make it alkaline, and extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (5: hydrazine). The organic layer was concentrated to dry. , the title compound was obtained, mg 0 W-NMR spectrum: (DMSO-d6) 6.70-6.80 (2H, m), 6.82 (2H, d J = 8.3 Hz), 7.10-7.52 (7H, m), 7.75 (2H, d5 J=8.3 Hz), 8.23 (1H, s), 8.85 (1H, s), 8·98 (1H, s), 8·98 (1H, s), 12·48 (1H, br s) o Example 474 1__-上上四二{6-"4-(2-diethylaminoethyl lactyl)-Winterjib 711-Yebu. Ha and "213_(^] pyridyl-4-yl氲丨莫某3-气笨基)urea 1-(3"fluorophenyl)-3-{4-[6-(4-hydroxyphenyl)-7H-pyrolo[2 3-d]pyrimidin-4-yloxy]phenyl}urea ruthenium 14 Mg is dissolved in dimethylformamide 2 ml, plus _____- 545 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 ~ -- Λ, . · _ ____B7 V. Invention Description Ϊ~&quot; 2-chloroethyldiethylamine hydrochloride 44 mg (about 1 equivalent) and potassium bicarbonate 63 mg (2.5 equivalent) were stirred at 50_6 Torr for 16 hours. Thereafter, 2 chloroethyldiethylamine hydrochloride 17 mg, potassium hydrogencarbonate 20 mg and dimethylformamide j ml were added, and the mixture was stirred at the same temperature overnight. Thereafter, the mixture was returned to room temperature, and water was added thereto, followed by extraction with ethyl acetate·tetrahydrofuran. The organic layer was washed with water and saturated brine, concentrated, and then applied to EtOAc (EtOAc). The crude solid 33 mg containing the title compound was obtained. This was washed with ethyl acetate to give the title compound 5 mg. MS spectroscopy (ESI): 555 (M+1), NMR spectrum: (DMS0-d6) 〇·96 (6H, t, J==7 4 Hz), 2 53 (4H, sJ = 7.4 Hz), 2 ·78 (2H, t, J = 6.2 Hz), 4.06 (2H, t, J = 6.2 Hz), 6.74-6.88 (2H, m), 7.02 (2H, d, J = 9.0 Hz), 7.09-7.54 ( 7H,m), 7.86 (2H, d, J=9.0 Hz), 8.25 (1H3 s), 8.83 (1H, br s), 8.96 (1H, br s), 12·50 (1H, br s). The intermediate is synthesized as follows. Preparation Example 474-1 Helium phenyl)-4' (4-nitropyrrolof 2,3-dl apricot in 4-nitropane 3.09 g, potassium carbonate 2.97 g and dimethyl group were added After 30 ml of methotrexate and stirring at 130 ° C for 10 minutes, add 6_(4•芊oxyphenyl anal chloride-7H-pyrrolo[2,3-d]pyrimidine 2.49 g at 13〇. After 5 hours and at 135 C, the mixture was stirred overnight. After returning to room temperature, water was added, and the precipitated solid was taken, and then applied to a NH column gel column chromatography (ethyl acetate), followed by diethyl ether and acetic acid. Ethyl ester' and ultrasonic treatment. The solid was collected by filtration to give the title compound 1.2 g. L________ - 546 - The paper size is the common Chinese national standard (CNS) A4 specification (210 X 297 public) 1304061 ' - A7 _ __Β7 ______ , inventive description (541) h-NMR spectrum: (DMSO-d6) 5.18 (2H, s), 6·99 (1H, d, J = 1.7 Hz), 7.08-7.13 (2H, m), 7.28-7.48 ( 5H, m), 7.53-7.60 (2H, m), 7.88-7.93 (2H, m), 8.30-8.35 (3H, m), 12.71 (1H, br s). Example 475 1 bis (3- benzene) Base)-3 - { 4-"6-M-port than hip-hop-〗-莘Benzene)-7H-p than eat and [2,3_ dl pyrimidine-4_yl chloride 1月} month urine in 4-chloro-6-(4-pyridin-1-ylphenyl)_7!1-pyhax[2,3-pyrimidine 63 0 mg, added 4-nitrophenol 646 Mg, 817 mg of potassium citrate and 6.3 ml of dimethylformamide, and stirred at 130 °C overnight. Add water, extract with ethyl acetate, wash the organic layer with water and saturated brine and concentrate. Drying, 510 mg of solid was obtained. In this solid, 500 mg of iron powder, 丄g of ammonium chloride, 20 ml of ethanol, 1 ml of tetrahydrofuran and 3 m of water were added and stirred at 80 ° C for 2 hours. After the temperature is filtered, the mixture is filtered through celite, and ethyl acetate, tetrahydrofuran and water are added to the filtrate, and the mixture is extracted by liquid separation. The organic layer is dried with anhydrous barium sulfate, and the mixture is dried and concentrated to obtain 3 80 mg. The crude product was added with 5 ml of toluene 5 m of acetonitrile and 5 ml of tetrahydrofuran and dissolved at 100 ° C. Then, the mixture was added to the mixture, and the mixture was shaken for 1 hour. The precipitated crystals were filtered, washed with diethyl ether, and evaporated to drynessielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel 2.02 (4H, m), 3.10 -3.32 (4H, m), 6.42 (1H, d5 J=8.2 Hz)5 6.60 (1H, d, J-8.2 Hz), 6.70-6.80 (2H, m), 7.02-7.53 (9H, m), 8.00 (1H, s), 8.99 (1H, s), 9.17 (1H, s), 1 1.81 (1H, br s). ___- 547 - This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)

裝 訂Binding

線 1304061 〜 -- A7 _____ B7 五、發明説明（542) 如下述合成中間體。 製造例475- 1 2 -胺墓-5 - (4- nh嘻咬-1-笨基）-1H- p比哮· - V淼酸乙酯 在2-腺基-乙酸乙g旨鹽酸鹽13.8 g (Liebigs Ann. Chem.， 1895 ( 1977)記載之公知化合物）中，加入乙醇15〇 ^1，並於 0°C加·入乙氧化鈉5·94 g (相對於2-脒基-乙酸乙酯鹽酸鹽為 0.97當量），然後於氮蒙氣下，攪拌10分鐘。此時加入2-溴-1-(4-吡.咯啶-1-苯基）-乙酮（Lancaster) 12 g，然後於室溫攪 拌48小時。加入乙酸乙酯，經超音波處理，過濾固體及濃 縮濾液，然後付諸於矽凝膠管柱層析（乙酸乙酯），得到標 題化合物4.82 g。 1H-NMR光譜：（DMSO-d6) 1.22 (3H，d，J=7.3 Ηζ)，1·88-1·98 (4H，m)，3.16-3.24 (4H，m)，4.06-4.14 (2H，m)，5·52 (2H，s)， 6.13 (1H，d，J=2.8 Hz), 6.48 (2H，d，J=8.8 Hz)，7.28 (2H，d， J=8.8 Hz)，10.48 (1H，s)。 製造例475-2 6-(4 “比哈咬-1-基笨基）-7H -口比啥 在2-胺基- 5-( 4-吨洛淀-1-苯基）-ΐ Η-p比洛-3-幾酸乙酉旨 4.80 g中，加入甲酸8 ml，甲醯胺31.8 ml及二甲基曱酿胺 15.9 m卜以及於140°C攪拌48小時後，放置於室溫24小時。 濾取析出之固體及減壓乾燥後，得到標題化合物3.〇 • Ο iH-NMR光譜：（DMSO-d6) 1.86-2.00 (4H，m)，3.08-3.13 (4H， m)5 6.54 (2H, d, J—8.8 Hz), 6.62 (1H, s), 7.61 (2H d J=8 8 Hz)，7.78 (1H，s)，12·40 (1H，br s)。 -548 - 本紙張尺度適用中國S家料(CNS) A4規格(210 x 297公营)'^ -- 1304061 A7 B7Line 1304061 ~ -- A7 _____ B7 V. Description of the invention (542) The following synthesis intermediates. Production Example 475- 1 2 -amine tomb-5 - (4-nh-bite-1-phenyl)-1H-p-rh--V-ethyl decanoate in 2-glycine-acetic acid 13.8 g (known compound of Liebigs Ann. Chem., 1895 (1977)), adding 15 〇^1 of ethanol, and adding sodium sulphate 5·94 g at 0 ° C (relative to 2-mercapto- The ethyl acetate hydrochloride was 0.97 equivalents, then stirred under nitrogen for 10 minutes. At this time, 12 g of 2-bromo-1-(4-pyridyl-1-phenyl)-ethanone (Lancaster) was added, followed by stirring at room temperature for 48 hours. Ethyl acetate was added, and the solid and concentrated filtrate were filtered, and then applied to a gel column chromatography (ethyl acetate) to give the title compound 4.82 g. 1H-NMR spectrum: (DMSO-d6) 1.22 (3H, d, J = 7.3 Ηζ), 1.88-1·98 (4H, m), 3.16-3.24 (4H, m), 4.06-4.14 (2H, m),5·52 (2H,s), 6.13 (1H,d,J=2.8 Hz), 6.48 (2H,d,J=8.8 Hz), 7.28 (2H,d, J=8.8 Hz),10.48 ( 1H, s). Production Example 475-2 6-(4 "Bihabit-1-ylphenyl"-7H-port 啥 in 2-amino-5-(4-tonaloxine-1-phenyl)-ΐ- p pilo-3-carboxylic acid ethyl acetate 4.80 g, add formic acid 8 ml, methotrexate 31.8 ml and dimethylamine amine 15.9 m b and stirred at 140 ° C for 48 hours, then placed at room temperature for 24 hours The precipitated solid was filtered and dried under reduced pressure to give the title compound 3. 〇• Ο iH-NMR spectrum: (DMSO-d6) 1.86-2.00 (4H, m), 3.08-3.13 (4H, m)5 6.54 ( 2H, d, J—8.8 Hz), 6.62 (1H, s), 7.61 (2H d J=8 8 Hz), 7.78 (1H, s), 12·40 (1H, br s). -548 - Paper The scale applies to China S material (CNS) A4 specification (210 x 297 public) '^ -- 1304061 A7 B7

五、發明説明（543) 製造例475-3 4-氯-6-(_4•吡咯啶-卜基茉甚）_7H-毗咯并f273-dl嘧啶 在6-(4-吡咯啶-1-基苯基）-7H-吡咯并[2,3_d]嘧啶·心醇 1.9 g中，加入氧氯化磷20 ml及於140°C攪拌3小時後，回到 室溫及濃縮反應系。在殘餘物中加入冰水，用碳酸氫鈉中 和，然後用乙酸乙酯分液萃取。將有機層用硫酸鈉乾燥及 濃縮乾固’得到包含標題化合物之粗製物12 g。 iH-NMR光譜：（DMS〇-d6) 1.86-2.02 (4H，m)，3.10-3.32 (4H， m)，6·60 (2H，d，J=8.9 Hz)，6.77 (1H，d，J=2.0 Ηζ)，7·81 (2H， d，J=8.9 Hz)，8.46 (1H，s)，12.70 (1H，br s)。 實施例476 止{4-「6-(甲胺基）羰基-7-甲氣某·心喹啉某1氫笨基 (4-氟笨基）脹 藉由實施例10之方法，從4-(4-胺基-苯氧基）-7-甲氧基-喹啉-6-羧酸甲醯胺（65 mg)及異氰酸4-氟苯酯（0_05 ml)， 仔到為淡黃色結晶之標題化合物（85 mg)。 lH-NMR (DMSO-d6) 5(ppm): 2.81-2.84 (3H, m), 4.00 (3H, s), 6.46 (1H, s), 7.07-7.24 (4H, m), 7.43-7.61 (5H, m), 8.32- 8.38 (1H, m), 8.59-8.65 (2H, m), 8.80 (1H, br s), 8.89 (1H, br s) 〇 以下述3步驟合成起始原料。 製造例476- 1 氯-7-甲氣基居淋-6-藉酸甲醯胺 將藉由製造例152-2之方法從7-甲氧基-4-酮基-1,4-二氫 _______ - 549 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（544) 喹啉-6-羧酸（947 mg)合成之7-甲氧基-4-氣-喳啉羰基氯 溶解於四氫呋喃（70 ml)中，並冷卻至0。〇。在其中加入4〇0/〇 甲胺水溶液（0.4 ml)，並於室溫攪拌30分鐘。加入水及用乙 酸乙醋萃取3次後’將有機層合併，用水及飽和食鹽水洗淨 及用硫酸鈉乾燥後，減壓乾燥，得到標題化合物（7 i 〇 mg)。- j-NMR (DMSO，d6)5(ppm): 3·07-3·10 (3H，m)，4·12 (3H，s)， 7.40-7.43 (1H, m), 7.56 (1H, s), 7.83 (1H, br s), 8.73-8.77 (1H，m)，9.13 (1H，s)。 製造例476-2 7-甲氧基-4- (4-硝基笨氣基）4 4 - 6-羧酸甲酿脖 藉由製造例7之方法，從4-氯-7-甲氧基p奎琳-6-幾酸甲酿 胺（492 mg)及4-硝基酚（492 mg)，得到為淡黃色結晶之標 題化合物（736 mg)。 ^-NMR (DMSO-d6) δ (ppm): 2.76-2.82 (3H, m), 4.02 (3H, s), 6.86 (1H，d，J=5.2 Hz)，7.45-7.51 (2H，m)，7.56 (1H，s)， 8.32-8.38 (2H，m)，8.45 (1H，s)，8.76-8.79 (1H，m)。 製造例476-3 4-(4-胺基笨氣基）-7-甲氣基4啉-6-藉酸甲醯胺 藉由製造例10之方法，從7-甲氧基-4-(4-硝基苯氧基）喳 啉-6-羧酸甲醯胺（73 6 mg)，得到標題化合物（250 mg)。 1 H-NMR (DMSO-d6) δ (ppm): 2.81-2.84 (3H, m), 3.99 (3H, s)5 5.14-5.19 (2H, m), 6.39 (1H, d, J-5.2 Hz), 6.45 (2H, d, J=8.4 Hz), 6.92 (2H, d, J=8.4 Hz), 7.46 (1H, s)5 8.30-8.38 (1H, m), -550 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐)V. INSTRUCTIONS (543) Manufacture Example 475-3 4-Chloro-6-(_4•pyrrolidinyl-buquimo)_7H-Pyro-f273-dl-pyrimidine in 6-(4-pyrrolidin-1-yl) To 1.9 g of phenyl)-7H-pyrrolo[2,3_d]pyrimidine-erythritol, 20 ml of phosphorus oxychloride was added and stirred at 140 ° C for 3 hours, and then returned to room temperature and the reaction system was concentrated. Ice water was added to the residue, which was neutralized with sodium hydrogen carbonate and then extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated to dryness to afforded 12 g of crude title compound. iH-NMR spectrum: (DMS〇-d6) 1.86-2.02 (4H, m), 3.10-3.32 (4H, m), 6·60 (2H, d, J=8.9 Hz), 6.77 (1H, d, J =2.0 Ηζ), 7·81 (2H, d, J=8.9 Hz), 8.46 (1H, s), 12.70 (1H, br s). Example 476 Stopping {4-"6-(methylamino)carbonyl-7-methyl-methyl-quinoline a 1-hydrophenyl (4-fluorophenyl) swell by the method of Example 10, from 4- (4-Amino-phenoxy)-7-methoxy-quinoline-6-carboxylic acid formamide (65 mg) and 4-fluorophenyl isocyanate (0_05 ml), slightly yellowish The title compound (85 mg) was crystallized. lH-NMR (DMSO-d6) 5 (ppm): 2.81-2.84 (3H, m), 4.00 (3H, s), 6.46 (1H, s), 7.07-7.24 (4H , m), 7.43-7.61 (5H, m), 8.32- 8.38 (1H, m), 8.59-8.65 (2H, m), 8.80 (1H, br s), 8.89 (1H, br s) 〇 with the following 3 The starting material was synthesized in the following manner. Production Example 476-1 Chloro-7-methyl carbazide-6-acid carbamide The 7-methoxy-4-keto group was obtained by the method of Production Example 152-2. 1,4-Dihydro _______ - 549 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (544) Quinoline-6-carboxylic acid (947) The resulting 7-methoxy-4-carbo-porphyrin carbonyl chloride was dissolved in tetrahydrofuran (70 ml) and cooled to 0. 〇 〇 〇 〇 〇 〇 , , , , And stirred at room temperature for 30 minutes. Add water and acetic acid The extract was combined with EtOAc (3 mL). (ppm): 3·07-3·10 (3H,m),4·12 (3H,s), 7.40-7.43 (1H, m), 7.56 (1H, s), 7.83 (1H, br s), 8.73-8.77 (1H, m), 9.13 (1H, s). Production Example 476-2 7-Methoxy-4-(4-nitrostylene) 4 4 - 6-carboxylic acid The title compound was obtained as the pale yellow crystal from 4-chloro-7-methoxyp- quine-6- succinic acid (492 mg) and 4-nitrophenol (492 mg). (736 mg) ^-NMR (DMSO-d6) δ (ppm): 2.76-2.82 (3H, m), 4.02 (3H, s), 6.86 (1H,d,J=5.2 Hz), 7.45-7.51 ( 2H, m), 7.56 (1H, s), 8.32-8.38 (2H, m), 8.45 (1H, s), 8.76-8.79 (1H, m). Production Example 476-3 4-(4-Amino-stupyl)-7-methyl-l-tetralin-6-bromo-carbamide The compound of Example 10 was obtained from 7-methoxy-4-( 4-Nitrophenoxy)porphyrin-6-carboxylic acid formamide (73 6 mg) gave the title compound (250 mg). 1 H-NMR (DMSO-d6) δ (ppm): 2.81-2.84 (3H, m), 3.99 (3H, s)5 5.14-5.19 (2H, m), 6.39 (1H, d, J-5.2 Hz) , 6.45 (2H, d, J=8.4 Hz), 6.92 (2H, d, J=8.4 Hz), 7.46 (1H, s)5 8.30-8.38 (1H, m), -550 - This paper size applies to China Standard (CNS) A4 size (210 x 297 mm)

裝 訂Binding

線 1304061 A7 * B7 五、發明説明（545) 8·57-8·61 (2H，m)。 實施例477 N- 甲胺基）羰基-7-甲氫某-4-崦琳基1氳笨某丨- N’- (2-4唑基）脲. 藉由實施例11之方法，從4-(4-胺基-苯氧基）-7-甲氧喹 琳-6-歎酸甲醯胺（65 mg)及Ν-(2·嘍唑基）胺基甲酸苯酯（49 mg)，得到為淡黃色結晶之標題化合物（32 mg)。 lH-NMR (DMSO-d6) δ (ppm): 2.80-2.85 (3H, m), 4.00 (3H, s), 6.47 (1H, d, J=5.2 Hz), 7.05-7.15 (1H, m), 7.25 (2H5 d, J=8.8Line 1304061 A7 * B7 V. Description of invention (545) 8·57-8·61 (2H, m). Example 477 N-Methylamino)carbonyl-7-methylhydrogen-4-indolyl 1 氲 丨-N--(2-4 oxazolyl)urea. By the method of Example 11, from 4 -(4-Amino-phenoxy)-7-methoxyquinolin-6-succinylamine (65 mg) and phenyl-(2. carbazolyl) phenyl carbamate (49 mg), The title compound (32 mg) was obtained as pale yellow crystal. lH-NMR (DMSO-d6) δ (ppm): 2.80-2.85 (3H, m), 4.00 (3H, s), 6.47 (1H, d, J=5.2 Hz), 7.05-7.15 (1H, m), 7.25 (2H5 d, J=8.8

Hz)，7.35-7.40 (1H，m)，7·50 (1H，s)，7.62 (2H，d，J=8.8 Hz)， 8.58-8.66 (2H，m) 〇 實施例478 N-(4-「6-( 一甲胺基）幾基-7-曱氧基-4-岭g林甚i氧苯某 唑基）脲 藉由實施例11之方法，從4-(4-胺基苯氧基）-7-甲氧，奎啉_ 6-羧酸二甲醯胺（100 mg)及N-(2-噻唑基）胺基曱酸苯酯（6〇 mg)，得到為淡黃色結晶之標題化合物（6〇 mg)。 W-NMR (DMSO-d6)5(ppm): 2.78 (3H，s)，3·0〇 (3H，s)，3.97 (3H，s)，6·47 (1H，d，J=5.2 Hz)，7·05-7·15 (1H，m)，7·24 (2H， d，J=8.8 Hz)，7.35·7·39 (1H，τη)，7.48 (1H，s)，7.60 (2H, d， J=8.8 Hz)，8.04 (1H，s)，8·62 (1H，d，J=5.2 Hz)。 以下述3步驟合成起始物質。 製造例4 7 8 - 1 4-氯-7-甲_氧-4淋-6-藉酸二曱醯脖 -551 - 七紙張尺度適用中ϋ國f標準(CNS) A4規格(21Q X 297公爱) '~ -- 1304061 A7 B7 五、發明説明（546) 將藉由製造例152-2之方法從7-甲氧基-4-酮基-1,4-二氫 喧琳羧酸（1.0 g)合成之7-甲氧基-4-氯-喹啉-6-羰基氯溶 解於四氫吱喃（60 ml)及2.0 Μ二甲胺四氫呋喃溶液（3 ml) 中’並冷卻至〇°C。在其中加入二異丙基乙胺（1.6 ml)，並 於室溫攪拌一夜。加入水及用乙酸乙酯萃取3次後，將有機 層合併，用水及飽和食鹽水洗淨及用硫酸鈉乾燥後，減壓 乾燥，得到標題化合物（933 mg)。 lH-NMR (DMSO-d6)5(ppm)： 2.75 (3H, s), 3.01 (3H, s), 3.97 (3H，s)，7.57 (1H，s)，7.63 (1H，d，J=4.8 Hz)，7.93 (1H，s)， 8·78 (1H，d，J=4.8 Hz)。 篮造例478-2Hz), 7.35-7.40 (1H, m), 7.50 (1H, s), 7.62 (2H, d, J = 8.8 Hz), 8.58-8.66 (2H, m) 〇 Example 478 N-(4- "6-(monomethylamino)-l--7-methoxy-4-indenyl oxalyl oxo-oxo-oxazolyl)urea from 4-(4-aminophenoxyl) by the method of Example Benzyl-7-methoxy, quinolin-6-carboxylic acid dimethyl hydrazine (100 mg) and N-(2-thiazolyl)amino phthalic acid phenyl ester (6 〇 mg), which are obtained as pale yellow crystals. The title compound (6 〇 mg). W-NMR (DMSO-d6) 5 (ppm): 2.78 (3H, s), 3·0 〇 (3H, s), 3.97 (3H, s), 6·47 (1H ,d,J=5.2 Hz),7·05-7·15 (1H,m),7·24 (2H, d,J=8.8 Hz), 7.35·7·39 (1H,τη), 7.48 (1H , s), 7.60 (2H, d, J = 8.8 Hz), 8.04 (1H, s), 8.62 (1H, d, J = 5.2 Hz) The starting material was synthesized in the following three steps. 8 - 1 4-Chloro-7-甲_氧-4淋-6-Acid acid 曱醯 - -551 - Seven paper scales apply to China National Standard f (CNS) A4 specifications (21Q X 297 public) '~ - 1304061 A7 B7 V. INSTRUCTION DESCRIPTION (546) It is synthesized from 7-methoxy-4-keto-1,4-dihydroindolecarboxylic acid (1.0 g) by the method of Production Example 152-2. 7-methoxy -4-Chloro-quinoline-6-carbonyl chloride was dissolved in tetrahydrofuran (60 ml) and 2.0 Μ dimethylamine tetrahydrofuran solution (3 ml) and cooled to 〇 ° C. Diisopropyl was added thereto. Ethylamine (1.6 ml), and stirred at room temperature overnight. After adding water and ethyl acetate for three times, the organic layer was combined, washed with water and brine, dried over sodium sulfate Title compound (933 mg). lH-NMR (DMSO-d6) 5 (ppm): 2.75 (3H, s), 3.01 (3H, s), 3.97 (3H, s), 7.57 (1H, s), 7.63 ( 1H, d, J = 4.8 Hz), 7.93 (1H, s), 8·78 (1H, d, J = 4.8 Hz). Basket example 478-2

Zi-f：氧基-4“ 4-硝某茉氣某）4啉-6-羧酸二甲醯胺 藉由製造例10之方法，從4-氯-7-甲氧基喳啉-6-羧酸二甲 酿胺（933 mg)及4-硝基酚（737 mg)得到為淡黃色結晶之標 題化合物（904 mg)。 lH-NMR (DMSO-d6) 5(ppm): 2.75 (3H, s), 2.99 (3H, s), 3.95 (3H，s)，6·87 (1H，d，J=5.2 Hz)，7·46 (2H，d，J=7.2 Hz)，7·55 (1H，s)，7.94 (1H，s)，8.33 (2H，d，J=7.2 Hz)，8·76 (1H，d， J=5.2 Hz)。 製造例478-3 4“ 4-胺基笨氣基）-7-甲氣某4啉-6-羧酸二甲醯胺 藉由製造例10之方法，從7-甲氧基-4-(4-硝基苯氧基）喹 琳-6-複酸二甲酿胺（904 mg)，得到標題化合物（5 11 mg)。 ^-NMR (CDCI3) 5 (ppm): 2.90 (3H, s), 3.18 (3H, s), 3.98 -552 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 B7 五、發明説明（ 547) (3H, s), 6.43 (1H, d5 J=5.6 Hz), 6.75 (2H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 7.45 (1H, s), 8.27 (1H, s), 8.57 (1H, d, J=5.6 Hz)。 實施例479 胺某）蕤基-7·甲氣某-4_g奎啉基1氣笨某^ 將實施例341合成之N-[ 4-(6-羧基-7-甲氧基-4-喹啉基）氧 苯基]氟苯基）脲（60 mg)溶於二甲基甲醯胺（i.5 ml) 後，加入1-乙基-3· (3-二乙胺基丙基）_碳化二亞胺鹽酸鹽 (39 mg)，1-羥基-1H-苯并三唑單水合物pi mg)，三乙胺 (30 #1)及環丙胺（0·05 ^1)，並於室溫攪捽一夜。將反應液 分溶於乙酸乙酯及水中，將有機層用水洗淨，以及用無水 硫酸制乾燥。餾去溶媒後，用乙酸乙酯析出結晶，濾取及 減壓乾燥’仔到為白色結晶之標題化合物（2 9 mg)。 ^-NMR (CDC13) 5 (ppm): 0.45-0.59 (2H, m), 0.67-0.73 (2H3 m)，2·82-2·89 (1H，m)，3.97 (3H，s)，6·45 (1H，d，J=5.2 Hz)， 7.08-7.23 (4H，m)，7,43-7.50 (3H，m)，7.55-7.60 (2H，m)， 8.32-8.35 (1H, m), 8.42 (1H, s), 8.62 (1H5 d5 J=5.2 Hz), 8.75 (1H，br s)，8·84 (1H，br s)。 實施例480 胺甲基-7-甲氧基崦啉笨某卜N，·茉某胧 三氟乙酸鹽 將實施例.37合·成之N-[4-(6-氰基甲氧基喹啉*心基氧） 苯基]-Ν’-苯基跞（1〇〇 mg)溶於乙崞（5以）與四氫呋喃（5 ml) -553 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱）Zi-f: oxy-4 "4-nitrogen sulphate" 4 oxo-6-carboxylic acid dimethyl hydrazine by the method of Production Example 10, from 4-chloro-7-methoxy porphyrin-6 - Carboxylic acid dimethylamine (933 mg) and 4-nitrophenol (737 mg) gave the title compound (904 mg) as pale yellow crystal. lH-NMR (DMSO-d6) 5 (ppm): 2.75 (3H , s), 2.99 (3H, s), 3.95 (3H, s), 6·87 (1H, d, J = 5.2 Hz), 7·46 (2H, d, J = 7.2 Hz), 7·55 ( 1H, s), 7.94 (1H, s), 8.33 (2H, d, J = 7.2 Hz), 8.76 (1H, d, J = 5.2 Hz). Production Example 478-3 4 "4-Amine Gas-based)-7-Methane a certain 4-lino-6-carboxylic acid dimethylamine from 7-methoxy-4-(4-nitrophenoxy)quinolin-6 by the method of Production Example 10. - dimethyl acetal (904 mg) gave the title compound (5 11 mg). ^-NMR (CDCI3) 5 (ppm): 2.90 (3H, s), 3.18 (3H, s), 3.98 -552 - This paper scale applies to Chinese National Standard (CNS) A4 size (210X297 mm) 1304061 A7 B7 5. Description of invention (547) (3H, s), 6.43 (1H, d5 J=5.6 Hz), 6.75 (2H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 7.45 ( 1H, s), 8.27 (1H, s), 8.57 (1H, d, J = 5.6 Hz). Example 479: amine (N-[6-carboxy-7-methoxy-4-quinoline] synthesized in Example 341. After the oxyphenyl]fluorophenyl)urea (60 mg) was dissolved in dimethylformamide (i.5 ml), 1-ethyl-3·(3-diethylaminopropyl) was added. Carbodiimide hydrochloride (39 mg), 1-hydroxy-1H-benzotriazole monohydrate pi mg), triethylamine (30 #1) and cyclopropylamine (0·05 ^1) Stir at room temperature overnight. The reaction solution was dissolved in ethyl acetate and water, and the organic layer was washed with water and dried over anhydrous sulfate. After distilling off the solvent, the crystals were crystallised from ethyl acetate, and the title compound (2 9 mg) was obtained as white crystals. ^-NMR (CDC13) 5 (ppm): 0.45-0.59 (2H, m), 0.67-0.73 (2H3 m), 2·82-2·89 (1H, m), 3.97 (3H, s), 6· 45 (1H,d,J=5.2 Hz), 7.08-7.23 (4H,m),7,43-7.50 (3H,m),7.55-7.60 (2H,m), 8.32-8.35 (1H, m), 8.42 (1H, s), 8.62 (1H5 d5 J=5.2 Hz), 8.75 (1H, br s), 8.84 (1H, br s). Example 480 Aminomethyl-7-methoxyporphyrin, a certain N, · jasmine trifluoroacetate, the compound of Example 37, N-[4-(6-cyanomethoxyquine) Phenyl*-based oxygen) Phenyl]-Ν'-phenylindole (1〇〇mg) is dissolved in acetamidine (5) and tetrahydrofuran (5 ml) -553 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 public)

裝 訂Binding

1304061 〜 A7 ；________B7_ 五、發明説明（548) 之混合溶媒中，加入三氟乙酸（〇.5 ml)及50%鈀/碳（50 mg) ’並於氫氣流·下攪拌一夜。濾取鈀/碳後，濃縮濾液。 將得到之殘餘物用四氫呋喃洗淨，得到標題化合物（7〇 mg)。 1 H-NMR (DMSO-d6) δ (ppm): 4.02 (3H, s), 4.24 (2Η, s), 6.64 (1H, d, J=5.6 Hz), 6.94-6.99 (1H, m), 7.21-7.31 (4H, m), 7.44-7.49 (2H，m)，7.53 (1H，s)，7.62-7.66 (2H，m)，8.25 (2H， br s), 8.48 (1H, s), 8.76 (1H, d, J=5.6 Hz), 8.87 (1H, br s)5 9·04 (1H，br s)。 實施例481 H4-(6-乙醯胺甲基-I甲氣基，杳啉甚氧）茉某，-黎其 m_ 將N- [4- (6-胺甲基-7-甲氧基峻琳-4-基氧）苯基]- Nf -苯基 脲三氟乙酸鹽（40 mg)溶於吡啶（ΐ·〇 ^1)及無水乙酸（1.〇 ml)，並於室溫攪拌一夜。將反應溶液減壓濃縮，將得到之 粗生成物用乙酸乙酯結晶化，得到標題化合物（13 mg)。 lH-NMR (DMSO-d6) δ (ppm): 1.90 (3H, s), 3.98 (3H, s) 4·37-4·40 (2H，m)，6.46 (1H，d，J=5,2 Hz)，6.93-6.99 (ih，m) 7.18-7.30 (4H，m)，7.40 (1H，s)，7.45 (2H，d，J=7.6 Hz) 7 59 (2H，d，J=8.8 Hz)，8.06 (1H，s)，8.38-8.44 (1H，m)，8.59 (1H d，J=5.2 Hz), 8.70 (1H，s)，8·83 (1H，s)。 ’ 實施例4821304061 ~ A7 ; ________ B7_ 5. In the mixed solvent of the invention (548), trifluoroacetic acid (〇.5 ml) and 50% palladium/carbon (50 mg) were added and stirred under a hydrogen stream for one night. After palladium/carbon was collected by filtration, the filtrate was concentrated. The residue obtained was washed with EtOAc (EtOAc) 1 H-NMR (DMSO-d6) δ (ppm): 4.02 (3H, s), 4.24 (2Η, s), 6.64 (1H, d, J=5.6 Hz), 6.94-6.99 (1H, m), 7.21 -7.31 (4H, m), 7.44-7.49 (2H, m), 7.53 (1H, s), 7.62-7.66 (2H, m), 8.25 (2H, s s), 8.48 (1H, s), 8.76 ( 1H, d, J=5.6 Hz), 8.87 (1H, br s)5 9·04 (1H, br s). Example 481 H4-(6-Acetylaminomethyl-I-methyl-based, porphyrin-oxygen) Momo,-Liqi m_ N-[4-(6-Aminomethyl-7-methoxy Lin-4-yloxy)phenyl]-Nf-phenylurea trifluoroacetate (40 mg) was dissolved in pyridine (ΐ·〇^1) and anhydrous acetic acid (1. 〇ml) and stirred at room temperature overnight . The reaction solution was concentrated under reduced pressure. lH-NMR (DMSO-d6) δ (ppm): 1.90 (3H, s), 3.98 (3H, s) 4·37-4·40 (2H, m), 6.46 (1H,d,J=5,2 Hz), 6.93-6.99 (ih, m) 7.18-7.30 (4H, m), 7.40 (1H, s), 7.45 (2H, d, J = 7.6 Hz) 7 59 (2H, d, J = 8.8 Hz) , 8.06 (1H, s), 8.38-8.44 (1H, m), 8.59 (1H d, J = 5.2 Hz), 8.70 (1H, s), 8. 83 (1H, s).例 Example 482

Κτ_—(2-氟-4一[(6-.胺甲醯基-7-曱氣某-4-α爷说 Ν、環丙基脲 -554 - 本紙張尺度適用中國國家標準(CNS) Α4規格（210X297公釐）Κτ_—(2-Fluoro-4-[(6-.Aminomethylmercapto-7-曱 gas a-4-α 爷 Ν, cyclopropyl urea-554 - This paper scale applies to China National Standard (CNS) Α 4 Specifications (210X297 mm)

1304061 五、發明説明（549) 將環丙胺（0·10 ml)加至二甲基亞颯（〇 8 ml)中，然後將 [4-(6-胺甲醯基-7-甲氧基喹啉-4-基氧）-2-氟苯基]胺基甲 酸苯醋（80 mg)溶於其中並攪摔1〇分鐘。在該反應溶液中加 入水及乙酸乙醋，然後濾取析出之結晶，得到標題化合物 (33 mg) 〇1304061 V. INSTRUCTIONS (549) Add cyclopropylamine (0·10 ml) to dimethyl hydrazine (〇 8 ml), then [4-(6-aminocarbazinyl-7-methoxyquine) Phenyl-4-yloxy)-2-fluorophenyl]carbamic acid phenylacetic acid (80 mg) was dissolved therein and stirred for 1 minute. Water and ethyl acetate were added to the reaction solution, and the precipitated crystals were filtered to give the title compound (33 mg).

JH-NMR (DMSO-d6) 5 (ppm): 0.38-0.41 (2H, m)3 0.62-0.66 (2H, m), 2.51-2.59 (1H, m), 4.01 (3H, s), 6.52 (1H, d, J=5.2 Hz), 6.78-6.81 (1H, m), 7.04-7.09 (1H, m), 7.28-7.34 (iH m), 7.50 (1H, s), 7.72 (1H, br s), 7.84 (1H, br s), 8.16-8.23 (2H，m), 8.63-8.67 (2H，m)。 如下述合成起始物質。 製造例482-1 「4二(A-胺甲醯基二7-甲氧喹啉-4-某氧）-2-氯苯某1脖葚甲碎 笨酯 藉由製造例17記載之方法，從製造例152-5合成之心胺甲 醯基-4-(4-胺基-3-氟苯氧基）-7-甲氧基喹啉得到標題化合 物。 lH-NMR (CDC13) δ (ppm): 4.13 (3H, s), 5.90 (1H, br s), 6.53 (1H，d，J=5.6 Hz)，6.99-7.06 (2H，m)，7.20-7.30 (4H m) 7.40-7.45 (2H, m), 7.59 (1H, s), 7.80 (IH, br s), 8.24 (1H, br s)，8.68 (1H，d，J=5.6 Hz)，9.27 (1H，s)。 實施例483 N—-(2-氟-·4-·「（6·-·胺甲醯基-7-甲氣某备啉某）蚤」节羊u N’-(2-嶁唑某）脲 -555 - 本紙張尺度適用中國國家標準(CNS)‘A4規格(210X297公釐） 1304061 〜 -- A7 ________ B7 五、發明説明（55〇) 藉由實施例224記載之方法，從實施例152-5合成之6-胺 甲醯基- 4-( 4-胺基-3-氟苯氧基）-7-甲氧喹啉（60 mg)及N-(2-噻唑基）胺基甲酸苯酯（6〇 mg)，得到為淡黃色結晶之標 題化合物（24 mg)。 ^-NMR (DMSO-d6) ^ (ppm): 4.02 (3H, s), 6.57 (1H3 d, J=5.2'Hz), 7.12-7.18 (2H, m), 7.37-7.45 (2H, m)5 7.51 (1H, s), 7.73 (1H, br s), 7.85 (1H, br s), 8.18-8.26 (1H, m)5 8.64-S-69 (2H, m) ° 實施例484 甲胺.，基）羰基-7-曱氫某-4-4啉基1氫苽某KN，- 環丙基脹 藉由實施例11記載之方法，從N_ [ 4- (7-甲氧基-6-甲胺甲 酸基σ奎淋-4-基氧）苯基]胺基甲酸苯酯（8〇 mg)及環丙胺（2〇 mg)，得到為淡黃色結晶之標題化合物（33 mg)。 ^-NMR (DMSO-d6) 5 (ppm)； 0.39-0.43 (2H, m)3 0.62-0.68 (2H, m), 2.50-2.58 (1H，m)，2.84 (3H，d，J=4.8 Hz)，4.02 (3H， s)，6.43-6.46 (2H，m)，7.14,7.20(2H，m)，7.50(lH，s)，7.53-7·57 (2H，m)，8·35-8·38 (1H，m)，8·47 (1H，br s)，8.61 (1H， s)，8·64 (1H，d，J=5,2 Hz)。 ’ 以下述方法合成起始物質。 製造例484-1 ^[+(7-甲氧基轰基喹啉^^基^苯基1胺某 甲酸笨酯_ - 藉由製造例17記載之方法，從‘（4_胺基苯氧基卜7_甲氧 _ - - - __ - 556 - 本纸張尺度適用中國國家標準(CNiS) A4規格（210X297公爱)-&quot;一^ -- 1304061 A7 B7 五、發明説明（551) 基喹啉-6-羧酸甲醯胺（53 mg)，得到標題化合物（6(3 mg)。 lH-NMR (CDCl3)&lt;5(ppm): 3.08 (3H, d, J=4.8 Hz), 4.12 (3H, s), 6.48 (1H, d, J=5.2 Hz), 7.14-7.29 (6H, m), 7.37-7.45 (2H, m), 7.55-7.63 (3H, m), 7.89 (1H, br s), 8.63 (1H, d, J=5.2 Hz)，9·28 (1H, s)。 實施例485 1(2-氟二4-「（6-胺甲醯基-7-曱氣某-4-啐嗾某）氣1笨基）-Ν·-環丁某月尿 藉由實施例11記載之方法，從[4- ( 6-胺甲醯基-7-甲氧基 4淋-4-基氧）-2-氟苯基]胺基甲酸苯酯（73 mg)及環丁胺（28 mg) ’得到標題化合物（28 mg)。 lH-NMR (DMSO-d6) ^ (ppm): 2.52-2.67 (2H, m), 2.72-2.87 (2H，m)，2·14,2·26 (2H，m)，4·01 (3H，s)5 4.04-4.18 (1H，m)， 6.51 (1H，d，J=5.2 Hz)，6·88 (1H，d，J=8.0 Hz)，7.02-7.08 (1H, m), 7.27-7.34 (1H, m), 7.50 (1H, s)5 7.72 (1H, br s)3 7.84 (1H，br s)，8·15-8·26 (2H，m)，8·63-8·67 (2H，m)。 實施例486 胺曱醯某-7-甲氫基-4〇奎啉基）氧1苯基）- 環戊某胧 藉由實施例11記載之方法，從[4- ( 6-胺甲醯基-7-甲氧基 喹啉-4-基氧）-2-氟苯基]胺甲酸苯酯（80 mg)及環戊胺（3 8 mg)，得到標題化合物（68 mg)。 丨 H-NMR _SO-d6)5(ppm): 1.30-1.40 (2H，m)，1.49-1.59 (4H, m), 1.78^1.88 (2H, m), 3.88-3.98 (1H, m), 4.01 (3H, s), ____- 557 - —____ 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 〜 … A7 __ __ B7 五、發明說明（552 ) 6*51 (1H, d, J=5.2 Hz), 6.67 (1H, d, J=7.2 Hz), 7.02-7.07 (1H, m), 7.27-7.33 (1H, m), 7.50 (1H, s), 7.72 (1H, br s), 7·84 (1H，br s), 8.20-8.28 (2H, m)，8·63-8·67 (2H，m)。 實施例487 胺曱醯基-7-甲氳基-4-4啉基）氣1笨基 丙某）Μ 藉由實施例11記載之方法，從[4- ( 6-胺甲醯基-7-甲氧基 4琳-4-基氧）-2-氟苯基]胺甲酸苯s旨（60 mg)及異丙胺（25 mg)，得到標題化合物（39 mg)。 lH-NMR (DMSO-d6) 5 (ppm): 1.09 (6H3 d, J=6.4 Hz), 3.70-3.80 (1H, m), 4.01 (3H, s), 6.50-6.55 (2H, m), 7.03-7.07 (1H, m), 7.27-7.34 (1H, m), 7.50 (1H, s), 7.72 (1H, br s)3 7.84 (1H，br s)，8.20-8.27 (2H，m)，8.63-8.66 (2H, m)。 實施例488JH-NMR (DMSO-d6) 5 (ppm): 0.38-0.41 (2H, m)3 0.62-0.66 (2H, m), 2.51-2.59 (1H, m), 4.01 (3H, s), 6.52 (1H , d, J=5.2 Hz), 6.78-6.81 (1H, m), 7.04-7.09 (1H, m), 7.28-7.34 (iH m), 7.50 (1H, s), 7.72 (1H, br s), 7.84 (1H, br s), 8.16-8.23 (2H, m), 8.63-8.67 (2H, m). The starting materials were synthesized as described below. Production Example 482-1 "4-2 (A-Aminomethylmercaptobis 7-methoxyquinolin-4-oxo)-2-chlorobenzene 1 葚 葚 碎 碎 酯 藉 藉 藉 藉 藉 藉 藉 藉 藉 藉 藉The title compound was obtained from the title compound of carbazyl-4-(4-amino-3-fluorophenoxy)-7-methoxyquinoline. mp NMR (CDC13) δ (ppm) ): 4.13 (3H, s), 5.90 (1H, br s), 6.53 (1H, d, J = 5.6 Hz), 6.99-7.06 (2H, m), 7.20-7.30 (4H m) 7.40-7.45 (2H , m), 7.59 (1H, s), 7.80 (IH, br s), 8.24 (1H, br s), 8.68 (1H, d, J = 5.6 Hz), 9.27 (1H, s). Example 483 N —-(2-Fluoro-·4-·"(6·-·Aminomethylhydrazin-7-A gas, a certain porphyrin) 蚤 节 u u u N'-(2-carbazole) urea-555 - This paper scale applies to the Chinese National Standard (CNS) 'A4 specification (210X297 mm) 1304061 ~ -- A7 ________ B7 V. Description of the invention (55〇) Synthesized from Example 152-5 by the method described in Example 224 6-Aminocarboxylidene 4-(4-amino-3-fluorophenoxy)-7-methoxyquinoline (60 mg) and N-(2-thiazolyl)carbamic acid phenyl ester (6 〇) The title compound (24 mg) was obtained as pale yellow crystals. NMR (DMSO-d6) m): 4.02 (3H, s), 6.57 (1H3 d, J=5.2'Hz), 7.12-7.18 (2H, m), 7.37-7.45 (2H, m)5 7.51 (1H, s), 7.73 (1H , br s), 7.85 (1H, br s), 8.18-8.26 (1H, m)5 8.64-S-69 (2H, m) ° Example 484 methylamine.,yl)carbonyl-7-hydrazine hydrogen- 4-4 phenyl 1 hydroquinone KN, - cyclopropyl swell by N_[4-(7-methoxy-6-methylcarbamic acid σ quinol-4-yl) by the method described in Example 11 Phenyl phenyl] phenyl carbamate (8 mg) and cyclopropylamine (2 mg) gave the title compound (33 mg) as pale yellow crystals. ^-NMR (DMSO-d6) 5 (ppm); 0.39-0.43 (2H, m)3 0.62-0.68 (2H, m), 2.50-2.58 (1H, m), 2.84 (3H,d,J=4.8 Hz ), 4.02 (3H, s), 6.43-6.46 (2H, m), 7.14, 7.20 (2H, m), 7.50 (lH, s), 7.53-7.57 (2H, m), 8·35-8 · 38 (1H, m), 8.47 (1H, br s), 8.61 (1H, s), 8.64 (1H, d, J = 5, 2 Hz). The starting material was synthesized by the following method. Production Example 484-1 ^[+(7-methoxy oxylquinolinyl) phenyl 1 amine carboxylic acid cumyl ester _ - by the method described in Production Example 17, from '(4-aminophenoxy)基卜7_methoxy_ - - - __ - 556 - This paper scale applies to Chinese National Standard (CNiS) A4 specification (210X297 public)-&quot;一^ -- 1304061 A7 B7 V. Description of invention (551) Quinoline-6-carboxylic acid decylamine (53 mg) gave the title compound (6 (3 mg). lH-NMR (CDCl3) &lt;5 (ppm): 3.08 (3H, d, J = 4.8 Hz), 4.12 (3H, s), 6.48 (1H, d, J=5.2 Hz), 7.14-7.29 (6H, m), 7.37-7.45 (2H, m), 7.55-7.63 (3H, m), 7.89 (1H, Br s), 8.63 (1H, d, J = 5.2 Hz), 9·28 (1H, s). Example 485 1 (2-Fluorobis 4-"(6-Aminocarboxam-7-曱 gas -4-啐嗾() gas 1 stupid base)-Ν·-cyclobutide month urine by the method described in Example 11, from [4-(6-aminocarbazinyl-7-methoxy 4 drip - Phenyl 4-yloxy)-2-fluorophenyl]carbamate (73 mg) and cyclobutylamine (28 mg) ield the title compound (28 mg). NMR (DMSO-d6) (ppm) : 2.52-2.67 (2H, m), 2.72-2.87 (2H,m),2·14,2·26 (2H,m),4·01 (3H,s)5 4.04-4.18 (1H,m), 6.51 ( 1H,d,J=5.2 Hz),6·88 (1H,d,J=8.0 Hz), 7.02-7.08 (1H, m), 7.27-7.34 (1H, m), 7.50 (1H, s)5 7.72 (1H, br s)3 7.84 (1H, br s), 8·15-8·26 (2H, m), 8·63-8·67 (2H, m). Example 486 Amine -7 -Methylhydro-4-indole quinolyl)oxylphenyl)-cyclopentanyl was synthesized from [4-(6-Aminomethylmercapto-7-methoxyquinoline) by the method described in Example 11. Phenyl 4-yloxy)-2-fluorophenyl]carbamate (80 mg) and cyclopentylamine (38 mg) gave the title compound (68 mg). 丨H-NMR _SO-d6)5 (ppm) : 1.30-1.40 (2H,m), 1.49-1.59 (4H, m), 1.78^1.88 (2H, m), 3.88-3.98 (1H, m), 4.01 (3H, s), ____- 557 - —____ This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1304061 ~ ... A7 __ __ B7 V. Invention description (552) 6*51 (1H, d, J=5.2 Hz), 6.67 (1H, d , J=7.2 Hz), 7.02-7.07 (1H, m), 7.27-7.33 (1H, m), 7.50 (1H, s), 7.72 (1H, br s), 7·84 (1H, br s), 8.20-8.28 (2H, m), 8·63-8·67 (2H, m). Example 487 Amidino-7-methylindol-4-ylpropanyl) gas (1,6-aminocarbazin-7) by the method described in Example 11 -Methoxy-4-lin-4-yloxy)-2-fluorophenyl]carbamic acid Benzene (60 mg) and isopropylamine (25 mg) lH-NMR (DMSO-d6) 5 (ppm): 1.09 (6H3 d, J=6.4 Hz), 3.70-3.80 (1H, m), 4.01 (3H, s), 6.50-6.55 (2H, m), 7.03 -7.07 (1H, m), 7.27-7.34 (1H, m), 7.50 (1H, s), 7.72 (1H, br s)3 7.84 (1H, br s), 8.20-8.27 (2H, m), 8.63 -8.66 (2H, m). Example 488

Mr「4- ( 6-胺甲酿基-7-甲氧基-4- 4成）氣-2-甲基-笨某1- Ν’ -環丙基Μ 將環丙胺（0·10 ml)加至二甲基亞颯（0·8 ml)中，然後將 [4-(6-胺甲醯基-7-甲氧基-4-喹啉基）氧卜2-甲基苯基]胺基 曱酸苯酯（136 mg)溶於其中並攪拌1〇分鐘。在該反應溶液 中加入水及乙酸乙酯，然後濾取析出之結晶，得到標題化 合物（90 mg)。 lH-NMR (DMSO-d6) 5 (ppm): 0.38-0.44 (2H, m), 0.62-0.69 (2H, m), 2.22 (3H, s), 2.53-2.60 (1H, m), 4.03 (3H, s), 6.46 (1H, d, J=5.2 Hz), 6.75-6.79 (1H, m), 7.01-7.12 (2H, m), -558 - __-- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 B7 553&gt; 五、發明説明（ 7.50 (1H, s), 7.62 (1H, s), 7.73 (1H, br s), 7.85 (1H, br s), 7.90-7.96 (1H，m)，8·62-8.69 (2H, m)。 以下述3步驟合成起始物質。 製造例488-1 甲表二硝某苯氫某卜7-曱單 藉由·與製造例7同樣之方法，從'甲氧基氯喹啉羧 醯胺（1·〇 g)及4-硝基-3-甲基酚（810 mg)，得到標題化合物 (1.2 g)。 H-NMR (DMSO-d6)c5(ppm): 2.54 (3H，s)，4·〇〇 (3H，s)，6.80 (1Η，d，J=5.2 Ηζ)，7.28-7.32 (1Η，m)，7·41·7·43 (1Η，m)， 7.54 (1H, s), 7.72 (1H, br s), 7.83 (1H, br s)5 S.13-8.16 (1H, m)，8·55 (1H，s)，8·72-8·76 (1H, m)。 製造例488-2 6-胺甲酿基-7-甲氧基-4-4淋基）氧-2-甲果-笨胺 藉由與製造例8同樣之方法，從6-胺甲醯基甲基-4-硝基苯氧基）-7-甲氧基喹啉（1·2 g)，得到標題化合物（〇 22 g) 0 !H-NMR (DMSO-d6) δ (ppm): 2.07 (3Η, s), 4.〇〇 (3H, s), 4.88-4.94 (2H, m), 6.39 (1H, d, J=5.2 Hz), 6.70-6.71 (1H, m), 6.77-6.88 (2H, m), 7.46 (1H, s), 7.70 (lH, br s), 7.83 (1H, br s)，8.59 (1H，d，J=5_2 Hz)，8.66 (1H，s)。 製造例4SS-3Mr"4-(6-Aminomethyl-7-methoxy-4-4) gas-2-methyl-stupid 1- Ν'-cyclopropyl hydrazine Cyclopropylamine (0·10 ml) Add to dimethyl hydrazine (0·8 ml), then [4-(6-aminomethylmethyl-7-methoxy-4-quinolinyl)oxy-2-methylphenyl]amine The phenyl decanoate (136 mg) was dissolved therein and stirred for 1 hr. Water and ethyl acetate were added to the reaction mixture, and the crystals crystals were filtered to give the title compound (90 mg). -d6) 5 (ppm): 0.38-0.44 (2H, m), 0.62-0.69 (2H, m), 2.22 (3H, s), 2.53-2.60 (1H, m), 4.03 (3H, s), 6.46 (1H, d, J=5.2 Hz), 6.75-6.79 (1H, m), 7.01-7.12 (2H, m), -558 - __-- This paper size applies to China National Standard (CNS) A4 specification (210X297) PCT) 1304061 A7 B7 553&gt; V. INSTRUCTIONS ( 7.50 (1H, s), 7.62 (1H, s), 7.73 (1H, br s), 7.85 (1H, br s), 7.90-7.96 (1H, m) , 8·62-8.69 (2H, m). The starting material was synthesized in the following three steps. Production Example 488.1 Azene, a benzene, a benzene, a hydrogen, a benzene, a ruthenium, and the same method as in Production Example 7, From 'methoxy chloroquinoline carboxamide (1·〇g) and 4-nitro-3-methyl Phenol (810 mg) gave the title compound (1.2 g). H-NMR (DMSO-d6) C5 (ppm): 2.54 (3H, s), 4 〇〇 (3H, s), 6.80 (1 Η, d, J=5.2 Ηζ), 7.28-7.32 (1Η,m),7·41·7·43 (1Η,m), 7.54 (1H, s), 7.72 (1H, br s), 7.83 (1H, br s) 5 S.13-8.16 (1H, m), 8·55 (1H, s), 8·72-8·76 (1H, m). Production Example 488-2 6-Amineyl-7-methoxy 4--4-mercaptomethyl-4-nitrophenoxy-7-methoxyl by the same method as in Production Example 8 Base quinoline (1. 2 g), the title compound ( 〇 22 g) </RTI> NMR (DMSO-d6) δ (ppm): 2.07 (3 Η, s), 4. 〇〇 (3H, s), 4.88-4.94 (2H, m), 6.39 (1H, d, J=5.2 Hz), 6.70-6.71 (1H, m), 6.77-6.88 (2H, m), 7.46 (1H, s), 7.70 (lH, Br s), 7.83 (1H, br s), 8.59 (1H, d, J=5_2 Hz), 8.66 (1H, s). Manufacturing Example 4SS-3

Li^L6-胺甲遍基·- 7-甲氧基-4- 4 g林義·丄氢二g-甲基茇某·[胺基 ΣΜΛΜ_ -559 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 χ 297公釐） 1304061 A7 B7 554&gt; 五、發明説明（ 藉由與製造例141-1記載之方法，從4_(心胺甲醯基甲 氧基-4-喹啉）氧-2-甲苯基胺，得到標題化合物。 iH-NMR (CDCl3)5(PPm): 2·38 (3H，s)，4·12 (3H，s)，5·88 (1Η, br s), 6.49 (1H, d5 J=5.6 Hz), 6.76 (1H, br s), 7.04-7.09 (2H，m)，7.20-7.29 (3H，m)，7.38-7.45 (2H，m)，7·54 (1H，s)， 7.80 (1H, br s), 7.94 (1H, br s), 8.64 (1H, d, J=5.6 Hz) 9 29 (lH，s)。 ，· 實施例489 6-胺甲酿基-7·甲氧茱·4-,奎啉某）氧'^^氣甲某-草 基環丙某胧 將環丙胺（0·10 ml)加至二甲基亞颯（〇·8加）中，然後將 [4-(6-胺甲醯基-7-甲氧基-4-喹啉基）氧-2-三氟甲基苯基] 胺基甲酸苯酯（140 mg)溶於其中並攪拌10分鐘。在該反應 溶液中加入水及乙酸乙酯，然後濾取析出之結晶，得到標 題化合物（103 mg)。 lH-NMR (DMSO-d6) 5 (ppm)： 0.38-0.44 (2H, m), 0.62-0.68 (2H, m), 2:51-2.59 (1H, m), 4.02 (3H, s)5 6.52 (1H, d, J=5.2Li^L6-amine methionyl·- 7-methoxy-4- 4 g linyi·丄hydrogen di g-methyl 茇··[Amine ΣΜΛΜ_ -559 - This paper scale applies to Chinese National Standard (CNS) Α4 size (210 χ 297 mm) 1304061 A7 B7 554&gt; 5. Description of the invention (by the method described in Production Example 141-1, from 4_(Hematic amine-mercaptomethoxy-4-quinoline)oxy- 2-Tolylamine, the title compound is obtained. iH-NMR (CDCl3) 5 (PPm): 2·38 (3H, s), 4·12 (3H, s), 5·88 (1Η, br s), 6.49 (1H, d5 J=5.6 Hz), 6.76 (1H, br s), 7.04-7.09 (2H, m), 7.20-7.29 (3H, m), 7.38-7.45 (2H, m), 7·54 (1H , s), 7.80 (1H, br s), 7.94 (1H, br s), 8.64 (1H, d, J = 5.6 Hz) 9 29 (lH, s)., · Example 489 6-Amine -7-methoxy 茱·4-, 奎 某 a) Oxygen '^^ 气甲甲-草基环丙胧 Add cyclopropylamine (0·10 ml) to dimethyl hydrazine (〇·8 plus) Then, [4-(6-Aminomethylamido-7-methoxy-4-quinolinyl)oxy-2-trifluoromethylphenyl]carbamic acid phenyl ester (140 mg) was dissolved therein Stir for 10 minutes. Water and ethyl acetate were added to the reaction solution, and the crystals thus precipitated were filtered to give the title compound (103 mg). lH-NMR (DMSO-d6) 5 (ppm): 0.38-0.44 (2H, m), 0.62-0.68 (2H, m), 2:51-2.59 (1H, m), 4.02 (3H, s)5 6.52 (1H, d, J=5.2

Hz), 7.18-7.24 (1H，m)，7·50-7·62 (3H，m)，7.70-7.77 (2H， m), 7.84 (1H, br s)3 8.07-8.14 (1H, m), 8.64-8.69 (2H, m) 用下述3步驟合成起始物質e 製造例489- 1 6-胺基甲基-4-硝基苯氣基）-7-甲氣某4咻 藉由與製·造例7同樣之方法，從7_甲氧基-4-氯喹啉-6-羧 酸（900 mg)及4-硝基(三氟甲基）酚，得到標題化合物 560 - 本紙張尺度適用中國國豕標準(CMS) A4規格（210 X 297公爱） 裝 訂 線 1304061 A7 ____B7 五、發明説明（555) (1_2 g)。 lH-NMR (DMSO-d6) 5 (ppm): 4.03 (3H, s), 6.91 (1H, d, J=5.2 Hz), 7.57 (1H, s), 7.72-7.87 (3H, m), 8.01-8.05 (1H, m), 8.27-8.32 (1H, m), 8.58 (1H, s), 8.75-8.79 (1H} m) 製造例489-2 ， m卜胺甲-鷗基三氟甲某苯眩 將6-胺甲醯基-4-(3-三氟甲基-4-硝基苯氧基）甲氧基 喹啉（0.60 g)溶於四氫呋喃（10 ml)及甲醇（1〇以），用鈀/碳 (600 mg)在氫氣蒙氣下，進行接觸還原1〇小時。得到標題 化合物（0.60 g)。 iH-NMR (DMS〇-d6)5(ppm): 4.00 (3H，s)，5·71 (2H，br s) 6.42 (1H, d, J=5.2 Hz), 6.93-6.98 (1H, m), 7.23-7.30 (2H m) 7·46-7·52 (1H，m)，7.71 (1H，br s)，7.83 (1H，br s)，8.6(M,69 (2H，m)。 ^ 製造例489-3 f 4- ( 6-胺甲酿基-7-甲氣某-4_邊g林基）氧-三氧甲某^ 胺基曱酸笨酯 藉由製造例141-1記載之方法，從4-(6-胺甲醯基-7-甲氧 基-4-喹啉基）氧-2-三氟甲基苯胺得到標題化合物。 ^H-NMR (CDCl3)5(ppm): 4·12 (3H，s)，5.90 (1H，br s)，6.48 (1H，d，J=5.6 Hz)，7.20-7.30 (4H，m)，7·38-7·51 (3H，m) 7·56 (1H，s)，7.80 (1H，br s)，8.27-8.31 (1H，m)，8.70 (1H，d J=5.2 Hz); 9·26 (1H，s)。 ’ 實施例490 -561 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） A7 B7Hz), 7.18-7.24 (1H, m), 7·50-7·62 (3H, m), 7.70-7.77 (2H, m), 7.84 (1H, br s)3 8.07-8.14 (1H, m) , 8.64-8.69 (2H, m) The starting material e was synthesized by the following three steps. Production Example 489-1 6-Aminomethyl-4-nitrobenzene group)-7-Methane A 4咻 by Preparation Example 7 In the same manner, from 7-methoxy-4-chloroquinolin-6-carboxylic acid (900 mg) and 4-nitro(trifluoromethyl)phenol, the title compound 560 was obtained. Applicable to China National Standard (CMS) A4 specification (210 X 297 public) Gutter 1304061 A7 ____B7 V. Invention description (555) (1_2 g). lH-NMR (DMSO-d6) 5 (ppm): 4.03 (3H, s), 6.91 (1H, d, J = 5.2 Hz), 7.57 (1H, s), 7.72-7.87 (3H, m), 8.01- 8.05 (1H, m), 8.27-8.32 (1H, m), 8.58 (1H, s), 8.75-8.79 (1H} m) Production example 489-2, m-amyl-gull-trifluoromethane 6-Aminomethylmercapto-4-(3-trifluoromethyl-4-nitrophenoxy)methoxyquinoline (0.60 g) was dissolved in tetrahydrofuran (10 ml) and methanol (1 g). Contact reduction was carried out for 1 hour using palladium on carbon (600 mg) under hydrogen atmosphere. The title compound (0.60 g) was obtained. iH-NMR (DMS〇-d6) 5 (ppm): 4.00 (3H, s), 5·71 (2H, br s) 6.42 (1H, d, J = 5.2 Hz), 6.93-6.98 (1H, m) , 7.23-7.30 (2H m) 7·46-7·52 (1H,m), 7.71 (1H,br s),7.83 (1H,br s),8.6 (M,69 (2H,m). ^ Manufacturing Example 489-3 f 4-(6-Amine-mercapto-7-methyl-a-4-side g-linyl)oxy-trimethoxymethyl-amino citric acid ester as described in Production Example 141-1 The title compound was obtained from 4-(6-aminocarbazin-7-methoxy-4-quinolinyl)oxy-2-trifluoromethylaniline.H-NMR (CDCl3) 5 (ppm): 4·12 (3H, s), 5.90 (1H, br s), 6.48 (1H, d, J = 5.6 Hz), 7.20-7.30 (4H, m), 7·38-7·51 (3H, m) 7·56 (1H, s), 7.80 (1H, br s), 8.27-8.31 (1H, m), 8.70 (1H, d J = 5.2 Hz); 9·26 (1H, s). 'Example 490 -561 - This paper size is applicable to China National Standard (CNS) A4 specification (21〇x 297 mm) A7 B7

1304061 五、發明説明（556) m4-(6-胺〒酷茱-7-甲氣基-4- P杳说基）氳二甲苯某]^ 環丙某Μ 將環丙胺（0·10 ml)加至二甲基亞颯（3.0 ml)中，然後將 [4-(6-胺甲醯基-7-甲氧基喹啉基）氧]_2,3_二甲苯基]胺 基甲酸苯酯（120 mg)溶於其中並攪拌10分鐘。在該反應溶 液中加入水及乙酸乙酯，然後濾取析出之結晶，得到標題 化合物（60 mg)。 'H-NMR (DMSO-d6) 5 (ppm)： 〇.37-0.44 (2H, m)5 0.60-0.65 (2H, m)，2.01 (3H，s)，2·14 (3H, s)，4.01 (3H，s), 6.23 (1Ή, d， J=5.2 Hz)，6.64-6.69 (1H，m)，6·98 (1H，d，J=8.8 Hz)，7·5〇 (1H，s)，7,60-7.69 (2H，m)，7·73 (1H, br s)，7·85 (1H，br s)， 8·60 (1H，d，5.2 Hz)，8·71 (1H，s)。 用下述2步驟合成起始物質。 製造例490- 1 1-.,(.6-胺甲醯基-7-甲氧基-4-崦嗾甚、荽.-2,3-二甲茉胺基 藉由與製造例7同樣之方法，從7-甲氧基-4-氯喹啉-6-羧 酸（890 mg)及4-硝基-2,3-二甲基酚（940 mg)得到標題化合 物（840 mg)。繼而將6-胺曱醯基-4-(2,3 -二甲基-4-硝基苯 氧基）-7-曱氧喹啉（840 mg)溶於四氫呋喃（25 ml)及甲醇（25 ml)，用鈀/碳（84〇 mg)在氫氣蒙氣下進行接觸還原10小 時。得到標題化合物（639 mg)。 H-NMR (DMS〇-d6) 5 (ppm): 1.92 (3H，s)，2·〇2 (3H，）’ 〇〇 (3Η，s)，4:82-4.88 (2Η，m)，6.22 (1Η，d，Ηζ)，6·60 (1Η， d, J=8.4 Hz), 6.75 (1H, d, J=8.4 Hz), 7.47 (lH, 7.71 (1H, -562 - 本畝張尺度適用中國國家標準(CNS) A4規格(210X297公爱）1304061 V. INSTRUCTIONS (556) m4-(6-Amine 〒 茱-7-Methane-4-P 杳 基) 氲 xylene ] ^ ^ 丙 Μ Μ 环 Cyclopropylamine (0·10 ml) Add to dimethyl hydrazine (3.0 ml), then [4-(6-aminocarbamido-7-methoxyquinolyloxy)oxy]_2,3-dimethylphenyl]carbamic acid phenyl ester (120 mg) was dissolved in it and stirred for 10 minutes. Water and ethyl acetate were added to the reaction mixture, and the crystals obtained were filtered to give the title compound (60 mg). 'H-NMR (DMSO-d6) 5 (ppm): 〇.37-0.44 (2H, m)5 0.60-0.65 (2H, m), 2.01 (3H, s), 2·14 (3H, s), 4.01 (3H, s), 6.23 (1Ή, d, J=5.2 Hz), 6.64-6.69 (1H, m), 6.98 (1H, d, J=8.8 Hz), 7·5〇 (1H, s ), 7,60-7.69 (2H,m),7·73 (1H, br s),7·85 (1H,br s), 8·60 (1H,d,5.2 Hz),8·71 (1H , s). The starting materials were synthesized in the following two steps. Production Example 490- 1 1-., (.6-Aminomethylindol-7-methoxy-4-oxime, oxime-2,3-dimethylmosamine) The same procedure as in Production Example 7 Method, the title compound (840 mg) was obtained from 7-methoxy-4-chloroquinoline-6-carboxylic acid (890 mg) and 4-nitro-2,3-dimethylphenol (940 mg). 6-Aminyl-4-(2,3-dimethyl-4-nitrophenoxy)-7-anthraquinoline (840 mg) dissolved in tetrahydrofuran (25 ml) and methanol (25 ml) Contact reduction with palladium on carbon (84 mg) under hydrogen atmosphere for 10 hours to give the title compound (639 mg). H-NMR (DMS 〇-d6) 5 (ppm): 1.92 (3H, s), 2·〇2 (3H,)' 〇〇(3Η,s), 4:82-4.88 (2Η,m), 6.22 (1Η,d,Ηζ),6·60 (1Η, d, J=8.4 Hz) , 6.75 (1H, d, J=8.4 Hz), 7.47 (lH, 7.71 (1H, -562 - this acre scale applies Chinese National Standard (CNS) A4 specification (210X297 public)

裝 訂Binding

1304061 A7 B7 五、發明説明（ 557 &gt; br s)，7·84 (1H，br s)，8·57 (1H，d，J=5.2 Hz)，8 7〇 (1H s)。 製造例490-2 ， 胺甲酿基-7-甲氣基-4-p备成某）备， ~~ -^甲某笨基 1 胺基甲酸笨酯 藉由製造例141-1 s己載之方法’從4-(6 -胺甲g乾里 ^ :¾ - 7 -甲氧i 基-4-喹啉基）氧-2,3-二甲苯胺得到標題化合物。 lH-NMR (CDC13) δ (ppm): 2.13 (3H, s), 2.33 (3h s) 4 13 (3H，s)，· 5·88 (1H，br s)，6·29 (1H，d，J=5.6 Hz) 6 98-701 (1H，m)，7.20-7.25 (4H，m)，7·38-7·42 (2H，m)，7 54 (1H s) 7·70 (1H，br s)，7.80 (1H，br s)，8.60 (1H，d，j&gt;5 6 Hz) 9 % (1H，s) ’ 實施例491 f 4-(6-胺甲醯基-7-甲氧基-4-4啉基）氣，^^甲茉某u Ν’-環丙基脲 將環丙胺（0.06 ml)加至二甲基亞颯（2.0 ml)中，然後將 [4-(6-胺甲酿基-7-曱氣基-4-峻〃林基）氣-2,5 -二甲苯基]胺 基甲酸苯酯（100 mg)溶於其中並攪拌10分鐘。在該反應溶 液中加入水及乙酸乙酯，然後濾取析出之結晶，得到標題 化合物（60 mg)。 lH-NMR (DMSO-d6) 5 (ppm): 0.40-0.44 (2H, m), 0.63-0.67 (2H，m)，2.04 (3H，s)，2·17 (3H，s)，2.53-2.60 (1H，m)，4.03 (3H, s), 6.29 (1H, d, J=5.2 Hz), 6.75-6.78 (1H, m), 7.02 (1H, s)，7.51 (iri，s)，7.58 (1H，s)，7·74 (1H，br s)，7.83-7.88 (2H， m)，8.62 (1H，d，5.2 Hz), 8·72 (1H，s)。 -563 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）1304061 A7 B7 V. Description of the invention ( 557 &gt; br s), 7.84 (1H, br s), 8.57 (1H, d, J = 5.2 Hz), 8 7 〇 (1H s). Production Example 490-2, Aminomethyl-7-Methane-4-p prepared into a certain preparation, ~~-^A Astyl 1 Aminocarbamic acid ester was produced by the production example 141-1 s The title compound was obtained from 4-(6-aminomethylglylider: 3⁄4-7-methoxyi-4-yl-2-quinolinyl)oxy-2,3-dimethylaniline. lH-NMR (CDC13) δ (ppm): 2.13 (3H, s), 2.33 (3h s) 4 13 (3H, s), · 5.88 (1H, br s), 6.29 (1H, d, J=5.6 Hz) 6 98-701 (1H, m), 7.20-7.25 (4H, m), 7·38-7·42 (2H, m), 7 54 (1H s) 7·70 (1H, br s), 7.80 (1H, br s), 8.60 (1H, d, j &gt; 5 6 Hz) 9 % (1H, s) ' Example 491 f 4-(6-Aminomethylindol-7-methoxy -4-4 phenyl) gas, ^^ 甲甲u u Ν'-cyclopropyl urea Cyclopropylamine (0.06 ml) was added to dimethyl hydrazine (2.0 ml), then [4-(6- Aminomethyl-7-helium-4-ylindole-based phenyl-2,5-dimethylphenyl]carbamic acid phenyl ester (100 mg) was dissolved therein and stirred for 10 minutes. Water and ethyl acetate were added to the reaction mixture, and the crystals obtained were filtered to give the title compound (60 mg). lH-NMR (DMSO-d6) 5 (ppm): 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), 2.04 (3H, s), 2·17 (3H, s), 2.53-2.60 (1H,m), 4.03 (3H, s), 6.29 (1H, d, J=5.2 Hz), 6.75-6.78 (1H, m), 7.02 (1H, s), 7.51 (iri, s), 7.58 ( 1H, s), 7.74 (1H, br s), 7.83-7.88 (2H, m), 8.62 (1H, d, 5.2 Hz), 8.72 (1H, s). -563 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm)

裝 訂Binding

線 1304061 〜 … A7 ___________B7 五、發明説明Ί ~) —&quot; 用下述2步驟合成起始物質。 篮^例491- 1 甲..里崦啉基）氫-2} 將4-胺基-2,5-二甲基酚（1,〇 g)溶於二甲基甲醯胺（5 ml)，加入60〇/〇氫化鈉（1·〇 g)並攪拌一會。在其中加入'甲 氧基-4-氯喹啉-6-羧醯胺（9〇〇 mg)並於100它加熱6小時。 在該反應溶液中加入水，用乙酸乙酯萃取，將有機層用水 及飽和食鹽水依次洗淨後，用無水硫酸鈉乾燥及減壓餾去 溶媒。將得到之粗生成物用乙酸乙酯洗淨，得到標題化合 物（135 mg)。 iH-NMR (DMSO-d6)5(ppm): 1·91 (3H，s)，2.03 (3H，s)，4·01 (3Η，s)，6·26 (1Η，d，J=5.2 Hz), 6.57 (1Η，s)，6.77 (1Η，s)， 7.46 (1H，s)，7.70 (1H，br s)，7·83 (1H，br s)，8·57 (1H，d， J=5.2 Hz)，8·69 (1H，s)。 製造例491-2 「4-(6-胺甲醯基-7-甲氣某-4·^杏琳基二甲基茉某1 胺基甲酸笨酯 藉由製造例141 - 1記載之方法，從4- ( 6-胺甲醯基-7-甲氧 基-4-喹啉基）氧-2,5-二甲苯胺得到標題化合物。 W-NMR (CDCl3)5(ppm): 2·13 (3H，s)，2.33 (3H，s)，4.13 (3Η，s)，5.88 (1Η，br s)，6.30 (1Η，d，J二5·6 Hz), 6.75 (1Η，br s), 6.94 (1H, s), 7.18-7.32 (3H, m), 7.38-7.45 (2H, m), 7.54 (1H，s), 7·82 (2H, br s), 8·62 (1H，d, )=5.6 Hz), 9·32 (1H， s) 〇 ____- 564 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 -. A7 ___B7 五、發明説明（~~ 實施例492 {4:丨6-氰基-Ό-# 咯啶·丨-基）丙氫某）峰毗j· 基氧Ulr氟苯基卜Ν’-(4-^笨某）踫 在Ν-[4-(6-氰基-7-環氧乙烷甲氧基喹啉_心基氧卜2•氟苯 基]-N -(4-氟苯基）脲（1〇〇 mg)中，加入四氫呋喃i 及吡 咯啶0·1 ml，並於5(TC加熱30分鐘，將該反應溶液用NH矽 凝膠官柱層析（乙酸乙酯-甲醇系）精製，得到為淡黃色結晶 之標題化合物（45 mg)。 W-NMR (DMSO-d6) 5 (ppm): 1.60-1.70 (4H，m)，2.40-2.75 (6H, m), 3.95-4.05 (1H, m), 4.20 (1H, dd5 J=l〇, 6.0 Hz), 4.30 (1H, dd, J=l〇, 4 Hz), 5.02 (1H, d, J=4.4 Hz), 6.61 (1H, d, J=5.2), 7.10-7.17 (3H, m), 7.35-7.50 (3H, m), 7.62 (1H, s), 8.21-8.27 (1H, m), 8.62-8.64 (1H, m), 8.72-8.75 (2H, m), 9.09 (1H，br s)。 用下述2步騾合成起始物質。 製造例492-1 心（4·疫蓋氟苯氧基）·7-環氧喹啉-6_甲腈 在心（‘胺基氟苯氧基）-6_氰基-7-羥基喹啉（400 mg) 中，加入一甲基甲醯胺6 ml，表溴醇13 Μ及碳酸鉀％〇 mg,並於1溫攪拌一夜。在該反應溶液中加入水及用乙酸 乙酯萃取，將有機層用水及飽和食鹽水依次洗淨後，用無 水硫酸鈉乾燥及減壓餾去溶媒，得到標題化合物（4〇〇 mg)。 . · lH-NMR (DMSO-d6) 5 (ppm)： 2.79-2.93 (2H, m), 3.42-3.49 _____- 565 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐）Line 1304061 ~ ... A7 ___________B7 V. Description of the invention Ί ~) -&quot; The starting materials were synthesized by the following two steps. Basket ^ 491 - 1 A.. ribolinyl) Hydrogen - 2} Dissolving 4-amino-2,5-dimethylphenol (1, 〇g) in dimethylformamide (5 ml) Add 60 〇/〇 sodium hydride (1·〇g) and stir for a while. 'Methoxy-4-chloroquinolin-6-carboxamide (9 mg) was added thereto and heated at 100 for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained crude product was washed with ethyl acetate to give the title compound (135 mg). iH-NMR (DMSO-d6) 5 (ppm): 1·91 (3H, s), 2.03 (3H, s), 4·01 (3Η, s), 6·26 (1Η, d, J=5.2 Hz ), 6.57 (1Η, s), 6.77 (1Η, s), 7.46 (1H, s), 7.70 (1H, br s), 7·83 (1H, br s), 8·57 (1H, d, J =5.2 Hz), 8·69 (1H, s). Production Example 491-2 "4-(6-Aminomethylmercapto-7-methyl-a-4-^-Plantyl-Dimethyl-Molyl 1 Aminocarbamic Acid) The method described in Production Example 141-1, The title compound was obtained from 4-(6-aminocarbazinyl-7-methoxy-4-quinolinyl)oxy-2,5-dimethylaniline. W-NMR (CDCl3) 5 (ppm): 2·13 (3H, s), 2.33 (3H, s), 4.13 (3Η, s), 5.88 (1Η, br s), 6.30 (1Η, d, J 2·5 Hz), 6.75 (1Η, br s), 6.94 (1H, s), 7.18-7.32 (3H, m), 7.38-7.45 (2H, m), 7.54 (1H, s), 7·82 (2H, br s), 8·62 (1H,d, )=5.6 Hz), 9·32 (1H, s) 〇____- 564 - This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 -. A7 ___B7 V. Invention description (~ ~ Example 492 {4: 丨6-cyano-Ό-# 咯 丨 丨 基 基 基 丙 丙 丙 丙 丙 丙 · · · · · · · · · · · - - - - - - - - - - - - - - - - - - - - Ν-[4-(6-Cyano-7-oxirane methoxyquinoline-cardoyloxybi-2-fluorophenyl]-N-(4-fluorophenyl)urea (1〇〇mg) Into the tetrahydrofuran i and pyrrolidine 0·1 ml, and heated at 5 (TC for 30 minutes, the reaction solution was chromatographed with NH矽 gel column chromatography (ethyl acetate- The title compound (45 mg) was obtained as a pale yellow crystal. W-NMR (DMSO-d6) 5 (ppm): 1.60-1.70 (4H, m), 2.40-2.75 (6H, m), 3.95 -4.05 (1H, m), 4.20 (1H, dd5 J=l〇, 6.0 Hz), 4.30 (1H, dd, J=l〇, 4 Hz), 5.02 (1H, d, J=4.4 Hz), 6.61 (1H, d, J=5.2), 7.10-7.17 (3H, m), 7.35-7.50 (3H, m), 7.62 (1H, s), 8.21-8.27 (1H, m), 8.62-8.64 (1H, m), 8.72-8.75 (2H, m), 9.09 (1H, br s). The starting material was synthesized by the following two steps: Production Example 492-1 Heart (4 epoxide fluorophenoxy)·7- Epoxyquinoline-6-carbonitrile in the heart ('aminofluorophenoxy)-6-cyano-7-hydroxyquinoline (400 mg), add 6 ml of monomethylformamide, epibromohydrin 13 Μ and potassium carbonate% 〇 mg, and stirred at 1 temperature for one night. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. · lH-NMR (DMSO-d6) 5 (ppm): 2.79-2.93 (2H, m), 3.42-3.49 _____- 565 - This paper size applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 mm) )

裝 訂Binding

1304061 、 A7 _____B7 五、發明説明(~' (1H, m), 4.15 (1H, dd, J=12, 7.2 Hz), 4.69 (1H, dd, J=12, 2.4 Hz), 5.25 (2H, br s), 6.53 (1H, d, J=5.2), 6.83-6.89 (2H, m), 7.07-7.15 (1H，m), 7.61 (1H, s)，8.69-8.74 (2H，m)。 製造例492-2 Μ:ί4:.(·6-竟^ -7二環氧乙烷某甲氳某，套啉-心某氣）·2-氩茉 基1 - Ν“ - (4-氟笨基）服 在4-(4-胺基-3-氟苯氧基）-7_環氧乙烷甲氧喹啉-6-曱腈 (400 mg)中，加入二甲基甲醯胺（2 ml)及異氰酸心氟苯酯 (0.15 ml)，並於室溫攪掉一夜。在該反應溶液中加入水及 滤取析出之結晶，得到為淡黃色結晶之標題化合物（48〇 mg)。 lH-NMR (DMSO-d6) (? (ppm): 2.79-2.95 (2H, m), 3.40-3.50 (1H, m)5 4.10-4.20 (1H, m), 4.65-4.76 (1H, m), 6.62 (1H, d, J=6.0 Hz), 7.05-7.18 (3H, m), 7.36-7.50 (3H, m), 7.62 (1H, s)5 8.20^8.28 (1H, m), 8.60-8.68 (1H, m), 8.73-8.80 (2H, m), 9.10 (1H, br s) o 實施例4 9 3 土丄土-『6-氰某- 7-(3-二乙胺某-2-蕤某雨氲基）4啉-4-某 氟笨基卜N1、4-氰苳萁、日平 在N- [ 4- ( 6-氛基-7- %氧乙燒甲氧基峻α林_ 4-基氧）-2-氣苯 基]·Ν’-(4-氟苯基）踩（1〇〇 mg)中，加入四氫呋喃1 mi及二 乙胺（0.1 ml)，並於50°C加熱30分鐘。將該反應溶液用NH 碎凝膠管柱·層析（乙酸乙酯-甲醇系）精製，得到為淡黃色結 晶之標題化合物（32 mg)。 ^7--—__· 566 - 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 1304061 A7 B7 五、發明説明（561) H-NMR (DMSO-d6) ^ (ppm): 〇 958 (6H, t, J=7 Hz), 2.4〇 2.68 (6H，m), 3·91，3·99 (1H，m)，4.20 (1H, dd, J=l〇, 5 2 4.31 (1H，dd，J=10, 3·6 Hz)，4.91 (1H，d，J=4.4 Hz)，6·61 (1Ή’ d，J=5.2 Hz)，7.10-7.17 (3H，m)，7·37·7·49 (3H，m)，7·62 (1H s)，8·21-8·27 (1H，m)，8·63 (1H，br s)，8 72_8 75 (2h， ’ 9·10 (·1Η，br s)。 ’ 叫， 實施例494 U 4-「6-氰棊-7-(π-嗎福嗾-4_某）丙氣某 基氧卜2-氟苯基卜氯1甚、B早 在N-[4-(6-氰基-7-環氧乙烷甲氧基喹啉基氧）-2•氟苯 基l· Ν’-(4-氟苯基）脲（loo mg)中，加入四氫呋喃1如及嗎 福琳0.1 ml，並.於50t：加熱30分鐘。將該反應溶液用？^矽 凝膠管柱層析（乙酸乙酯-甲醇系）精製，得到為淡黃色結晶 之標題化合物（32 mg)。 'H-NMR (DMSO-d6) (5 (ppm): 2.38-2.58 (6H, m), 3.53-3.59 (4H，m)，4.03-4.09 (1H，m)5 4.22 (1H，dd，J=10, 6 〇 Hz)， 4.31 (1H, dd, J=10, 4.0 Hz), 5.03 (1H, d5 1=4.8), 6.61 (1H, d, J=5.2 Hz)，7·10-7·17 (3H，m)，7.36-7.49 (3H，m)，7 64 (说 s)，8.20-8.27 (1H，m)，8.60-8.64 (1H，m)3 8·73·8 75 (2H ⑷， 9·10 (1H，br s)。 ’ ’ 實施例495 基氣1-2-氩·笑篡i-N、卜塞唑-2-某）脲 在N-[4-(6-氰基-7-環氧乙烷甲氧基喹啉基氧）2氣苯 567 - 本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐） 1304061 、、 、， A7 _-____B7 五、發明説明（—~' —〜-— 基]-Ν’- ( 口塞咬-2-基）月尿（120 rng) Φ , ^ , g)甲’加入四風咬喃1 ml及口比 咯疋0.1 ml並於50 C加熱40分鐘。將該反應溶液用NH矽 凝膠管柱層析（乙酸乙酿-甲醇系）精製，得到為淡黃色結晶 之標題化合物（70 mg)。 lH-NMR (DMSO-d6) 5 (ppm): 1.6〇«ι.7〇 (4H, m), 2.40-2.75 (6H, m), 3.95-4.05 (1H, in), 4.20 〇Η, dd, J=l〇, 6.0 Hz), 4.31 (1H, dd, J=10, 4 Hz), 5.02 (1H, br s), 6.62 (1H, d, J=5.21304061, A7 _____B7 V. Description of invention (~' (1H, m), 4.15 (1H, dd, J=12, 7.2 Hz), 4.69 (1H, dd, J=12, 2.4 Hz), 5.25 (2H, br s), 6.53 (1H, d, J=5.2), 6.83-6.89 (2H, m), 7.07-7.15 (1H, m), 7.61 (1H, s), 8.69-8.74 (2H, m). 492-2 Μ: ί4:. (·6- actually ^ -7 ethylene oxide a certain carbamide, set of porphyrin - heart a gas) · 2-argon oleyl 1 - Ν " - (4-fluoro phenyl Served in 4-(4-amino-3-fluorophenoxy)-7-oxirane methoxyquinoline-6-indolecarbonitrile (400 mg) with dimethylformamide (2 ml) And fluorophenyl phenyl isocyanate (0.15 ml), and the residue was stirred at room temperature overnight. lH-NMR (DMSO-d6) (? (ppm): 2.79-2.95 (2H, m), 3.40-3.50 (1H, m)5 4.10-4.20 (1H, m), 4.65-4.76 (1H, m), 6.62 (1H, d, J=6.0 Hz), 7.05-7.18 (3H, m), 7.36-7.50 (3H, m), 7.62 (1H, s)5 8.20^8.28 (1H, m), 8.60-8.68 ( 1H, m), 8.73-8.80 (2H, m), 9.10 (1H, br s) o Example 4 9 3 soil bauxite-"6-cyanyl- 7-(3-diethylamine-2-pyrene a certain rain 氲 base) 4 olin-4- fluorophenyl卜N1, 4-cyanoguanidine, and iripine in N-[ 4-(6-Akyl-7-% oxyethylidene methoxy aryl alpha _ 4-yloxy)-2- phenyl] Ν In the '-(4-fluorophenyl) step (1 〇〇mg), tetrahydrofuran 1 mi and diethylamine (0.1 ml) were added, and heated at 50 ° C for 30 minutes. The reaction solution was treated with NH crushed gel tube. Column chromatography (ethyl acetate-methanol) to give the title compound (32 mg) as pale yellow crystals. </ br> <br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br><br> X 297 mm) 1304061 A7 B7 V. Inventive Note (561) H-NMR (DMSO-d6) ^ (ppm): 〇958 (6H, t, J=7 Hz), 2.4〇2.68 (6H,m), 3·91,3·99 (1H,m), 4.20 (1H, dd, J=l〇, 5 2 4.31 (1H, dd, J=10, 3·6 Hz), 4.91 (1H, d, J= 4.4 Hz),6·61 (1Ή' d, J=5.2 Hz), 7.10-7.17 (3H,m),7·37·7·49 (3H,m),7·62 (1H s),8· 21-8·27 (1H, m), 8·63 (1H, br s), 8 72_8 75 (2h, ' 9·10 (·1Η, br s). ' 叫, Example 494 U 4-"6-Cyanide-7-(π-?福嗾-4_) Propylene a certain oxygen bromide 2-fluorophenyl bromide 1 and B as early as N-[ 4-(6-Cyano-7-oxirane methoxyquinolyloxy)-2•fluorophenyl l·Ν'-(4-fluorophenyl)urea (loo mg), tetrahydrofuran 1 For example, a mixture of 0.1 ml of hydralin and 50 ml of the title compound (50 ml) was purified by column chromatography (ethyl acetate-methanol). 32 mg) 'H-NMR (DMSO-d6) (5 (ppm): 2.38-2.58 (6H, m), 3.53-3.59 (4H, m), 4.03-4.09 (1H, m)5 4.22 (1H, Dd, J=10, 6 〇Hz), 4.31 (1H, dd, J=10, 4.0 Hz), 5.03 (1H, d5 1=4.8), 6.61 (1H, d, J=5.2 Hz), 7·10 -7·17 (3H,m), 7.36-7.49 (3H,m),7 64 (say s), 8.20-8.27 (1H,m), 8.60-8.64 (1H,m)3 8·73·8 75 (2H (4), 9·10 (1H, br s). ' 'Example 495 base gas 1-2-argon · grin iN, bexozol-2-) urea in N-[4-(6-cyanide) -7-Ethylene oxide methoxyquinolinyloxy) 2 gas benzene 567 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 13040 61 , , , , A7 _-____B7 V. Description of invention (—~' —~-—base]-Ν'- (mouth plug-2-base) monthly urine (120 rng) Φ , ^ , g) A ' Add 1 ml of tetradamine and 0.1 ml of sputum, and heat at 50 C for 40 minutes. The reaction solution was purified by NH(R) gel column chromatography (ethyl acetate-methanol) to give pale yellow crystals. The title compound (70 mg). lH-NMR (DMSO-d6) 5 (ppm): 1.6〇«ι.7〇(4H, m), 2.40-2.75 (6H, m), 3.95-4.05 (1H, in ), 4.20 〇Η, dd, J=l〇, 6.0 Hz), 4.31 (1H, dd, J=10, 4 Hz), 5.02 (1H, br s), 6.62 (1H, d, J=5.2

Hz), 6.85 (1H, s), 7.10-7.20 (2H, m), 7.37-7.47 (2H, m), 7.62 (1H, s), 8.20-8.26 (1H, m), 8.71-8.76 (2H, m), 9.05 (1H, br s) ° 以下述方法合成起始物質。 製造例495-1 m 4- d-.A.基-7-環氧乙燒甲氣基林-4-基氣n f,茉基1 -唑-2-某）Μ 在4-(4-胺基-3-氟苯氧基）-7-環氧乙胺甲氧基喹啉-6-甲 腈（100 mg)中，加入二曱基亞礙1 ml及N-( 2-噻唑基）胺基 甲酸苯酯（94 mg)，然後於80°C加熱90分鐘。在其中加入水 及濾取析出之結晶，得到為淡黃色結晶之標題化合物（16 mg)。 j-NMR (DMSO-d6) 5 (ppm): 2.78-2.94 (2H，m)，3.41-3.49 (1H，m)，4.17 (1H，dd，J=12，6.4 Hz)，4·71 (1H，dd，&gt;12, 2.0)，6·64 (1H，d，J=5.2 Hz)，7.08-7·20 (3H，m)，7.36-7.48 (2H，m)，7·έ5 (1H，s)，8·20-8·27 (1H，m)，8.73-8.79 (2H，m)， 9.07 (1H，br s)。 _ - 568 -_______ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 、 A7 ' ' '__^B7__ 五、發明説明（563) f旅例496 ]^^11「0二氦基-7-(2-羥基-3-(六新|吡啶-〗：1^^氧某^杏成_ 土^暮氣1 1 2_氟苯基卜n，-(3 4 5_氟笨基）脈 在N- [4- ( 6-氰基-7-環氧乙燒甲氧基逢α林_ 4-基氧）_ 2-氟苯 基]-Ν - (4-氟冬基）月尿（78 mg)中’加入四氫π夫喃1 5 mi及二 氫p比淀（0.08 ml)，並於50°C加熱30分鐘。將該反應溶液用 NH矽凝膠管柱層析（乙酸乙酯-甲醇系）精製，得到為淡黃 色結晶4標題化合物（32 mg)。 ]H-NMR (DMSO-d6) (5 (ppm): 1.30-1.55 (6H, m), 2.35-2.55 (6H，m)，4.00-4.08 (1H, m)，4·20 (1H，dd，J=l〇，6·0 Hz)，Hz), 6.85 (1H, s), 7.10-7.20 (2H, m), 7.37-7.47 (2H, m), 7.62 (1H, s), 8.20-8.26 (1H, m), 8.71-8.76 (2H, m), 9.05 (1H, br s) ° The starting material was synthesized in the following manner. Production Example 495-1 m 4- d-.A.yl-7-epoxyethyl carbazide-4-yl gas nf, mazyl-1-azole-2-one) Μ 4-(4-amine Addition of dimercapto 1 gram and N-(2-thiazolyl)amine to benzyl-3-fluorophenoxy)-7-epoxyethylamine methoxyquinoline-6-carbonitrile (100 mg) Phenyl benzoate (94 mg) was then heated at 80 ° C for 90 minutes. The title compound (16 mg) was obtained as a pale yellow crystal. j-NMR (DMSO-d6) 5 (ppm): 2.78-2.94 (2H, m), 3.41-3.49 (1H, m), 4.17 (1H, dd, J=12, 6.4 Hz), 4·71 (1H ,dd,&gt;12, 2.0),6·64 (1H,d,J=5.2 Hz),7.08-7·20 (3H,m),7.36-7.48 (2H,m),7·έ5 (1H, s), 8·20-8·27 (1H, m), 8.73-8.79 (2H, m), 9.07 (1H, br s). _ - 568 -_______ This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061, A7 ' ' '__^B7__ V. Invention description (563) f Travel example 496 ]^^11"0 Dimercapto-7-(2-hydroxy-3-(hexaxin|pyridine-〗: 1^^ Oxygen ^^ 杏成_土^暮气1 1 2_Fluorophenyl b n,-(3 4 5_Fluorine Stupid) veins in N-[4-(6-cyano-7-epoxyethylidene methoxy-alkaline _ 4-yloxy)- 2-fluorophenyl]-indole-(4-fluorodongyl) In the urine of the month (78 mg), 'tetrahydropyridinium 1 5 mi and dihydrogen p-precipitate (0.08 ml) were added and heated at 50 ° C for 30 minutes. The reaction solution was coated with NH 矽 gel column The title compound (32 mg) was obtained as a pale-yellow crystals. (H-NMR (DMSO-d6) (5 (ppm): 1.30-1.55 (6H, m), 2.35- 2.55 (6H, m), 4.00-4.08 (1H, m), 4·20 (1H, dd, J=l〇, 6·0 Hz),

4.30 (1H, dd, J=l〇, 4.0 Hz), 4.94 (1H, d, J=4.8 Hz), 6.61 (1H, d, J—5.6 Hz), 7.10-7.17 (3H, m), 7.36-7.50 (3H, m), 7.63 (1H m), 8.20-8.23 (1H, m), 8.62-8.64 (1H, m), 8.72-8.75 (2H m) 9·10 (1H, m) 〇 實施例497 1 1.30-1.55 (6H3 m), 2.35-2.55 (6H, m), 4.00-4.08 (1H, m)5 2 4.20 (ΙΗ/dd, J=l〇, 6.0 Hz), 4.30 (1H, dd, J=10, 4.0 Hz), 3 4.94 (1H, d, J=4.8 Hz), 6.61 (1H, d, J=5.6 Hz), 7.10-7.17 4 _____- 569 - _ 5 本紙張尺度適用中國國家標準(CNS) A4規格(21Q x 297公釐)' '' 1304061 ' A7 ____B7 五、發明説明（564) (3H，m)，7·36-7·50 (3H，m)，7·63 (1H，m)，8·20-8·23 (1H，m)， 8.62-8.64 (1Η，m)，8·72-8·75 (2Η，m)，9·10 (1Η，m)。 藉下述2步驟合成起始物質。 ΆΜΜΔ21ζ± 基-3-氣_苯氧棊)二環氧乙烷-2-某1甲氫，奎 ^林-6 -〒赌 在4- (4-胺基-3 -氟苯氧基）-6-氰基-7-經基P奎淋（1000 mg) 中，加入二甲基甲醯胺8 ml，對甲苯磺酸（2R)-縮水甘油酯 ( 1000 mg)及碳酸鉀（940 mg)，並於50 °C加熱4小時。在該 反應溶液中加入水及用乙酸乙酯萃取，將有機層用水及飽 和食鹽水依次洗淨後用無水硫酸鈉乾燥及減壓餾去溶媒。 將得到之粗生成物用矽凝膠管柱層析（乙酸乙酯）精製，得 到為淡黃色結晶之標題化合物（659 mg)。 ^H-NMR (DMSO-d6) 5 (ppm): 2·79-2·93 (2H，m)，3.42-3.49 (1Η，m)，4·15 (1Η，dd，J=12, 7·2 Ηζ)，4·69 (1Η，dd，J=12, 2·4 Hz), 5.25 (2H, br s), 6.53 (1H, d5 J=5.2 Hz), 6.83-6.89 (2H, m)，7·07-7·15 (1H，m)，7·61 (1H，s)，8.69-8.74 (2H，m)。 製造例497-2 N-(4-{6-氰基-7-K2R)-環氲乙烷-2-基1甲氳某4啉-4-基 氲卜2-氯茉某氣苽某 依照製造例492- 1記載之方法，從4-(4-胺基-3-氟苯氧 基）-7-[(2R)-環氧乙烷-2-基]甲氧喹啉-6-甲腈（150 mg)得 到標題化合物（200 mg)。 ^-NMR (DMSO-d6) 5 (ppm): 2.79-2.95 (2H5 m)5 3.40-3.50 __- 570 -_ _ 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） 1304061 〜 A7 B7 五、發明説明（565) (1H，m)，4.10-4.20 (1H，m)，4.65-4.76 (1H，m)，6·62 (1H，d， J=6.0 Hz), 7.05-7.18 (3H, m), 7.36-7.50 (3H, m), Ί.62 (1H, s), 8.20-8.28 (1H, m), 8.60-8.68 (1H, m), 8.73^8.80 (2H, m), 9·10 (1H, br s) o 實施例4 9 8 !^-(4-]6-~^基-7-『3-^乙胺基-(2 R) - 2 -手空某丙氣基ί - 口奎峨二 4-某氫卜2-氟茉基氣笨基）脲 藉由實施例493之方法，從Ν-(4-{6-氰基-7-[(2R)-環氧 乙烷-2-基]甲氧基喹啉-4-基氧}-2-氟苯基）-N’-(4-氟苯基） 躲( 200 mg)’付到為淡叉色結η日之標題化合物（120 mg)。 ^-NMR (DMSO-d6)d(ppm): 0.96 (6H, t, J=7 Hz), 2.40-2.68 (6H, m), 3.91-3.99 (1H, m), 4.20 (1H, dd, J-l〇, 5.2 Hz), 4.31 (1H, dd, J=10, 3.6 Hz), 4.91 (1H, d, 1=4.4 Hz), 6.61 (1H, d, J=5.2 Hz), 7.10-7.17 (3H, m), 7.37-7.49 (3H, m), 7.62 (1H, s), 8.21-8.27 (1H, m), 8.63 (1H, br s), 8.72-8.75 (2H, m), 9.10 (1H，br s) 〇 實施例499 仏（4-丨6-氣基-7-「3-二甲胺基-(21〇-2-#登基-丙氣某1-4说' 4-基氣卜2-氣苯某Ν’-(4-氣笨基）脲 在N-(4- {6-氰基-7-[(2R)-環氧乙烷-2-基]甲氧基喹啉·4-基氧}-2-氣尽基）-N’-(4-氣木基）肠·（40 mg)中，加入四氫 呋喃0.5 ml及二曱胺2N四氫呋喃溶液（Aldrich公司製）〇.2 ml ’並於室·溫授·拌一夜。將該反應溶液用NH碎凝膠管柱層 析（乙酸乙酯-甲醇系）精製，得到為淡黃色結晶之標題化合 __ - 571 - 本紙悵尺度適用中國國家標準(CNS) Μ規格(210X297公釐） 裝 訂4.30 (1H, dd, J=l〇, 4.0 Hz), 4.94 (1H, d, J=4.8 Hz), 6.61 (1H, d, J-5.6 Hz), 7.10-7.17 (3H, m), 7.36- 7.50 (3H, m), 7.63 (1H m), 8.20-8.23 (1H, m), 8.62-8.64 (1H, m), 8.72-8.75 (2H m) 9·10 (1H, m) 〇Example 497 1 1.30-1.55 (6H3 m), 2.35-2.55 (6H, m), 4.00-4.08 (1H, m)5 2 4.20 (ΙΗ/dd, J=l〇, 6.0 Hz), 4.30 (1H, dd, J =10, 4.0 Hz), 3 4.94 (1H, d, J=4.8 Hz), 6.61 (1H, d, J=5.6 Hz), 7.10-7.17 4 _____- 569 - _ 5 This paper scale applies to Chinese national standards ( CNS) A4 size (21Q x 297 mm) ' '' 1304061 ' A7 ____B7 V. Description of invention (564) (3H, m), 7·36-7·50 (3H, m), 7·63 (1H, m), 8·20-8·23 (1H, m), 8.62-8.64 (1Η, m), 8·72-8·75 (2Η, m), 9·10 (1Η, m). The starting materials were synthesized by the following two steps. ΆΜΜΔ21ζ±yl-3-gas_phenoxypurine)dioxirane-2-some 1 methylhydrogen, Kui^lin-6-〒 bet on 4-(4-amino-3-fluorophenoxy)- 6-Cyano-7-ionyl P-Penyl (1000 mg), 8 ml of dimethylformamide, p-toluenesulfonic acid (2R)-glycidyl ester (1000 mg) and potassium carbonate (940 mg) And heated at 50 °C for 4 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by EtOAc EtOAc (EtOAc) ^H-NMR (DMSO-d6) 5 (ppm): 2·79-2·93 (2H, m), 3.42-3.49 (1Η, m), 4·15 (1Η, dd, J=12, 7· 2 Ηζ), 4·69 (1Η, dd, J=12, 2·4 Hz), 5.25 (2H, br s), 6.53 (1H, d5 J=5.2 Hz), 6.83-6.89 (2H, m), 7·07-7·15 (1H, m), 7.61 (1H, s), 8.69-8.74 (2H, m). Production Example 497-2 N-(4-{6-Cyano-7-K2R)-cyclodecaneethane-2-yl 1methylhydrazine, a 4-pyridyl-4-ylindole-2-chloromethane Process described in Production Example 492-1, from 4-(4-amino-3-fluorophenoxy)-7-[(2R)-oxiran-2-yl]methoxyquinoline-6- The nitrile (150 mg) gave the title compound (200 mg). ^-NMR (DMSO-d6) 5 (ppm): 2.79-2.95 (2H5 m)5 3.40-3.50 __- 570 -_ _ This paper size applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1304061 ~ A7 B7 V. Description of invention (565) (1H, m), 4.10-4.20 (1H, m), 4.65-4.76 (1H, m), 6.62 (1H, d, J = 6.0 Hz), 7.05 -7.18 (3H, m), 7.36-7.50 (3H, m), Ί.62 (1H, s), 8.20-8.28 (1H, m), 8.60-8.68 (1H, m), 8.73^8.80 (2H, m), 9·10 (1H, br s) o Example 4 9 8 !^-(4-]6-~^基-7-『3-^ethylamino-(2 R) - 2 -hand empty A propylene-(4-{6-cyano-7-[(2R) method by the method of Example 493. )-Ethylene oxide-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N'-(4-fluorophenyl) hiding (200 mg) The title compound (120 mg) of the y. ^-NMR (DMSO-d6)d (ppm): 0.96 (6H, t, J = 7 Hz), 2.40-2.68 (6H, m), 3.91-3.99 (1H, m), 4.20 (1H, dd, Jl 〇, 5.2 Hz), 4.31 (1H, dd, J=10, 3.6 Hz), 4.91 (1H, d, 1=4.4 Hz), 6.61 (1H, d, J=5.2 Hz), 7.10-7.17 (3H, m), 7.37-7.49 (3H, m), 7.62 (1H, s), 8.21-8.27 (1H, m), 8.63 (1H, br s), 8.72-8.75 (2H, m), 9.10 (1H,br s) 〇 Example 499 仏(4-丨6-gas-based-7-"3-dimethylamino--(21〇-2-#登基-丙气一1-4说' 4-base gas b 2- Gas Benzene -'-(4-Azyl) Urea in N-(4-{6-Cyano-7-[(2R)-oxiran-2-yl]methoxyquinoline·4- Addition of tetrahydrofuran 0.5 ml and diammonium 2N tetrahydrofuran solution (manufactured by Aldrich Co., Ltd.) to a solution of 2% of tetrahydrofuran in the intestine (40 mg). And the mixture was heated and stirred overnight. The reaction solution was purified by NH-gel column chromatography (ethyl acetate-methanol) to give the title compound as pale yellow crystals __ - 571 - China National Standard (CNS) Μ Specifications (210X297 mm) Binding

線 1304061 〜 A7 ' ' B7 五、發明説明（566) 物（45 mg) 0 !H-NMR (DMSO-d6) 5 (ppm): 2.20 (6H, m), 2.30-2.58 (2H, m)，3.95-4.95 (1H，m)，4·19 (1H，dd，J=10, 5.6 Hz)，4.29 (1H， dd，J=10, 4·0 Hz)，4·99 (1H，d，J=4.4 Hz)，6·61 (1H，d，J=5.6 Hz)，7·10-7·17 (3H，m)，7.37-7.50 (3H，m), 7·62 (1H，s)， 8.20-8-.30 (1H, m)5 8.64 (1H, br s)5 8.70-8.76 (2H, m), 9.11 (1H，br s)。 實施例500 4-(6-氰基-7-Π-二乙胺基-(2R)-2-羥基丙氣基卜4啉-4-基氣卜2-氟笨基Ν’-唑-2-基）脲 在Ν-(4- {6-氰基-7-[(2R)-環氧乙烷-2-基]甲氧基喹啉-4-基氧卜2-氟苯基（嘍唑-2-基）脲（200 mg)中，加入四氫 呋喃4 ml及二乙胺0.2 nd，並於50°C加熱2小時。將該反應 溶液用NH矽凝膠管拄層析（乙酸乙酯-甲醇系）精製，得到 為淡黃色結晶之標題化合物（60 mg)。 ^-NMR (DMSO-d6) 5 (ppm): 0.96 (6H, t, J=7.0 Hz), 2.40-2.70 (6H，m)，3.90-3.98 (1H，m)，4·21 (1H，dd，J=10, 5.2 Hz)， 4.31 (1H，dd，J=10, 3.2 Hz)，4.90-4.95 (1H，m)，6·62 (1H，d， J=5.2 Hz)，7.11-7·20 (2H，m)，7.36-7.47 (2H，m)，7·62 (1H， s)，8·20·8.27 (1H，m)，8.72-8.76 (2H，m) 〇 如下述合成起始物質。 製造例500- 1 N“4- {6-·希：基-7-「（2R卜環氣乙烷-2-某1甲氣4啉-4-基 氣卜2-氣笨基W-(嘍唑-2-基）脲 ___- 572 -_ 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 1304061 A7 B7 567〉 五、發明説明（ 藉由實施例495記載之方法，從4-(4-胺基-3-氟苯氧基卜 7-[(2R)-環氧乙烷基]甲氧喹啉·6-甲腈（3〇〇瓜“得到為 淡黃色結晶之標題化合物（370 mg)。 H-NMR (DMSO-d6) δ (ppm): 2.78-2.94 (2H, m), 3.41-3.49 (1H，s)，4·17 (1H，d，J=12, 6.4 Hz), 4·71 (1H，dd，J=12, 2·〇Line 1304061 ~ A7 ' ' B7 V. Description of the invention (566) (45 mg) 0 !H-NMR (DMSO-d6) 5 (ppm): 2.20 (6H, m), 2.30-2.58 (2H, m), 3.95-4.95 (1H, m), 4·19 (1H, dd, J=10, 5.6 Hz), 4.29 (1H, dd, J=10, 4·0 Hz), 4·99 (1H, d, J =4.4 Hz),6·61 (1H,d,J=5.6 Hz),7·10-7·17 (3H,m),7.37-7.50 (3H,m), 7·62 (1H,s), 8.20-8-.30 (1H, m)5 8.64 (1H, br s)5 8.70-8.76 (2H, m), 9.11 (1H, br s). Example 500 4-(6-Cyano-7-indole-diethylamino-(2R)-2-hydroxypropionyl-4-phenyl-4-yl-cyclohexane 2-fluoro-p-indolinyl-azole-2 -Based urea in Ν-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy-2-fluorophenyl (喽) To the oxazol-2-yl)urea (200 mg), 4 ml of tetrahydrofuran and 0.2 nd of diethylamine were added, and the mixture was heated at 50 ° C for 2 hours. -Methanol-purified, the title compound (60 mg) was obtained as pale yellow crystals. NMR (DMSO-d6) 5 (ppm): 0.96 (6H, t, J = 7.0 Hz), 2.40-2.70 (6H, m), 3.90-3.98 (1H, m), 4·21 (1H, dd, J=10, 5.2 Hz), 4.31 (1H, dd, J=10, 3.2 Hz), 4.90-4.95 (1H, m) ,6·62 (1H,d, J=5.2 Hz), 7.11-7·20 (2H,m), 7.36-7.47 (2H,m),7·62 (1H, s),8·20·8.27 ( 1H,m), 8.72-8.76 (2H,m) The starting material is synthesized as follows. Production example 500- 1 N "4- {6-·希:基-7-"(2R-cyclohexaneethane-2 - a certain gas, 4, 4, 4, 4, 2, 2, 2, 2, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 297 1304061 A7 B7 567> V. Description of the invention (by the method described in Example 495, from 4-(4-amino-3-fluorophenoxybu 7-[(2R)-oxiranyl]-) Oxyquinoline·6-carbonitrile (3 〇〇 “ “ 标题 标题 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 370 -3.49 (1H, s), 4·17 (1H, d, J=12, 6.4 Hz), 4·71 (1H, dd, J=12, 2·〇

Hz), 6.64 (1H, d, J=5.2 Hz), 7.08-7.20 (2H, m), 7.36-7.48 (2H，m)，7.65 (1H，s)，8.20-8.27 (1H，m)，8.73_8·79 (2H，m)， 9.07 (1H，br s)。 5 實施例501 N- {J 6-氰基- 7-(4-六氫吡啶甲氣基K g杳说某1 ^ 苯基Hf- (4-氟笨基）脹 、· 將心（6·氰基-4-{3-氟-4-[3-(4-氟苯基）脲基]苯氧基}喹 啉-7-基氧甲基）六氫吡啶-1-羧酸第三丁酯（395 mg)溶於三 氟乙fei(2 ml) ’並於室溫揽捽1〇分鐘。在其中加入水 及用緩酸氫鈉中和，濾取析出之結晶，得到標題化合物 (260 mg) 〇 ^-NMR (DMSO-d6) (5 (ppm): 1.15-1.30 (2H, m), 1.69-1.76 (2H，m)，1.85-2.00 (1H，m)，2.44-2.70 (2H，m)，2·90-2·99 (2H，m)，4,09-4.25 (3H，m)，6.61(lH，d，J=5.2Hz)，7.05- 7.14 (3H, m), 7.34-7.40 (1H, m), 7.48-7.55 (2H, m), 7.59 (1H，s)，8.10-8.17 (1H，m)，8·70-8·76 (2H，m)。 用下述2步驟合成起始物質。 览i告例5 01 -1 4-「4-(4:-胺基-3-氣茉氳基）-6-氰基g套淋-7-甚氧甲基1 -六&amp; -573 - 中㈣家標準(CNS) A4規格(210 X 297公爱) : 〜Hz), 6.64 (1H, d, J=5.2 Hz), 7.08-7.20 (2H, m), 7.36-7.48 (2H, m), 7.65 (1H, s), 8.20-8.27 (1H, m), 8.73 _8·79 (2H,m), 9.07 (1H,br s). 5 Example 501 N-{J 6-cyano-7-(4-hexahydropyridinylmethyl group K g杳 said that 1 ^ phenyl Hf- (4-fluorophenyl) swell, · heart (6 · Cyano-4-{3-fluoro-4-[3-(4-fluorophenyl)ureido]phenoxy}quinolin-7-yloxymethyl)hexahydropyridine-1-carboxylic acid tert-butyl The ester (395 mg) was dissolved in trifluoroethyl hexane (2 ml) and taken at room temperature for 1 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Mg) 〇^-NMR (DMSO-d6) (5 (ppm): 1.15-1.30 (2H, m), 1.69-1.76 (2H, m), 1.85-2.00 (1H, m), 2.44-2.70 (2H, m), 2·90-2·99 (2H, m), 4, 09-4.25 (3H, m), 6.61 (lH, d, J = 5.2 Hz), 7.05- 7.14 (3H, m), 7.34- 7.40 (1H, m), 7.48-7.55 (2H, m), 7.59 (1H, s), 8.10-8.17 (1H, m), 8·70-8·76 (2H, m). Use the following 2 steps Synthesis of starting materials. Example 5 01 -1 4-"4-(4:-Amino-3-carbamoyl)-6-cyano g lysyl-7-oxymethyl 1 -6 &amp; -573 - Medium (four) home standard (CNS) A4 specification (210 X 297 public): ~

裝 訂Binding

線 A7 B7 1304061 五、發明説明（568) 吡唣-卜羧酸第三丁酯 在4-(4-胺基-3-氟苯氧基）-6-氰基-7-羥基喹啉（500 mg) 中，加入二甲基甲醯胺4 ml，4-(溴曱基）-1-六氫吡啶羧酸 第三丁酯（708 mg)及碳酸鉀（467 mg)，並於50°C加熱4小 時。在該反應溶液中加入水及用乙酸乙酯萃取，將有機層 用水及飽和食鹽水依次洗淨後，用無水硫酸鈉乾燥及減壓 餾去溶媒。將得到之粗生成物用矽凝膠管柱層析（正己烷： 乙酸乙酯）精製，得到標題化合物（398 mg)。 h-NMR (DMSO-d6)5(ppm): 1·16-1·31 (2H，m)，1.39 (9H，s)， 1.72- 1.82 (2H, m), 2.00-2.08 (1H, m), 2.65-2.83 (2H, m)5 3.93-4.03 (2H, m), 4.11-4.18 (2H, m), 5.20-5.26 (2H, m), 6.50 (1H, d5 J=5,2 Hz), 6.82-6.85 (2H, m), 7.02-7.10 (1H, m), 7.56 (1H，s)，8.65-8.72 (2H，m) 〇 製造例501-2 4-(6-氰基-4-(3-氣-4-「3-(4-氟笨基）脲基1苯氣某丨，杏毗-7_ 基氧甲基）六g.吡啶-1-#酸第三丁酯 以與實施例492同樣之方法，從4-[4-(4-胺基-3-氟苯氧 基）-6-氰基4淋-7-基氧甲基]六氫0比淀-1-幾酸第三丁醋 (619 mg)及異氰酸4-氟苯酯（0.22 ml)，得到為淡黃色結晶 之標題化合物（500 mg)。 W-NMR (DMSO-d6) 5 (ppm): 1.20-1.3 5 (2H，m)，ι·39 (9H，s)， 1.73- 1.85 (2H, m), 2.00-2.10 (1H, m), 2.63-2.86 (2H, m), 3.92-4.06 (2H，m)，4.13-4.20 (2H，m)，6·61 (1H，d，J=5.6 Hz), 7.10-7.16 (3H，m)，7·36-7·50 (3H，m)，7·60 (1H，s)，8.20- ___ - 574 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公¢) ' A7 B7 1304061 五、發明説明（569) 8·28 (1H，m)，8.68-8.76 (2H，m)，9·27 (1H，br s) 〇 實施例502 N-(4-「6-氧U-(卜甲基六氫吡啶-4-基）甲氲某g套啉-4-某 氫1-2-氯苽某丨氟苯基）脲 將Ν-(2-氟-4- {[6-氰基-7-(4-六氫吡啶基甲氧基）-心喳啉 基]氧·}苯基）-Ν’-(4-氟苯基）脲（180 mg)溶於四氫呋喃（1〇 ml) -甲醇（10 ml)後，於室溫加入37%甲醛水溶液（〇.5 ml)， 乙酸（0.04 ml)及氰基硼氫化鈉（43 mg)，並攪拌1小時。將 反應液分溶於乙酸乙醋及飽和碟酸氫納水溶液中，將有機 層用飽和食鹽水洗淨，以及用無水硫酸鈉乾燥。藉由館去 溶媒，懸浮於乙酸乙酯中，將其用己烷稀釋，濾取結晶及 通風乾躁，得到為白色結晶之標題化合物（13 0 mg)。 lH-NMR (DMSO-d6) 5 (ppm): 1.13-1.47 (2H, m), 1.73-1.92 (5H，m)，2·15 (3H，s)，2.77-2.85 (2H，m)，4·13-4·16 (2H，m)， 6.61 (1H, d, J=5.6 Hz), 7.10-7.16 (3H, m)5 7.36-7.49 (3H, m)3 7.59 (1H, s), 8.20-8.26 (1H, m)5 8.62-8.68 (1H, m), 8.72-8·76 (2H，m)，9·08-9·15 (1H，m)。 實施例503 H.4·「6-氰茱-7.-_(..六_£ ♦啶-4-基甲氛某）g套啉-4_某爭卜9' 盡^葱基卜&gt;^’-(2-遠唑基）脲 藉由實施例501之方法，從心{6-氰基·4·[3-氟-4-(3-(^ 嗤-2-基）踩）本氧基]p奎琳-7-基氧甲基}六氫p比淀幾酸第 三丁酯（37(Tmg)，得到標題化合物（240 mg)。 JH-NMR (DMSO-d6) (5 (ppm): 1.45-1.56 (2H, m), 1.92-2.00 !304061Line A7 B7 1304061 V. INSTRUCTIONS (568) Pyridinium-bucarboxylic acid tert-butyl ester in 4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (500) In mg), add 4 ml of dimethylformamide, tert-butyl 4-(bromoindenyl)-1-hexahydropyridinecarboxylate (708 mg) and potassium carbonate (467 mg) at 50 °C. Heat for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained crude product was purified by EtOAcjjjjjj elut elut h-NMR (DMSO-d6) 5 (ppm): 1·16-1·31 (2H, m), 1.39 (9H, s), 1.72-1.82 (2H, m), 2.00-2.08 (1H, m) , 2.65-2.83 (2H, m)5 3.93-4.03 (2H, m), 4.11-4.18 (2H, m), 5.20-5.26 (2H, m), 6.50 (1H, d5 J=5,2 Hz), 6.82-6.85 (2H, m), 7.02-7.10 (1H, m), 7.56 (1H, s), 8.65-8.72 (2H, m) 〇 Manufacturing Example 501-2 4-(6-Cyano-4-( 3-ox-4-"3-(4-fluorophenyl)ureido-1 benzene gas, apricot -7-yloxymethyl) hexagram. Pyridin-1-# acid tert-butyl ester and examples 492, in the same manner, from 4-[4-(4-amino-3-fluorophenoxy)-6-cyano-4-ylidene-7-yloxymethyl]hexahydro- 0-precipitate-1-acid acid Tributyl vinegar (619 mg) and 4-fluorophenyl isocyanate (0.22 ml) gave the title compound (500 mg) as pale yellow crystals. W-NMR (DMSO-d6) 5 (ppm): 1.20-1.3 5 (2H,m), ι·39 (9H,s), 1.73- 1.85 (2H, m), 2.00-2.10 (1H, m), 2.63-2.86 (2H, m), 3.92-4.06 (2H,m ), 4.3-4.20 (2H, m), 6.61 (1H, d, J = 5.6 Hz), 7.10-7.16 (3H, m), 7·36-7·50 (3H, m), 7.60 (1H, s), 8.20- ___ - 574 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) ' A7 B7 1304061 V. INSTRUCTIONS (569) 8·28 (1H, m), 8.68-8.76 (2H, m), 9·27 (1H, br s) 〇 Example 502 N-(4-"6-Oxygen U -(P-methylhexahydropyridin-4-yl)formamidine, a g-polyphenylene-4-one hydrogen 1-2-chloroindole, a fluorinated phenyl)urea, hydrazine-(2-fluoro-4-{[6-cyanide Base-7-(4-hexahydropyridylmethoxy)-cardoindolyl]oxy}}phenyl)-indole-(4-fluorophenyl)urea (180 mg) is dissolved in tetrahydrofuran (1 〇 ml) -Methanol (10 ml), 37% aqueous formaldehyde solution (〇5 ml), acetic acid (0.04 ml) and sodium cyanoborohydride (43 mg) were added at room temperature, and stirred for 1 hour. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was dissolved in EtOAc, EtOAc (EtOAc)EtOAc. lH-NMR (DMSO-d6) 5 (ppm): 1.13-1.47 (2H, m), 1.73-1.92 (5H, m), 2·15 (3H, s), 2.77-2.85 (2H, m), 4 ·13-4·16 (2H,m), 6.61 (1H, d, J=5.6 Hz), 7.10-7.16 (3H, m)5 7.36-7.49 (3H, m)3 7.59 (1H, s), 8.20 -8.26 (1H, m)5 8.62-8.68 (1H, m), 8.72-8·76 (2H, m), 9·08-9·15 (1H, m). Example 503 H.4·"6-Cyanogenic 茱-7.-_(..六_£ ♦ -4--4-yl 甲甲) g ligament-4_ _ _ _ _ _ _ _ _ _ _ _ ;^'-(2-Oxazolyl)urea by the method of Example 501, from the heart {6-cyano·4·[3-fluoro-4-(3-(^ 嗤-2-yl)) The present oxy]p- quinolin-7-yloxymethyl}hexahydrop-p-butyric acid tributyl acrylate (37 (Tmg) gave the title compound (240 mg). JH-NMR (DMSO-d6) (5 (ppm): 1.45-1.56 (2H, m), 1.92-2.00 !304061

五、發明説明（ A7 B7 570 ) (2H, m), 2.13-2.23 (1H, m)3 2.45-2.50 (2H, m), 2.85-2.98 (2H，m)，4.18-4.23(2H，m)，6.64(lH，d，J=5.2Hz)，7.14-7·19 (2H，m)，7.37-7.47 (2H，m)，7·65 (1H，s)，8·21-8·28 (1H， m)，8.74-8.79 (2H，m)，9.06(iH，brs)。 藉由下述方法合成起始物質。 造例5 0 3 - 1 氰基-4:J 4- ( 某 m ^ 某 套啉 _ 7_ 赢急曱基ϋΑ嗑啶·卜藉良蓋^丁酯 藉由實施例495記載之中間體合成方法，從心[4_(‘胺基_ 3-氟苯氧基）-6-氰基喹啉基氧甲基]六氫吡啶_ :卜羧酸第 三丁酯合成。 'H-NMR (DMSO-d6)5(PPm): 1.18-1,32 (2H, m), 1.39 (9H, s), 1.73-1.83 (2H, m), 2.00-2.10 (1H, m), 2.63-2.86 (2H, m), 3.95-4.05 (2H, m), 4.13-4.20 (2H, m), 6.62 (1H, d, J=5.2 Hz), 7.10-7.20 (2H, m), 7.36-7.47 (2H, m), 7.61 (1H, s), 8.20-8.27 (1H，m)，8.72-8.77 (2H，m)。 實施例504 基-幕六 氧墓啉-4-某 里J-2 -氟苯基咬某）月尿 藉由實施例502記載之方法，從N-{4_[6_氰基·7_(六氫吡 啶-4-基甲氧基）喹啉-4-基氧]-2-氟苯基}-Ν，气塞唑基） 脲，得到標題化合物。 W-NMR (.DMSO，d6) 5 (ppm): 1.30-1.46 (2Η，m)，L70-1.93 (5H, m), 2.15 (3H, s), 2.77-2.85 (2H, m), 4.13.4.17 (2H m) -576 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） 13〇4〇61 A7 B7 五、發明説明（571) 6.62 (1H, d, J=5.2 Hz), 7.12-7.19 (2H, m), 7.37-7.47 (2H, m); 7·60 (1H，s)，8·20-8·30 (1H，m)，8.73-8.76 (2H，m)。 复jfe例505 ^{4-「6-氰1-7-(1-甲皋六氳吡啶-3-|^基）?杳啉_4•某 - 2-氟笨基丄-N’ - (2- 4唑基）Μ 用實施例495記載之中間體合成方法，從4-(4_胺基-3_氣 苯氧基）-7-(1-曱基τς·氫ρ比咬-3-基甲氧基）唆琳_6-甲腈，得 到標題化合物。 iH-NMR (DMSO-d6)(5(ppm): 1.10-1.20 (ijj，m)，143-1.95 (5H，m)，2.05-2.15 (1H，m)，2·16 (3H，s)，2.61-2.67 (1H，m)， 2.80^2.87 (1H, m), 4.15-4.19 (2H, m), 6.62 (1H3 d, J=5.6 Hz), ^•12-7.20 (2H, m), 7.37-7.47 (2H, m), 7.60 (1H3 s), 8.20-8·26 (1H，m)，8.72-8.77 (2H，m)。 用下述方法合成起始物質。 复造例505- 1 ΙιίΑ-胺基-3-氟苯氧基）-7-(1-甲基六氣外卜.重-3_基甲氣基） !|^林-6·曱月音 在4- (4-胺基-3 -氟苯氧基）-6-氰基-7-幾基;^淋（4〇〇 mg) 中’加入二甲基甲醯胺4 ml，3-氯曱基-ΐ_甲基六氫吡啶鹽 酸鹽621 mg及竣酸钾840 mg，並於120°C授捽3小時。在該 反應溶液中加入水及用乙酸乙酯萃取，將有機層用水及飽 和食鹽水依次洗淨後，用無水硫酸鈉乾燥及減壓餾去溶 媒。將得到之粗·生成物用NH碎凝膠管柱層析（乙酸乙g旨）精 製’得到標題化合物（60 mg)。 _— _- 577 - 木紙張尺度適用中國國家標準(CNS) A4規格(2i〇X297公釐〉 1304061 A7 B7 五、發明説明（572) lH-NMR (DMSO-d6)1.10-1.20 (1H, m), 1.45-1.95 (5H, m), 2.03-2.14 (1H, m), 2.14 (3H, s), 2.56-2.68 (1H, m), 2.78-2.88 (1H, m), 4.12-4.18 (2H, m)3 5.23-5.28 (2H, m), 6.51 (1H, d3 J=5.2 Hz), 6.83-6.89 (2H, m), 7.03-7.10 (1H, m), 7.56 (1H，s), 8·65-8·72 (2H，m)。 音施例506]^(心「（7-氨基-6-甲氣某-4-崦嗾、声11苯某^-(企氟苯某） 在4-(4-胺基苯氧基）-6-甲氧喹啉-7-甲腈（180 mg)中加入 甲苯（5 ml)，乙腈（1·5 ml)及異氰酸4-氟苯酯（0.105 ml)， 並加熱回流30分鐘。放冷後濾取析出之結晶，用甲苯洗 淨，得到為淡黃色結晶之標題化合物（230 mg)。 lH-NMR (DMSO-d6) 5 (ppm): 4.05 (3H, m), 6.66 (1H, d5 J=5.2 Hz), 7.08-7.14 (2H, m), 7.24 (2H, d, J=8.8 Hz), 7.43-7·48 (2H，m)，7·59 (2H，d，J = 8.8 Hz)，7.76 (1H，s)，8.54 (1H， s)，8·64 (1H，d，J=5.2 Hz)，8.74 (1H，br s)，8·84 (1H，br s)。 .用下述4步驟合成起始物質。 製造例5 0 6 - 1 6-甲氧基-4-(4-硝某苽氫某h杏毗-7-醇 在7-芊氧基-6-甲氧基-4-(4-硝基苯氧基）喹啉（4·〇 g)中， 加入三氟乙酸（30 ml)及硫代苯甲醚（3 ml)，然後於7〇。〇加 熱攪拌2小時。冷卻後，將反應溶液減壓濃縮，在其中加入 重礙酸氫鈉·水溶·液及甲醇，以及過濾析出之結晶。將其用 乙醚洗淨，得到標題化合物4.0 g。 -578 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 裝 訂 1304061 、 、 A7 ________B7__ 五、發明説明（573) lH-NMR (DMSO-d6) δ (ppm): 3.94 (3H, s), 6.93 (1H, d, J=5.6 Hz), 7.42 (1H, s), 7.55-7.60 (3H, m), 8.40 (2H, d, J=l〇 Hz)，8·71 (1H，d, J=6 Hz) 〇 製造例506-2 一氣甲確酸「6-甲氧基-4-(4-硝某苯氧基）g奎g林-7-基1酉旨 將6‘甲氧基-4- (4-硝基苯氧基）tr奎琳-7-醇（1.0 g)溶於二甲 基曱醯胺（10 ml)，加入三氟曱磺酸4-硝基苯酯（640 mg)及 碳酸鉀（1.3 g)並於室溫攪拌5小時。加入水及用乙酸乙酯萃 取，將有機層用水及飽和食鹽水依次洗淨後，用無水硫酸 鈉乾燥及減壓餾去溶媒。將其用乙酸乙g旨再結晶，得到標 題化合物（1.0 g)。 ^-NMR (DMSO-d6) δ (ppm): 4.04 (3H, s), 7.01 (1H, d, J=4.8 Hz), 7.52-7.57 (2H, m), 7.80 (1H, s), 8.18 (1H, s), 8.34-8.39 (2H，m)，8·72-8·76 (1H，m)。 製造例506-3 ii-fL氧基-4-(心硝基笨氣基啉-7-甲月青 將三氟甲磺酸[6-曱氧基-4-(4-硝基苯氧基）喹啉-7-基]酯 (500 mg)溶於二甲基甲醯胺（5 ml)，加入氰化鋅（260 mg)及 肆（三苯膦）鈀（〇價）（130 mg)，然後於氮蒙氣及11〇艺下加 熱檟:拌2小時。加入水及用乙酸乙醋萃取，將有機層用水及 飽和食鹽水依次洗淨後，用無水硫酸鈉乾燥及減壓餾去溶 媒。將其用乙酸乙酯再結晶，得到標題化合物（300 mg)。 W-NMR (DMSO-d6) 5 (ppm): 4.03 (3H，s)，7.05 (1H，d， J=5.2 Hz), 7.51-7.56 (2H, m), 7.68 (1H, s), 8.34-8.39 (2H, __ - 579 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） ： A7 B7 1304061 五、發明説明（574 ) m)，8.62 (1H，s)，8·76 (1H，d，J=5.2 Hz)。 製造例506-4 4·(4ν胺..基苯氧基甲氣某g争说_7· γ月奪 用製造例1 0之方法，將6-甲氧基_ 4- (4-硝基苯氧基）峻啉-7-甲腈（290 mg)進行鐵還原，得到標題化合物（18〇 mg)。 ^-NMR (DMS〇.d6)5(ppm): 4.05 (3H, s), 5.19 (2H, s), 6.59 (1H, d, J=5.2 Hz), 6.66 (2H, d, J=8.8 Hz), 6.94 (2H5 d, J=8.8 Hz), 7.73 (1H, s), 8.51 (1H, s), 8.61 (1H, d, J=5.2 Hz) 〇 實施例507 二i_4-「（ 7-胺甲 g适基-6-甲氧基-4- 4 g株基）氧1莕基）- N，-氟笨基）脲 將N-(4-[(7-氰基-6-甲氧基-4-喹啉基）氧]苯基）-N，-(心 氟苯基）脲（43 mg)於80°C溶於二曱基亞颯ι·5 mi中，在其中 加入5N NaOH水溶液及加熱攪拌2小時。將反應液用1N HC1 中和後，濾取析出之結晶，然後用乙醇洗淨，得到標題化 合物17 mg。 lH-NMR (DMSO-d6) δ (ppm): 4.00 (3H, s), 6.58 (1H, d, J=5.2 Hz), 7.06-7.14 (2H, m), 7.17-7.24 (2H, m), 7.45-7.53 (2H5 m), 7.55-7.67 (3H, m), 7.70 (1H, br s), 7.86 (1H, br s), 8·22 (1H，s)，8.56 (1H，d，J=5.2 Hz)。V. Description of the invention (A7 B7 570) (2H, m), 2.13-2.23 (1H, m)3 2.45-2.50 (2H, m), 2.85-2.98 (2H, m), 4.18-4.23 (2H, m) , 6.64 (lH, d, J = 5.2 Hz), 7.14-7·19 (2H, m), 7.37-7.47 (2H, m), 7·65 (1H, s), 8·21-8·28 ( 1H, m), 8.74 - 8.79 (2H, m), 9.06 (iH, brs). The starting material was synthesized by the following method. Example 5 0 3 -1 cyano-4:J 4- (a m ^ a set of porphyrin _ 7_ 赢 曱 ϋΑ嗑 ϋΑ嗑 · · 借 良 ^ ^ ^ ^ 藉 藉 藉 藉 藉 藉 藉 中间体 中间体 中间体 中间体 中间体, synthesized from the heart [4_('Amino-3-fluorophenoxy)-6-cyanoquinolinyloxymethyl]hexahydropyridine_: carboxylic acid tert-butyl ester. 'H-NMR (DMSO- D6)5(PPm): 1.18-1,32 (2H, m), 1.39 (9H, s), 1.73-1.83 (2H, m), 2.00-2.10 (1H, m), 2.63-2.86 (2H, m ), 3.95-4.05 (2H, m), 4.13-4.20 (2H, m), 6.62 (1H, d, J=5.2 Hz), 7.10-7.20 (2H, m), 7.36-7.47 (2H, m), 7.61 (1H, s), 8.20-8.27 (1H, m), 8.72-8.77 (2H, m). Example 504 base-screen hexa-oxy-t- s-- Moon urine by the method described in Example 502, from N-{4_[6-cyano-7-(hexahydropyridin-4-ylmethoxy)quinolin-4-yloxy]-2-fluorophenyl} - hydrazine, gaszozolyl) urea to give the title compound. W-NMR (.DMSO, d6) 5 (ppm): 1.30-1.46 (2Η, m), L70-1.93 (5H, m), 2.15 (3H, s), 2.77-2.85 (2H, m), 4.13. 4.17 (2H m) -576 - This paper size is applicable to China National Standard (CNS) A4 specification (21〇x 297 mm) 13〇4〇61 A7 B7 V. Invention description (571) 6.62 (1H, d, J= 5.2 Hz), 7.12-7.19 (2H, m), 7.37-7.47 (2H, m); 7·60 (1H, s), 8·20-8·30 (1H, m), 8.73-8.76 (2H, m). Compound jfe 505 ^{4-"6-Cyanide 1-7-(1-carboxamidinepyridine-3-?^-yl)? Porphyrin_4•A-2-fluoroindolyl-N'- ( 2- 4-oxazolyl) Μ using the intermediate synthesis method described in Example 495, from 4-(4-amino-3- phenoxy)-7-(1-indolyl hydrazide. - methoxyl) 唆 _6- carbonitrile, the title compound is obtained. iH-NMR (DMSO-d6) (5 (ppm): 1.10-1.20 (ijj, m), 143-1.95 (5H, m), 2.05-2.15 (1H,m),2·16 (3H,s),2.61-2.67 (1H,m), 2.80^2.87 (1H, m), 4.15-4.19 (2H, m), 6.62 (1H3 d, J=5.6 Hz), ^•12-7.20 (2H, m), 7.37-7.47 (2H, m), 7.60 (1H3 s), 8.20-8·26 (1H,m), 8.72-8.77 (2H,m The starting material was synthesized by the following method: Replica 505- 1 ΙιίΑ-Amino-3-fluorophenoxy)-7-(1-methylhexafluoroethylene. Heavy-3-ylmethyl group )||^林-6·曱月音 in 4-(4-Amino-3-fluorophenoxy)-6-cyano-7-yl group; ^L (4〇〇mg) in 'Add two Methylformamide 4 ml, 3-chloroindolyl-indole-methylhexahydropyridine hydrochloride 621 mg and potassium citrate 840 mg, and incubated at 120 ° C for 3 hours. Add water to the reaction solution. And extracted with ethyl acetate, The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by NH column chromatography (ethyl acetate). Compound (60 mg). _- _- 577 - Wood paper scale applicable to China National Standard (CNS) A4 specification (2i〇X297 mm> 1304061 A7 B7 V. Description of invention (572) lH-NMR (DMSO-d6) 1.10 -1.20 (1H, m), 1.45-1.95 (5H, m), 2.03-2.14 (1H, m), 2.14 (3H, s), 2.56-2.68 (1H, m), 2.78-2.88 (1H, m) , 4.12-4.18 (2H, m)3 5.23-5.28 (2H, m), 6.51 (1H, d3 J=5.2 Hz), 6.83-6.89 (2H, m), 7.03-7.10 (1H, m), 7.56 ( 1H, s), 8·65-8·72 (2H, m). Sound Example 506]^(Heart "(7-Amino-6-methyl-a certain 4-oxime, acoustic 11-benzone----fluorobenzene) in 4-(4-aminophenoxy)- 6-methoxyquinoline-7-carbonitrile (180 mg) was added toluene (5 ml), acetonitrile (1·5 ml) and 4-fluorophenyl isocyanate (0.105 ml), and the mixture was refluxed for 30 minutes. After cooling, the precipitated crystals were crystallized eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted , d5 J=5.2 Hz), 7.08-7.14 (2H, m), 7.24 (2H, d, J=8.8 Hz), 7.43-7·48 (2H,m),7·59 (2H,d,J = 8.8 Hz), 7.76 (1H, s), 8.54 (1H, s), 8.64 (1H, d, J = 5.2 Hz), 8.74 (1H, br s), 8.84 (1H, br s). The starting material was synthesized by the following four steps: Production Example 5 0 6 -1 6-Methoxy-4-(4-nitrogen hydrazine H. apricot-7-alcohol in 7-decyloxy-6- To methoxy-4-(4-nitrophenoxy)quinoline (4·〇g), trifluoroacetic acid (30 ml) and thioanisole (3 ml) were added, followed by 7 〇. The mixture was heated and stirred for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and sodium hydrogencarbonate, water-soluble solution and methanol were added thereto. The precipitated crystals were filtered, washed with diethyl ether to give the title compound 4.0 g. -578 - The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) Binding 1304061, A7 ________B7__ V. Invention description ( 573) lH-NMR (DMSO-d6) δ (ppm): 3.94 (3H, s), 6.93 (1H, d, J = 5.6 Hz), 7.42 (1H, s), 7.55-7.60 (3H, m), 8.40 (2H, d, J=l〇Hz), 8·71 (1H, d, J=6 Hz) 〇Production Example 506-2 A gas-based acid "6-methoxy-4-(4-nitrogen) Phenoxy)g quinolin-7-yl 1 溶于 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 Indoleamine (10 ml), 4-nitrophenyl trifluorosulfonate (640 mg) and potassium carbonate (1.3 g) were added and stirred at room temperature for 5 hours. Water was added and extracted with ethyl acetate. After washing with water and saturated brine, the mixture was dried over anhydrous sodium sulfate and evaporated. This was recrystallized from ethyl acetate to give the title compound (1.0 g). ^-NMR (DMSO-d6) δ (ppm): 4.04 (3H, s), 7.01 (1H, d, J = 4.8 Hz), 7.52-7.57 (2H, m), 7.80 (1H, s), 8.18 ( 1H, s), 8.34-8.39 (2H, m), 8·72-8·76 (1H, m). Production Example 506-3 ii-fLoxy-4-(heart nitro-stupyl phenyl -7-methionine trifluoromethanesulfonic acid [6-decyloxy-4-(4-nitrophenoxy) Quinoline-7-yl]ester (500 mg) dissolved in dimethylformamide (5 ml), zinc cyanide (260 mg) and hydrazine (triphenylphosphine) palladium (valence) (130 mg) Then, the mixture is heated under nitrogen atmosphere and 11 〇: mixing for 2 hours. Water is added and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate and evaporated. The solvent was recrystallized from ethyl acetate to give the title compound (300 mg): EtOAc (EtOAc: EtOAc) , 7.51-7.56 (2H, m), 7.68 (1H, s), 8.34-8.39 (2H, __ - 579 - This paper is available in Chinese National Standard (CNS) A4 size (210 x 297 mm): A7 B7 1304061 V. Inventive Note (574) m), 8.62 (1H, s), 8.76 (1H, d, J = 5.2 Hz). Production Example 506-4 4·(4νamine..Phenylphenoxymethyl) g _7· γ 夺 夺 制造 制造 制造 制造 制造 制造 制造 制造 制造 制造 制造 制造 制造 制造 制造 制造 制造 制造 制造 制造 制造 制造 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 Get the mark Compound (18 〇 mg). ^-NMR (DMS 〇.d6) 5 (ppm): 4.05 (3H, s), 5.19 (2H, s), 6.59 (1H, d, J = 5.2 Hz), 6.66 ( 2H, d, J=8.8 Hz), 6.94 (2H5 d, J=8.8 Hz), 7.73 (1H, s), 8.51 (1H, s), 8.61 (1H, d, J=5.2 Hz) 〇Example 507 Ii_4-"(7-Aminomethylglycosyl-6-methoxy-4-4g)-oxyl-indenyl)-N,-fluorophenyl)urea will be N-(4-[(7- Cyano-6-methoxy-4-quinolinyl)oxy]phenyl)-N,-(heart fluorophenyl)urea (43 mg) was dissolved in dimercaptopurine 5·5 at 80 °C A 5N NaOH aqueous solution was added thereto and stirred under heating for 2 hours. After the reaction mixture was neutralized with 1N HCl, the crystals which crystallised were collected by filtration and then washed with ethanol to give the title compound 17 mg. lH-NMR (DMSO-d6) δ (ppm): 4.00 (3H, s), 6.58 (1H, d, J=5.2 Hz), 7.06-7.14 (2H, m), 7.17-7.24 (2H, m), 7.45-7.53 (2H5 m), 7.55-7.67 (3H, m), 7.70 (1H, br s), 7.86 (1H, br s), 8·22 (1H, s), 8.56 (1H, d, J = 5.2 Hz).

實施例50S 胺甲基-6-甲氧基-4-喹啉某）氫1茇基 脲三氣乙醢镑 藉由實施例480之方法，從N-(4-[(7-氰基-6-甲氧基-4〇奎 -580 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 575 &gt; 五、發明説明（ 林基）氧]苯基）-Ν'-(4-氟苯基）脲（50 mg)，得到標題化合物 (52 mg)。 H-NMR (DMSO-d6) 5 (ppm): 4.01 (3H, s), 4.21^4.26 (2H, m), 6.66 (1H，d，J=5.2 Hz), 7.08-7.15 (2H，m)，7.23 (2H，d，J=8.8Example 50S Aminemethyl-6-methoxy-4-quinoline a) Hydrogen 1 hydrazinyl trioxanthene by the method of Example 480, from N-(4-[(7-cyano)- 6-Methoxy-4〇奎-580 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 575 &gt; V. Description of invention (林基)氧氧) - Ν'-(4-Fluorophenyl)urea (50 mg) gave the title compound (52 mg). H-NMR (DMSO-d6) 5 (ppm): 4.01 (3H, s), 4.21^4.26 (2H , m), 6.66 (1H,d,J=5.2 Hz), 7.08-7.15 (2H,m), 7.23 (2H,d,J=8.8

Hz), 7.43-7.50 (2H, m), 7.61 (2H, d, J=8.8 Hz), 7.67 (1H3 s), 8.08 (-1H, s)5 8.63 ( 1H3 d, J=5.2 Hz), 8.85 (lH, br s), 8.95 (1H，br s) 〇 實施例509 ϋι_,(4-「（7,乙醯胺甲基-6_甲氫基-4- 4啉某）氧i草甚w-氟笨基）月尿 藉由在實施例481中記載之方法，從Ν-(4-[(7-胺甲基-6-甲氧基-4-奎啉基）氧]苯基）-Ν，-(4-氟苯基）脲三氟乙酸鹽 (30 mg) ’得到標題化合物（5 mg)。 H-NMR (DMSO-d6) 5 (ppm): 1·94 (3H，s)，3.96 (3H，s)， 4.37-4.40 (2Η, m), 6.51 (1H, d, J=5.2 Hz), 7.08^7.14 (2H, m)5 7.20 (2H, d, J=8.8 Hz), 7.43-7.50 (2H, m), 7.50^7.60 (3H, m)5 7.74 (1H, s), 8.39-8.45 (1H, m), 8.50 (1H5 d3 J=5.2 Hz), 8.80 (1H，br s)，8·88 (1H，br s) 〇 實施例5 10 氟苯幕t脲基i笨氣基}呋喃并「2丄h] w 酸甲酯 在4-(4-胺基苯氧基）呋喃并[2,3-b]吡啶-2-羧酸甲醋（28 mg)中加入.甲苯·（丨ml)，乙腈（0·5 ml)及異氰酸心氟苯酯 (0.02 ml)，並加熱回流30分鐘。放冷後濾取析出之結晶， -581 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 装 訂 1304061 A7 B7 五、發明説明（576) 用甲冬洗淨，得到為淡黃色結晶之標題化合物（24 mg)。 ^-NMR (DMSO-d6) 5 (ppm): 3.87 (3H, s), 6.75 (1H, d, 、z), 7.08 7.14 (2H, m), 7.21-7.25 (2H, m), 7.40 (1H, s), 7.43-7.48 (2H, m), 7.55-7.60 (2H, m), 8.35 (iH, d, J=5.6 z)，8·79 (1H, br s)，8·89 (1H，br s)。 起始物質用下述5步驟合成。 1造例510- 1 基六圜某甲某、脖 酸甲酯 將蘭卡斯特公司製之5-胺基-2-呋喃曱酸曱酯（4 g)加至原 裝 甲酸二乙酯（20 ml)與異丙醇（2〇 mi)之混合溶液中，然後加 入麥爾多拉姆酸（4.5 g)並於i〇〇t：加熱攪拌2小時。放冷 後’濾取析出之結晶，將其用異丙醇洗淨，得到標題化合 物（7.8 g) 〇 H-NMR (CDC13) 5 (ppm): 1.75 (6H, s), 3.89 (3H, s), 6.04-Hz), 7.43-7.50 (2H, m), 7.61 (2H, d, J=8.8 Hz), 7.67 (1H3 s), 8.08 (-1H, s)5 8.63 ( 1H3 d, J=5.2 Hz), 8.85 (lH, br s), 8.95 (1H, br s) 〇 Example 509 ϋι_,(4-"(7, acetylamine methyl-6-methylhydro-4--4-phenylene)oxyi grass -Fluorophenyl)monthly urine by the method described in Example 481, from Ν-(4-[(7-aminomethyl-6-methoxy-4-quinolinyl)oxy]phenyl)- Ν,-(4-Fluorophenyl)ureatrifluoroacetic acid salt (30 mg) 'mqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 3.96 (3H, s), 4.37-4.40 (2Η, m), 6.51 (1H, d, J=5.2 Hz), 7.08^7.14 (2H, m)5 7.20 (2H, d, J=8.8 Hz), 7.43 -7.50 (2H, m), 7.50^7.60 (3H, m)5 7.74 (1H, s), 8.39-8.45 (1H, m), 8.50 (1H5 d3 J=5.2 Hz), 8.80 (1H, br s) ,8·88 (1H,br s) 〇Example 5 10 fluorobenzene curtain t urea group i stupid base} furan "2丄h] w acid methyl ester in 4-(4-aminophenoxy)furan And [2,3-b]pyridine-2-carboxylic acid methyl vinegar (28 mg) was added with toluene·(丨ml), acetonitrile (0.5 ml) and fluorophenylphenyl isocyanate (0.02 ml). And heating and refluxing for 30 minutes. After cooling, the precipitated crystals were collected by filtration. -581 The paper size applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) Binding 1304061 A7 B7 V. Inventive Note (576) Washed with formazan to give the title compound (24 mg) ^-NMR (DMSO-d6) 5 (ppm): 3.87 (3H, s), 6.75 (1H, d, z), 7.08 7.14 (2H, m), 7.21-7.25 (2H, m), 7.40 (1H, s), 7.43-7.48 (2H, m), 7.55-7.60 (2H, m), 8.35 (iH, d, J=5.6 z), 8.79 (1H, br s), 8·89 ( 1H, br s) The starting material is synthesized in the following 5 steps. 1 Example 510- 1 圜 圜 圜 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲The decyl ester (4 g) was added to a mixture of the original diethyl formate (20 ml) and isopropanol (2 〇mi), then added with merdoram acid (4.5 g) and i〇〇t : Heating and stirring for 2 hours. After cooling, the precipitated crystals were filtered, washed with isopropyl alcohol to give the title compound (7.8 g) 〇H-NMR (CDC13) 5 (ppm): 1.75 (6H, s), 3.89 (3H, s ), 6.04-

6.09 (1H, m), 7.08-7.12 (1H, m), 8.56-8.64 (1H, m), 11.4-11 ·6 (1H，m) 〇 製造例5 1 0- ? 酮基-4,7-二氫-吱喃并f 2,3- bl p比症-2-费酸甲醋 將5-[(2,2-二甲基-4,6-二酮基-[1，3]亞二氧六圜-5-基甲 基）胺基]呋喃-2-羧酸甲酯（4·0 g)加至（Dowtherm A)(30 ml) 中，並於200 °C加熱攪拌1小時。放冷後，濾取析出之結 晶，將其用·乙醚洗淨，得到標題化合物（2,0 g)。 lH-NMR (DMSO-d6) δ (ppm): 3.86 (3H, s), 6.77 (1H, d, -582 - 本纸張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐) A7 B7 1304061 五、發明説明（577 J=5.6 Hz), 7.71 (1H, s), 8.18 (1H, d, J=5.6 Hz), 11.85 (1H, br s) o 製造例510-22 4-氩-咭喃#「2,3-bl吡啶-2-#醢甲酷 在4-酮基-4,7-二氫-呋喃并[2,3-b]吡啶-2-羧酸甲酯（2.0 g) 中，加入亞硫醯氯（8·0 ml)及二甲基甲醯胺（0.08 ml)，並加 熱回流1小時。放冷後，於減壓下濃縮，濾取析出之結晶， 將其用四氫呋喃及乙酸乙酯洗淨，得到標題化合物（2.1 g)。 lH-NMR (DMSO-d6) δ (ppm): 3.92 (3H, s), 7.66 (1H, d, J=5.2 Hz), 7·86 (1H, s), 8.49 (1H，d，J=5.2 Hz)。 製造例510-3 K 4-硝基苯氣基呋喃并f 2,3-bl吡啶-2-#酸甲酯 在心氯-呋喃并[2,3-b]吡啶-2-羧酸甲酯（1·〇 g)中，加入 N-甲基咐咯啶酮（4·〇 ml)，二異丙基乙胺（13 ^1)及對-硝 基紛（822 mg)，並於140°C加熱攪拌5小時。放冷後，加入 水及用乙酸乙酯萃取，將有機層用水及飽和食鹽水依次洗 淨後，用無水硫酸鈉乾燥及減壓餾去溶媒。將其用四氫呋 喃再結晶，得到標題化合物（7〇 mg)。 H-NMR (DMSO-d6) 5 (ppm): 3·87 (3H，s)，7·〇4 (1H，d， J=5.6 Hz), 7.48-7.53 (2H, m), 7.59 (1H, s), 8.32-8.37 (2H, m)，8·47 (1H，d，J=5.6 Hz)。 製造例5 1 Oj . 1: (4-胺表不乳基）_g夬味并龄甲啼 :297公釐） 1304061 A7 - _ B7 五、發明説明（578) 將4-(4-硝基苯氧基）呋喃并[2,3^]咐啶-孓羧酸甲醋（7〇 mg)用製造例10之方法進行鐵還原’得到標題化合物（55 mg) 〇 &quot; iH-NMR (DMS〇-d6)5(ppm): 3·86 (3H，s)，5·23 (2H，br s) 6.64 (2Η, d, J=8.4 Hz), 6.72 (1H, d, J=6.0 Hz), 6.93 (2H, d, J=8.4 Ήζ)，7·23 (1H，s)，8.31 (1H，d，J=6.0 Hz)。 t施例511 基氧）茉某1蟬 將4- { 4- [ 3 - (4-氟苯基）躲基]苯氧基}咳喃并[2,3-b] p比咬- 2-羧酸甲酯（13 mg)溶於四氫呋喃（3 ml)中，在其中加入硼 氫化鋰（1 0 mg)並於室溫攪拌一夜。加入少量丙酮後加入 水，用乙酸乙酯萃取，將有機層用水及飽和食鹽水依次洗 淨後，用無水硫酸鈉乾燥，減壓餾去溶媒，得到標題化合 物（10 mg) 〇 !H-NMR (DMSO-d6) 5 (ppm)： 4.52 (2H, d, J=6.0 Hz), 5.52 (1H, t, J=6.0 Hz), 6.38 (1H, s), 6.69 (1H, d, J=5.6 Hz), 7.07-7.19 (4H, m), 7.43-7.49 (2H, m), 7.51-7.57 (2H, m), 8.11 (1H，d, J=5.4 Hz)，8·11 (1H，br s), 8.81 (1H，br s)。 實施例5 12 ίί.：· (4-乳冬乳基）笨某夬喃并f2,3-bl喻症-4-基 氧）笨基1脲 在4-(6-·.苯基·-·呋喃并[2,3-b]嘧啶-4-基氧）苯胺（4〇 mg) 中，加入甲苯（1 ml)，乙腈（〇·5 ml)及異氰酸心氟苯酯（0·03 —___- 584 - 本紙張尺度適用中國國家標準(CNS) Α4規格（210X^97公爱） 1304061 、 A7 - ~_____B7 五、發明説明(~~) —- ml)，並加熱回流30分鐘。放冷後濾取析出之結晶，用甲苯 洗淨’得到為淡黃色結晶之標題化合物（42 mg)。 lH-NMR (DMSO-d6) δ (ppm): 7.08-7.15 (2H, m), 7.23 (2H d J=8.4 Hz)，7.43-7.57 (7H，m)，7·65 (1H，s)，7.97 (2H，d， J=8.4 Hz), 8.50 (1H，s)，8.74-8.81 (2H，m)。 ’ ’ 起始原料以下述4步騾合成。 製造例512胃1 t苯基-呋喃并「2,3-dl嘧啶-4-某脖 在用 J. Heterocyclic Chem·，35，1313 ( 1998)記載之方法合 成之2-胺基-5-苯基-3-吱喃甲腈（1.8 g)中，加入甲酿胺（1〇 ml)及2滴無水乙酸，並於20(TC加熱攪拌2小時。放冷後， 濾取析出之結晶及用乙醚洗淨，得到標題化合物（1.3 g)。 lH-NMR (DMSO-d6) 5(ppm): 7.30 (1H, s), 7.35-7.41 (1H, m), 7.46-7.53 (2H，m)，7.74-7.79 (2H，m)，8,16 (1H，m)。 製造例51 2-7 生-(4_確某苯氧基-6-笨基-咭喃# |~2,3- dl喊畦 在6-苯基-呋喃并[2,3-d]嘧啶-4-基胺（211 mg)中，加入 二溴甲烷（1.2 ml)及亞硝酸異戊酯（1.2 ml)，並於80°C加熱 擾摔30分鐘。將反應落液於減壓下濃縮，加入水，用乙酸 乙醋萃取，將有機層用水及飽和食鹽水依次洗淨後，用無 水硫酸鈉乾燥及減壓餾去溶媒。在其中加入二Τ基甲醯胺 (10 ml)，對-硝基苯（222 mg)及碳酸鉀（414 mg)，然後於80 °C加熱攪拌·1小.時。在該反應溶液中加入水，用乙酸乙酯萃 取’將有機層用水及飽和食鹽水依次洗淨後，用無水硫酸 ____- 585 -______ 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（58〇) 納乾燥及減壓館去溶媒。將其用乙酸乙g旨再結晶，得到標 題化合物（150 mg” H-NMR (DMSO-d6) 5 (ppm)： 7.43-7.67 (5H, m), 7.76 (1H, s), 7.98-8.03 (2H, m)，8·34-8·39 (2H, m)，8·56 (1H，s)。 製造例512-36.09 (1H, m), 7.08-7.12 (1H, m), 8.56-8.64 (1H, m), 11.4-11 ·6 (1H,m) 〇Manufacturing Example 5 1 0- ? Keto group-4,7- Dihydro-purine f 2,3- bl p ratio-2-fetoic acid methyl vinegar 5-[(2,2-dimethyl-4,6-dione-[1,3] sub-two Methyl hexamethylene-5-ylmethyl)amino]furan-2-carboxylate (4.0 g) was added to (Dowtherm A) (30 ml), and stirred at 200 ° C for 1 hour. After allowing to cool, the precipitated crystals were filtered, washed with diethyl ether to give the title compound (2,0 g). lH-NMR (DMSO-d6) δ (ppm): 3.86 (3H, s), 6.77 (1H, d, -582 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) A7 B7 1304061 V. INSTRUCTIONS (577 J=5.6 Hz), 7.71 (1H, s), 8.18 (1H, d, J=5.6 Hz), 11.85 (1H, br s) o Manufacturing example 510-22 4-argon -咭喃# "2,3-blpyridine-2-#醢甲酷 in 4-keto-4,7-dihydro-furo[2,3-b]pyridine-2-carboxylic acid methyl ester (2.0 g), adding sulfoxide (8·0 ml) and dimethylformamide (0.08 ml), and heating under reflux for 1 hour. After cooling, concentrate under reduced pressure, and crystallize the precipitated crystals. This was washed with tetrahydrofuran and ethyl acetate to give the title compound (1. g). NMR (DMSO-d6) δ (ppm): 3.92 (3H, s), 7.66 (1H, d, J = 5.2 Hz), 7·86 (1H, s), 8.49 (1H, d, J=5.2 Hz). Production Example 510-3 K 4-Nitrobenzene-based furan-f 2,3-blpyridine-2-carboxylic acid methyl ester In the heart chlorine-furo[2,3-b]pyridine-2-carboxylic acid methyl ester (1·〇g), N-methylpyrrolidone (4·〇ml), diisopropylethylamine (13 ^1) and p-nitroso (822 mg), and stirred at 140 ° C for 5 hours. After cooling, add The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. NMR (DMSO-d6) 5 (ppm): 3·87 (3H, s), 7·〇4 (1H, d, J = 5.6 Hz), 7.48-7.53 (2H, m), 7.59 (1H, s) , 8.32-8.37 (2H, m), 8·47 (1H, d, J = 5.6 Hz). Production Example 5 1 Oj . 1: (4-amines are not milky) _g 夬 并 龄 龄 297: 297 1304061 A7 - _ B7 V. Description of the invention (578) Manufacture of 4-(4-nitrophenoxy)furo[2,3^]acridine-indolecarboxylic acid methyl vinegar (7 〇mg) The method of Example 10 was carried out for iron reduction to give the title compound (55 mg) 〇 &quot; iH-NMR (DMS 〇-d6) 5 (ppm): 3·86 (3H, s), 5·23 (2H, br s) 6.64 (2Η, d, J=8.4 Hz), 6.72 (1H, d, J=6.0 Hz), 6.93 (2H, d, J=8.4 Ήζ), 7·23 (1H, s), 8.31 (1H, d , J = 6.0 Hz). t Example 511 oxy) 茉 蝉 4- 4- 4- 4- 4-[3-(4-fluorophenyl) hexyl] phenoxy} cough and [2,3-b] p than bite 2- The methyl carboxylate (13 mg) was dissolved in tetrahydrofuran (3 ml), and lithium borohydride (10 mg) was added and stirred at room temperature overnight. After adding a small amount of acetone, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. (DMSO-d6) 5 (ppm): 4.52 (2H, d, J = 6.0 Hz), 5.52 (1H, t, J = 6.0 Hz), 6.38 (1H, s), 6.69 (1H, d, J=5.6 Hz), 7.07-7.19 (4H, m), 7.43-7.49 (2H, m), 7.51-7.57 (2H, m), 8.11 (1H,d, J=5.4 Hz),8·11 (1H,br s ), 8.81 (1H, br s). Example 5 12 ίί.:·(4-milk winter base) stupid 并 and f2,3-bl 症-4-yloxy) phenyl 1 urea in 4-(6-·.phenyl·- · Furano[2,3-b]pyrimidin-4-yloxy)aniline (4 〇mg), adding toluene (1 ml), acetonitrile (〇·5 ml) and fluorophenyl isocyanate (0· 03 —___- 584 - This paper size applies to Chinese National Standard (CNS) Α4 specification (210X^97 public) 1304061, A7 - ~_____B7 5. Invention description (~~) —- ml), and heated to reflux for 30 minutes. After cooling, the crystals which crystallized from crystals eluted eluted eluted eluted eluted elution elution lH-NMR (DMSO-d6) δ (ppm): 7.08-7.15 (2H, m), 7.23 (2H d J=8.4 Hz), 7.43-7.57 (7H, m), 7·65 (1H, s), 7.97 (2H,d, J=8.4 Hz), 8.50 (1H, s), 8.74-8.81 (2H, m). The starting materials were synthesized in the following four steps. Production Example 512 stomach 1 t phenyl-furan "2,3-dl pyrimidine-4-one neck 2-amino-5-benzene synthesized by the method described in J. Heterocyclic Chem., 35, 1313 (1998) In the base of 3-oxancarbonitrile (1.8 g), add the brewed amine (1 〇ml) and 2 drops of anhydrous acetic acid, and stir at 20 (TC for 2 hours). After cooling, the precipitated crystals were filtered and used. The title compound (1.3 g) was obtained.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 7.74-7.79 (2H,m),8,16 (1H,m). Production Example 51 2-7 Raw-(4_真某苯氧-6-笨基-咭喃# |~2,3- dl Shouting in 6-phenyl-furo[2,3-d]pyrimidin-4-ylamine (211 mg), adding dibromomethane (1.2 ml) and isoamyl nitrite (1.2 ml), and at 80 The mixture was heated and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure. Water was added and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate and evaporated. Solvent, adding dimethylformamide (10 ml), p-nitrobenzene (222 mg) and potassium carbonate (414 mg), then heating at 80 °C for 1 hour. Water is added to the reaction solution, and extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, and anhydrous sulfuric acid is used. _-585 -______ This paper scale is applicable to the Chinese National Standard (CNS) Α4 specification ( 210 X 297 mm) 1304061 A7 B7 V. Description of the invention (58〇) The solvent was removed from the drying and decompression chamber. The title compound (150 mg) H-NMR (DMSO-d6) was obtained by recrystallization from ethyl acetate. 5 (ppm): 7.43-7.67 (5H, m), 7.76 (1H, s), 7.98-8.03 (2H, m), 8·34-8·39 (2H, m), 8.56 (1H, s). Manufacturing Example 512-3

K 6-笨某-呋喃并「2.3-dl嘧啶-4-基氳）H 將4- (4-硝基苯氧基-6-苯基-吱喃并[2,3- d]。密咬（150 mg) 用製造例6之方法進行鐵還原，得到標題化合物（5〇 mg)。 lH-NMR (DMSO-d6)5(ppm): 5.10 (2H, br s), 6.59-6.63 (2H, m)，6.91-6.96 (2H，m)，7.42-7.56 (4H，m)，7·91·7·95 (2H，m)， 8.47 (1H, s) 〇 ， 實施例5 13 羧基-7-甲氧基-4“吲哚-5-某氣V奎啉 將6-甲氧羰基甲氧基(峋哚-5-基氧）喹啉（4〇〇 mg) 溶於四氫呋喃（5 ml)，在其中加入1·5當量氫氧化鋰水溶液 (2.5 ml)並於室溫攪拌3小時。將該反應溶液用1當量鹽酸水 溶液調成pH 4，濾取析出之結晶及用乙酸乙酯洗淨，得到 標題化合物（280 mg)。 iH-NMR (DMS〇-d6) (5 (ppm): 3·94 (3H，s)，6·37 (1H d J=5.2 Hz), 6.43-6.47 (1H, m), 6.95-7.01 (1H, m), 7.40-7.55 (4H, m)，8.55-8.61 (2H，m)，11.3 (1H，br s) 〇 如下述合成中間體。 製造例513-.1 ·. t甲氧羰基· 7-甲氧基-4- (Η卜果-5 -某氧）峻啦^ _ - 586 - 本紙張尺度適用中國國家標準(CNS) Α4規格（210 X 297公釐） !3〇4〇61 五、發明説明（ A7 B7 將4-氯-7-甲氧tr奎淋-卜幾酸甲酯（WO 0050405，p .34 , 8·5 g ’ 33·77 mmol)，5-羥基旬哚（7 g)，二異丙基乙胺（8 9 ml)與N-甲基p比洛咬酮（8.9 ml)混合，並於130 °C授摔5小 時，繼而於15〇°C加熱攪拌8小時。將放冷後之溶液吸著於 碎凝膠，用矽凝膠管柱（己烷-乙酸乙酯系）生成，在得到之 黃色油狀物中加入乙醇，乙醚及己烷，放置使結晶析出。 將其濾取，用乙醚及己烷洗淨及吸引乾燥，得到淡黃色結 晶（3.506 g，10.06 mmol，29.80%) 〇 i-NMR 光譜（DMSO-d6)5(ppm): 3·86 (3H，s)，3·97 (3H，s) 6.38 (1Η, d, J=5.2 Hz), 6.46 (1H, s)3 6.98 (1H3 d3 J=8.8 Hz), 7·44-7·52 (4H，m)，8·60-8·65 (2H，m)，11.29 (1H，s)。 實施例5 14 甲氧乙基胺甲醯某甲氣某丨哚-5_某氧u矣畔 將6-羧基-7-甲氧基-4-(啕哚-5-基氧）喹啉（1〇〇 mg)溶於 二曱基曱醯胺（4.0 ml)，加入曱氧乙胺（〇·〇4 ml)，三乙胺 (0.08 ml)，苯并三唑-1-基氧參（二甲胺基）鱗六氟磷酸鹽 (198 mg)並於室溫攪捽5小時。在反應溶液中加入水及用乙 酸乙酯萃取，有機層用水及飽和食鹽水依次洗淨後，用無 水硫酸鈉乾燥及減壓餾去溶媒。將其用乙酸乙酯再結晶， 得到標題化合物（86 mg)。 lH-NMR (DMSO-d6) δ (ppm): 3.29 (3H, s), 3.46-3.49 (4H, m) 4.02 (3H, s), 6.37 (1H, d5 J=5.2 Hz), 6.45-6.47 (1H, m), 6.95-7.00 ..(1H, -m), 7.41-7.54 (4H, m), 8.42-8.45 (1H, m),8·59 (1H，d, J=5.2 Hz), 8.68 (1H, s)，11.3 (1H, br s)。 _- 587 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐厂K 6-Stupo-furan and "2.3-dl pyrimidin-4-ylindole" H 4-(4-nitrophenoxy-6-phenyl-indolo[2,3-d]. (150 mg) The title compound (5 〇mg) was obtained by the method of the method of the method of the method of the method of the method of the method of the product. m), 6.91-6.96 (2H, m), 7.42-7.56 (4H, m), 7·91·7·95 (2H, m), 8.47 (1H, s) 〇, Example 5 13 Carboxyl-7- Methoxy-4"吲哚-5-a certain V-quinoline 6-methoxycarbonylmethoxy(indol-5-yloxy)quinoline (4 〇〇mg) was dissolved in tetrahydrofuran (5 ml). 1 to 5 equivalents of an aqueous lithium hydroxide solution (2.5 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction solution was adjusted to pH 4 with 1N aqueous hydrochloric acid, and crystals were separated and washed with ethyl acetate. The title compound (280 mg) was obtained. iH-NMR (DMS 〇-d6) (5 (ppm): 3·94 (3H, s), 6.37 (1H d J=5.2 Hz), 6.43-6.47 (1H, m), 6.95-7.01 (1H, m), 7.40-7.55 (4H, m), 8.55-8.61 (2H, m), 11.3 (1H, br s) The following synthetic intermediates are as follows: Manufacturing Example 513-.1 · t-methoxycarbonyl · 7-methoxy-4- (Η卜果-5 - an oxygen) ^ _ - 586 - This paper size applies to Chinese National Standard (CNS) Α 4 specifications (210 X 297 mm) !3〇4〇61 V. Invention description (A7 B7 will 4-chloro-7-methoxy triqueline - Methyl benzoate (WO 0050405, p.34, 8.5 g '33·77 mmol), 5-hydroxyxanthine (7 g), diisopropylethylamine (89 ml) and N-methyl p is mixed with ketone (8.9 ml) and dropped for 5 hours at 130 ° C, followed by heating and stirring at 15 ° C for 8 hours. The solution after cooling is sorbed on the broken gel, with a gel tube Column (hexane-ethyl acetate) was formed, and ethanol, diethyl ether and hexane were added to the obtained yellow oil, and the crystals were allowed to stand to precipitate crystals, which were collected by filtration, washed with diethyl ether and hexane, and then dried and dried. Light yellow crystals (3.506 g, 10.06 mmol, 29.80%) 〇i-NMR spectrum (DMSO-d6) 5 (ppm): 3·86 (3H, s), 3·97 (3H, s) 6.38 (1Η, d , J=5.2 Hz), 6.46 (1H, s)3 6.98 (1H3 d3 J=8.8 Hz), 7·44-7·52 (4H,m),8·60-8·65 (2H,m), 11.29 (1H, s). Example 5 14 methoxyethylamine formazan, a certain gas, a certain 丨哚-5_, an oxygen oxon group, 6-carboxy-7-methoxy-4-(indol-5-yloxy)quinoline ( 1〇〇mg) dissolved in dimethyl decylamine (4.0 ml), added with oxime ethylamine (〇·〇 4 ml), triethylamine (0.08 ml), benzotriazol-1-yloxy ginseng ( Dimethylamino)sodium hexafluorophosphate (198 mg) was stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate and evaporated. This was recrystallized from ethyl acetate toield lH-NMR (DMSO-d6) δ (ppm): 3.29 (3H, s), 3.46-3.49 (4H, m) 4.02 (3H, s), 6.37 (1H, d5 J=5.2 Hz), 6.45-6.47 ( 1H, m), 6.95-7.00 ..(1H, -m), 7.41-7.54 (4H, m), 8.42-8.45 (1H, m), 8.59 (1H,d, J=5.2 Hz), 8.68 (1H, s), 11.3 (1H, br s). _- 587 This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm factory)

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缘 1304061 A7 B7Edge 1304061 A7 B7

五、發明説明（582) 實施例5 1 5 LI?-甲氧0基）-7-甲氣墓-乙某胺甲醯羞叫卜朵.5_&lt; 氧）口奎淋 將60%氫化鈉（10 mg)加至二甲基甲醯胺（1访丨）中，於室 溫攪摔，在其中加入6-(2-甲氧乙基胺甲醯基）-7-甲氧基-心 (吲哚·_5-基氧）喹啉（10 mg)，然後攪拌15分鐘。在其中加 入乙基胺基甲酸苯酯（43 mg)並授拌1小時。在反應溶液中 加入水及用乙酸乙酯萃取，有機層用水及飽和食鹽水依次 洗淨後’用我水硫酸納乾燥及減壓餘去溶媒。將其用乙酸 乙醋再結晶’得到標題化合物（27 mg)。 H-NMR (DMSO-d6) 5 (ppm): 1.18 (3H, t, J=7.2 Hz), 3.27-3.29 (5H, m), 3.47-3.49 (4H, m), 4.02 (3H, s), 6.42 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.6 Hz), 7.15-7.20 (1H, m), 7.50-7.52 (2H, m), 7.93 (1H, d3 J=3.6 Hz), 8.20-8.50 (3H, m), 8.61 (1H，d，J=5.2 Hz)，8.67 (1H, s)。 實施例5 16 K2-甲氧基乙羰某甲氳某4- f i“2-氣乙基胺甲醯基）⑷ 生-5-基氣啉 以與實施例5 1 5同樣之方法，使用2-氟乙胺甲酸苯酯從6-(2-曱氧基乙胺甲醯基卜7-甲氧基-4-(吲哚-5-基氧）4啉， 得到標題化合物。 lH-NMR (DMSO-d6) 5(ppm): 3.24 (3H, s), 3.45-3.67 (6H, m), 4.02 (3H, s)*, 4.50-4.68 (2H, m), 6.43 (1H, d, J=5.2 Hz), 6.72 (1H, d, J=3.6 Hz), 7.16-7.21 (1H, m), 7.50-7.54 (2H, m), —- ____- 588 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公爱） 1304061 A7 B7 五、發明説明（583 7.98 (1H, d, J=3.6 Hz), 8.35 (lH, d, J=9.2 Hz), 8.42-8.53 (2H，m)，8.61 (1H，d, J=5.2 Hz), 8.76 (1H, s)。 實施例5 17 K 氟乙胺甲龜基）-7:甲氧基-(4丨嗓-5_基氧）P杏P林 以與實施例514同樣之方法，使用2-氟乙胺鹽酸鹽從6_幾 基-7-甲氧基-4- ( 朵-5-基氧）u奎琳，得到標題化合物。 !H-NMR (DMSO-d6) δ (ppm): 3.53-3.71 (2H, m), 4.02 (3H, s) 4.48-4.63 (2H，m)，6·37 (1H，d，J=5.2 Hz)，6·45-6·47 (1H，m) 6.95-7.00 (1H，m)，7.42-7.46 (2H，m)，7·48-7·53 (2H，m) 8.57-8.63 (2H，m)，8·66 (1H，s)，&quot;·6 (1H，br s)。 ’ 實施例51 8 (2-氟乙羰基）-7-甲氧基4-((1- △其胺甲酿基丨哮· ς — 氧）口奎淋 以與實施例515同樣之方法，從6-(2_氟乙胺甲醯基甲 氧基-4-(啕哚-5-基氧）喹啉，得到標題化合物。 iH-NMR (DMSO-d6)5(ppm): 1.18 (3H，t，J=7.2 Hz)，3 27_ 3·32 (2H，m)，3.56-3.68 (2H，m)，4·02 (3H，s)，4·47-4·65 (2H m), 6.42 (1H, d, J-5.2 Hz), 6.70 (1H，d，J=4.0 Hz)，7 15-7 2〇 (lH，m)，7.50-7.52 (2H，m)，7.93(lH，d，J=4.0Hz)，8.22-8·27 (1H，m)，8·34 (1H，d，J=8.9 Hz)，8.57-8.66 (3H，m)。 實施例519 甲氧胺甲酿基-7-甲氧基-4- ( 4卜条-5 -某氧）p奎成 以與實施例514同樣之方法，使用甲基羥胺鹽酸鹽，從6_ 叛基-7-甲氧基-4-(^噪-5-基氧）峻琳，得到標題化合物。 -589 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 裝 訂V. DESCRIPTION OF THE INVENTION (582) Example 5 1 5 LI?-Methoxy 0)-7-methane tomb - B-aminoamine 醯 醯 卜 . .. 5_&lt; Oxygen) koulin will be 60% sodium hydride ( 10 mg) was added to dimethylformamide (1 visit) and stirred at room temperature, to which 6-(2-methoxyethylaminemethanyl)-7-methoxy-heart (吲哚·_5-yloxy)quinoline (10 mg) was then stirred for 15 minutes. Phenylethylamine (43 mg) was added thereto and the mixture was stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried with sodium sulfate and decompressed to remove solvent. This was recrystallized from ethyl acetate to give the title compound (27 mg). H-NMR (DMSO-d6) 5 (ppm): 1.18 (3H, t, J = 7.2 Hz), 3.27-3.29 (5H, m), 3.47-3.49 (4H, m), 4.02 (3H, s), 6.42 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.6 Hz), 7.15-7.20 (1H, m), 7.50-7.52 (2H, m), 7.93 (1H, d3 J=3.6 Hz), 8.20-8.50 (3H, m), 8.61 (1H, d, J = 5.2 Hz), 8.67 (1H, s). Example 5 16 K2-methoxyethylcarbonyl a formazan 4-fi "2-aeroethylamine-carbamoyl group" (4) A 5--5-based porphyrin was used in the same manner as in Example 5 1-5, using 2 -Phenylethyl fluoroacetate from 6-(2-decyloxyethylamine carbazyl 7-methoxy-4-(indol-5-yloxy) 4 phenyl, the title compound was obtained. DMSO-d6) 5 (ppm): 3.24 (3H, s), 3.45-3.67 (6H, m), 4.02 (3H, s)*, 4.50-4.68 (2H, m), 6.43 (1H, d, J= 5.2 Hz), 6.72 (1H, d, J=3.6 Hz), 7.16-7.21 (1H, m), 7.50-7.54 (2H, m), —- ____- 588 - This paper scale applies to the Chinese National Standard (CNS) A4 size (210 x 297 public) 1304061 A7 B7 V. Description of invention (583 7.98 (1H, d, J=3.6 Hz), 8.35 (lH, d, J=9.2 Hz), 8.42-8.53 (2H, m) , 8.61 (1H, d, J = 5.2 Hz), 8.76 (1H, s). Example 5 17 K fluoroethylamine tomazan)-7:methoxy-(4丨嗓-5-yloxy)P Apricot P. In the same manner as in Example 514, using 2-fluoroethylamine hydrochloride from &lt;RTI ID=0.0&gt; !H-NMR (DMSO-d6) δ (ppm): 3.53-3.71 (2H, m), 4.02 (3H, s) 4.48-4.63 (2H,m),6·37 (1H,d J=5.2 Hz),6·45-6·47 (1H,m) 6.95-7.00 (1H,m),7.42-7.46 (2H,m),7·48-7·53 (2H,m) 8.57- 8.63 (2H, m), 8.66 (1H, s), &quot;·6 (1H, br s). 'Example 51 8 (2-fluoroethylcarbonyl)-7-methoxy 4-((1) - △ 胺 甲 丨 丨 · ς 以 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 The title compound is obtained as the title compound. iH-NMR (DMSO-d6) 5 (ppm): 1.18 (3H, t, J = 7.2 Hz), 3 27_ 3·32 (2H, m), 3.56-3.68 ( 2H,m),4·02 (3H,s),4·47-4·65 (2H m), 6.42 (1H, d, J-5.2 Hz), 6.70 (1H,d,J=4.0 Hz), 7 15-7 2〇(lH,m), 7.50-7.52 (2H,m), 7.93 (lH,d,J=4.0Hz), 8.22-8·27 (1H,m),8·34 (1H, d, J = 8.9 Hz), 8.57-8.66 (3H, m). Example 519 methoxyamine-mercapto-7-methoxy-4-(4-Bu-5-anoxy)p-quine was obtained in the same manner as in Example 514 using methylhydroxylamine hydrochloride from 6_ Retinyl-7-methoxy-4-(^--5-yloxy) Junlin gave the title compound. -589 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm).

1304061 A7 B7 五、發明説明（584) 1 H-NMR (DMSO-d6) 5 (ppm): 3·73 (3H，s)，3.98 (3H，s)，6.38 (1Η，d，J=5.2 Ηζ)，6.44-6.48 (1Η，m)，6.95-7.00 (1H，m)， 7.40-7.54 (4H, m), 8.49 (1H, s)5 8.59 (1H, d, 1=5.2 Hz), 11·29 (1H，br s)，11·45 (1H，br s) 〇 實施例520 L甲氧胺甲酿基-7-甲氧基4-((1二&amp;某脖平醯莘、叫嗓-5^^ 氧V奎啉 以與實施例515之方法，從6」甲氧胺甲醯基-7-甲氧基-4-(吲哚-5-基氧）喹啉，得到標題化合物。 1 H-NMR (DMSO-d6) 5 (ppm): 1.16 (3H, t, J=7.2 Hz), 3.27-3·30 (2H，m)，3.73 (3H，s)，3·98 (3H，s)，6·43 (1H，d，J=5.2 Hz), 6.70 (1H, d, J=3.2 Hz), 7.15-7.20 (1H, m), 7.45-7.53 (2H，m)，7·93 (1H，d，J=3.6 Hz)，8.21-8.26 (1H，m)，8.35 (1H， d，J=8.8 Hz)，8.48 (1H，s)，8·61 (1H，d，J=5.2 Hz)，11.45 (1H， br s) 〇 實施例521 L甲氣胺甲醯基-7-甲氧基4-((1-環丙某胺甲醯基）㈣哚-5-基氣）g奋成 以與實施例5 1 5同樣之方法，用環丙基胺基甲酸苯酯從6-甲氧胺甲醯基-7-甲氧基-4-(吲哚-5-基氧）喹啉，得到標題 化合物。 ^-NMR (DMSO-d6) (5 (ppm): 0.58-0.65 (2H, m), 0.70-0.77 (2H，m)，2.73-2.82 (1H，m)，3.73 (3H，s)，3.98 (3H，s)，6·42 (1H, d, J=5.2 Hz), 6.68 (1H, d, J=3.6 Hz), 7.15-7.20 (1H, m), ________· 590 -__ 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）1304061 A7 B7 V. INSTRUCTIONS (584) 1 H-NMR (DMSO-d6) 5 (ppm): 3·73 (3H, s), 3.98 (3H, s), 6.38 (1Η, d, J=5.2 Ηζ ), 6.44-6.48 (1Η, m), 6.95-7.00 (1H, m), 7.40-7.54 (4H, m), 8.49 (1H, s)5 8.59 (1H, d, 1=5.2 Hz), 11· 29 (1H, br s), 11·45 (1H, br s) 〇 Example 520 L methoxyamine-mercapto-7-methoxy 4-((1二&amp; a neck flat, 嗓-5^^ Oxy-V-quinoline The title compound was obtained from the title compound from </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 1 H-NMR (DMSO-d6) 5 (ppm): 1.16 (3H, t, J = 7.2 Hz), 3.27-3·30 (2H, m), 3.73 (3H, s), 3·98 (3H, s),6·43 (1H,d,J=5.2 Hz), 6.70 (1H, d, J=3.2 Hz), 7.15-7.20 (1H, m), 7.45-7.53 (2H,m),7·93 (1H, d, J = 3.6 Hz), 8.21-8.26 (1H, m), 8.35 (1H, d, J = 8.8 Hz), 8.48 (1H, s), 8.61 (1H, d, J = 5.2 Hz), 11.45 (1H, br s) 〇 Example 521 L-methaneamine-mercapto-7-methoxy 4-((1-cyclopropylaminocarbamoyl)(tetra)indole-5-yl) g In the same manner as in Example 5 1 5, using cyclopropylaminocarboxylic acid The title compound was obtained from 6-methoxylaminomethyl-7-methoxy-4-(indol-5-yloxy)quinoline. NMR (DMSO-d6) (5 (ppm): 0.58 -0.65 (2H, m), 0.70-0.77 (2H, m), 2.73-2.82 (1H, m), 3.73 (3H, s), 3.98 (3H, s), 6.42 (1H, d, J= 5.2 Hz), 6.68 (1H, d, J=3.6 Hz), 7.15-7.20 (1H, m), ________· 590 -__ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)

裝 訂Binding

k 1304061 五、發明説明（k 1304061 V. Description of invention (

7.47-7.52 (2H, m), 7.89 (1H, d, J=3.6 Hz), 8.28-8.36 (2H m) 8.48 (1H，s)，8·61 (1H，d，J=5.2 Hz)，ΐι·44 (ih，br s)。 實施例522 b(吨淀-2-基胺甲晚盖菊·某致 以與實施例514同樣之方法.，用2_胺基吡啶，從心羧基_ 7-甲氧基-4-(⑼嗓-5-基氧）,奎琳，得到標題化合物。土 1 H-NMR (DMSO-d6) 5 (ppm): 4.08 (3H, s), 6.39-6.48 (2H? m): 6.97-7.02 (1H, m), 7.15-7.20 (1H, m)5 7.43-7.60 (4H, m), 7.83-7.89 (1H, m), 8.25-8.38 (2H, m)5 8.60-8.80 (2H, m), 10.70 (1H，br s)，11.30 (1H，br s)。 ’ ’ 實施例523 6·(,比_咬_ 2_基胺7_ T氧^胺甲酿某 哚-5-基氣）喹啉 以與實施例515同樣之方法，從6_(吡啶基胺甲酿基）_ 7-甲氧基-4-(啕哚-5-基氧）喹啉，得到標題化合物： lH-NMR (DMSO-d6) 5(ppm): 1.18 (3H, t5 J=7.6 Hz), 3.27-3.30 (2H, m), 4.10 (3H, s), 6.46 (1H, d, J=5.2 Hz), 6.71 (1H, d, J=3.6 Hz), 7.15-7.21 (2H, m), 7.53 (1H, d, J=2.8 Hz), 7.60 (1H, s), 7.83-7.89 (1H, m)? 7.93 (1H, d, J=3.6 Hz), 8.22-8.38 (4H，m)，8·65 (1H，d，J=5.2 Hz)，8·76 (1H，d，J=5.2 Hz), 10.70 (1H，br s)。 ’ f施例524 k〒氧談基，Ί氧M2-氟哚·5_基 f.卜奎啉 -591 - 紙浪尺度適用中國國家標準(CNS) A4規格(210X297公釐） A7 B7 1304061 五、發明説明（586) 以與實施例515同樣之方法，用2-氟乙基胺基甲酸苯酯’ 從6-甲氧羰基-7-甲氧基-4-(吲哚-5-基氧）喹啉，得到標題 化合物。 lH-NMR (DMSO-d6)(5(ppm): 3.50-3.68 (2H, m), 3.84 (3H, s), 3.97 (3H, s), 4.48-4.70 (2H, m), 6.42 (1H, d, J=5.6 Hz), 6.72 (1H, d, J=3.6 Hz), 7.17-7.22 (1H, m)5 7.45-7.56 (2H, m), 7.98 (1H, d, J=3.6 Hz), 8.35 (1H, d, J=9.2 Hz), 8.46-8.53 (1H，m)，8·58-8·64 (2H，m) 〇 實施例525 6 -致基-7-甲氧基-4-|~ 1-(2-氟乙基胺甲酿基）卜朵-5-基氧1 口奎淋 以與實施例513同樣之方法，用2-苯基胺基甲酸苯酯，從 6-甲氧幾基-7-甲氧基-4-[1-(2&quot;•氟乙基胺甲酿基）巧嗓-5-基 氧]喹琳，得到標題化合物。 lH-NMR (DMSO-d6) δ (ppm): 3.50-3.70 (2H, m), 3.94 (3H, s), 4.48-4.70 (2H, m), 6.42 (1H, d, J=5.2 Hz), 6.72 (1H, d, J=3.6 Hz), 7.18-7.22 (1H, m), 7.42-7.55 (2H, m), 7.98 (1H, d, J=3.6 Hz), 8.35 (1H, d, J=9.2 Hz), 8.46-8.52 (1H, m), 8.54-8·64 (2H，m)。 實施例526 6-甲氣基胺甲一S|一基-7-甲氧基-4-『1-(2-氟乙葚胺甲醯基）巧丨 唤-5-某氫14:啉 以與實施例514同樣之:方法，用甲基經胺鹽酸鹽，從6-幾 基-7-甲氧基-4-[1-(2-氟乙基胺甲醯基）啕哚-5_基氧]峻 -592 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（587) 啉，得到標題化合物。 ^-NMR (DMSO-d6) 5 (ppm): 3.53-3.66 (2H, m), 3.73 (3H, s), 3.98 (3H，s)，4.50-4.68 (2H，m)，6.43 (1H，d，J=5.2 Hz)，6.73 (1H，d，J=3.6 Hz)，7.15-7.21 (1H, m), 7.47-7.54 (2H, m), 7·98 (1H，d，J=3.6 Hz)，8·35 (1H，d，J=8.4 Hz)，8.46-8.53 (2H，ra)，8·61 (1H，d5 J=5.2 Hz)，11·5 (1H，br s) 〇 實施例527 6-異丁氧基胺甲醯基-7-甲氣基-4-「1-( 2-氟乙基胺甲醯基） 吲嗓-5 -基氧1 4^林 以與實施例514同樣之方法，用異丁基羥胺鹽酸鹽，從6-羧基-7-甲氧基-4-[ 1-(2-氟乙基胺甲醯基）吲哚-5-基氧]喹 啉，得到標題化合物。 ^-NMR (DMSO-d6) 5 (ppm): 0.93 (6H, d), 1.90-2.00 (1H, m)，3.52-3.67 (2H，m)，3.70 (2H，d，J=6.8 Hz)，3.97 (3H，s)， 4·50-4·69 (2H，m)，6.43 (1H，d，J=5.6 Hz)，6.73 (1H，d，J=4.0 Hz)，7.15-7.21 (1H，m)，7.47-7.54 (2H，m)，7.98 (1H，d， J=4.0 Hz)，8·35 (1H，d，J=9.2 Hz)，8.41 (1H，s)，8.45-8.55 (1H，m)，8.61 (1H，d，J=5.6 Hz)，11.84 (1H，br s)。 實施例528 ^^『2-氣-4-(「6-亂基-7-(「（21〇-2-輕基-3-(1-^7比哈咬基）丙 基1氣）-4 - 4啉基1氣）笨基Ί - N1 ( 2 -嘧唑基）脲 用實施例495記載之方法，從N-(4-{6-氰基-7- [(2R)-環 氧乙烷-2-··基]甲氧喹啉-4-基氧卜2-氟苯基）-Ν^(嘧唑-2-基） 脲，得到標題化合物。 _ - 593 - 本紙張尺度適用中國國家標準(CNS) Α4規格（210 X 297公釐）7.47-7.52 (2H, m), 7.89 (1H, d, J=3.6 Hz), 8.28-8.36 (2H m) 8.48 (1H, s), 8.61 (1H, d, J=5.2 Hz), ΐι · 44 (ih, br s). Example 522 b (Ten-Phen-2-ylamine-Azuramide) was obtained in the same manner as in Example 514. Using 2-aminopyridine from the carboxyl group 7-methoxy-4-((9)嗓-5-yloxy), quinine, the title compound was obtained. </ RTI> <1>H-NMR (DMSO-d6) 5 (ppm): 4.08 (3H, s), 6.39-6.48 (2H?m): 6.97-7.02 ( 1H, m), 7.15-7.20 (1H, m)5 7.43-7.60 (4H, m), 7.83-7.89 (1H, m), 8.25-8.38 (2H, m)5 8.60-8.80 (2H, m), 10.70 (1H, br s), 11.30 (1H, br s). ' ' Example 523 6·(, _ _ 2_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The title compound was obtained from 6-(pyridylaminomethyl)-7-methoxy-4-(indol-5-yloxy)quinoline in the same manner as Example 515: lH-NMR (DMSO- D6) 5 (ppm): 1.18 (3H, t5 J=7.6 Hz), 3.27-3.30 (2H, m), 4.10 (3H, s), 6.46 (1H, d, J=5.2 Hz), 6.71 (1H, d, J=3.6 Hz), 7.15-7.21 (2H, m), 7.53 (1H, d, J=2.8 Hz), 7.60 (1H, s), 7.83-7.89 (1H, m)? 7.93 (1H, d , J=3.6 Hz), 8.22-8.38 (4H,m),8·65 (1H,d,J=5.2 Hz),8·76 (1H,d,J=5.2 Hz), 10.70 (1H,br s ). f Example 524 k〒 Oxygen Forum, Oxygen M2-Fluorine ·5_基f.Buquirin-591 - Paper Wave Scale Applicable to China National Standard (CNS) A4 Specification (210X297 mm) A7 B7 1304061 V. Invention Description (586) In the same way as Example 515, use 2 - fluoroethylaminobenzoic acid phenyl ester 'from 6-methoxycarbonyl-7-methoxy-4-(indol-5-yloxy)quinoline gave the title compound. lH-NMR (DMSO-d6) 5 (ppm): 3.50-3.68 (2H, m), 3.84 (3H, s), 3.97 (3H, s), 4.48-4.70 (2H, m), 6.42 (1H, d, J=5.6 Hz), 6.72 (1H, d, J=3.6 Hz), 7.17-7.22 (1H, m)5 7.45-7.56 (2H, m), 7.98 (1H, d, J=3.6 Hz), 8.35 (1H, d, J=9.2 Hz), 8.46-8.53 (1H, m), 8·58-8·64 (2H, m) 〇 Example 525 6 -Acetyl-7-methoxy-4-|~ 1-(2-Fluoroethyl Alkylamine-based acetophenone-5-yloxyl-l-quinone in the same manner as in Example 513, using 2-phenylphenylcarbamic acid phenyl ester, from 6-methoxybenzyl-7-methoxy -4-[1-(2&quot;•Fluoroethylamine), indole-5-yloxyquinolin, gave the title compound. lH-NMR (DMSO-d6) δ (ppm): 3.50-3.70 (2H, m), 3.94 (3H, s), 4.48-4.70 (2H, m), 6.42 (1H, d, J = 5.2 Hz), 6.72 (1H, d, J=3.6 Hz), 7.18-7.22 (1H, m), 7.42-7.55 (2H, m), 7.98 (1H, d, J=3.6 Hz), 8.35 (1H, d, J= 9.2 Hz), 8.46-8.52 (1H, m), 8.54-8·64 (2H, m). Example 526 6-Methylamine A-S|-yl-7-methoxy-4-"1-(2-fluoroacetamimidyl) 丨-5- a hydrogen 14: porphyrin The same procedure as in Example 514: using a methyl-amine hydrochloride salt from 6- benzyl-7-methoxy-4-[1-(2-fluoroethylamine carbazyl) oxime-5 _基氧]峻-592 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Inventive Note (587) porphyrin, the title compound is obtained. ^-NMR (DMSO-d6) 5 (ppm): 3.53-3.66 (2H, m), 3.73 (3H, s), 3.98 (3H, s), 4.50-4.68 (2H, m), 6.43 (1H, d , J=5.2 Hz), 6.73 (1H, d, J=3.6 Hz), 7.15-7.21 (1H, m), 7.47-7.54 (2H, m), 7·98 (1H, d, J=3.6 Hz) , 8.35 (1H, d, J = 8.4 Hz), 8.46-8.53 (2H, ra), 8.61 (1H, d5 J = 5.2 Hz), 11·5 (1H, br s) 〇 Example 527 6-Isobutoxyamine-mercapto-7-methyl-l--4-"1-(2-fluoroethylaminocarbamoyl) 吲嗓-5-yloxy 1 4 lin was the same as Example 514. a method using isobutylhydroxylamine hydrochloride from 6-carboxy-7-methoxy-4-[1-(2-fluoroethylaminemethylmercapto)indol-5-yloxy]quinoline, The title compound is obtained. ^-NMR (DMSO-d6) 5 (ppm): 0.93 (6H, d), 1.90-2.00 (1H, m), 3.52-3.67 (2H, m), 3.70 (2H, d, J = 6.8 Hz), 3.97 (3H, s), 4·50-4·69 (2H, m), 6.43 (1H, d, J = 5.6 Hz), 6.73 (1H, d, J = 4.0 Hz), 7.15- 7.21 (1H, m), 7.47-7.54 (2H, m), 7.98 (1H, d, J = 4.0 Hz), 8.35 (1H, d, J = 9.2 Hz), 8.41 (1H, s), 8.45 -8.55 (1H, m), 8.61 (1H, d, J = 5.6 Hz), 11.84 (1H, br s). Example 528 ^^ 2-Q4--4-("6-乱基-7-("(21〇-2-light-based-3-(1-^7-habita)propyl 1 gas)-4 - 4 phenyl group 1 Gas) stupid base - N1 (2-pyrazolyl) urea by the method described in Example 495, from N-(4-{6-cyano-7-[(2R)-oxirane-2- · methoxy] quinolin-4-yloxybu- 2-fluorophenyl)-indole (pyrazol-2-yl)urea to give the title compound. _ - 593 - This paper scale applies to Chinese National Standard (CNS) Α4 size (210 X 297 mm)

裝 訂Binding

k 1304061 A7 B7 五、發明説明（588) lH-NMR (DMSO-d6) (5 (ppm): 1.60-1.70 (4H, m), 2.40-2.75 (6H，m)，3·95-4·05 (1H，m)，4·20 (1H, dd，J=10，6·0 Hz)， 4.31 (1H，dd，J=10, 4 Hz)，5.02 (1H，br s)，6·62 (1H，d，J=5.2 Hz)，7.10-7.20 (2H，m)，7.37-7.47 (2H，m)，7,62 (1H，s)， 8·20-8·26 (1H，m)，8.71-8.76 (2H，m)，9.05 (1H，br s)。 實施例529 N-「2-氣-4-(「6-氨基-7-( K2R)-2-羥基-3-Π -六氤吡啶基） 丙基1氣）-4-4啉基1氳）苯基1-ΝΉ-4唑某）脲 用實施例496記載之方法，從N-(4-{6-氰基-7-[(2R)-環 氧乙烷-2-基]甲氧喹啉-4-基氧}-2-氟苯基）-Ν’-噻唑-2-基-脲，得到標題化合物。 1H-NMR (DMSO-d6) 5 (ppm): 1·30-1.55 (6Η，m)，2.32-2.55 (6H，m)，3·97-4·16 (1H，m)，4.20 (1H，dd，J=10, 6 Hz)，4.30 (1H，dd，J=10, 4.0 Hz)，4.44 (1H，br s)，6·62 (1H，d，J=5.2 Hz)，7.11-7.21 (2H，m)，7.37-7.47 (2H，m)，7·64 (1H，s)， 8.20-8.27 (1H，m)，8.72-8.76 (2H，m) 〇 實施例530 Ν-|~2·氣-4-(「6·氨某- 7-(K2R)-2-羥基-3-Π -吡咯啶基）丙 基1氣）-4-4啉墓1氣）苯基1-N^環丙基脲 用實施例492記載之方法，從N-(2-氟-4-[(6·氰基- 7-[(2R)-(環氧乙烷-2-基）甲氧]-4-喹啉基）氧]苯基）-Ν·-環丙 脲，得到標題化合物。 ^-NMR (DMSO-d6) 5 (ppm): 0.37-0.44 (2H, m), 0.62-0.69 (2H，m)，1.63-1.75 (4H，m)，2·45-2·60 (6H，m)，2·65-2·77 _- 594 -_____ 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐）k 1304061 A7 B7 V. INSTRUCTIONS (588) lH-NMR (DMSO-d6) (5 (ppm): 1.60-1.70 (4H, m), 2.40-2.75 (6H, m), 3.95-4·05 (1H,m),4·20 (1H, dd, J=10,6·0 Hz), 4.31 (1H, dd, J=10, 4 Hz), 5.02 (1H, br s), 6·62 ( 1H,d,J=5.2 Hz), 7.10-7.20 (2H,m),7.37-7.47 (2H,m),7,62 (1H,s), 8·20-8·26 (1H,m), 8.71-8.76 (2H, m), 9.05 (1H, br s). Example 529 N-"2-Gas-4-("6-amino-7-(K2R)-2-hydroxy-3-indole-6氤pyridyl) propyl 1 gas)-4-4 phenyl 1 phenyl) phenyl 1-indole oxazole) Urea was treated with N-(4-{6-cyano-7) by the method described in Example 496. -[(2R)-Ethylene oxide-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-indole--thiazol-2-yl-urea gave the title compound. NMR (DMSO-d6) 5 (ppm): 1·30-1.55 (6Η, m), 2.32-2.55 (6H, m), 3.97-4.16 (1H, m), 4.20 (1H, dd, J=10, 6 Hz), 4.30 (1H, dd, J=10, 4.0 Hz), 4.44 (1H, br s), 6.62 (1H, d, J = 5.2 Hz), 7.11-7.21 (2H, m), 7.37-7.47 (2H, m), 7.64 (1H, s), 8.20-8.27 (1H, m), 8.72-8.76 (2H, m) 〇 Example 530 Ν-|~2· Gas-4-("6-amino--7-(K2R)-2-hydroxy-3-indolyl-pyrrolidinyl)propyl 1 gas)-4-4 phenyl tomb 1 gas) phenyl 1-N^ ring Propylurea was prepared by the method described in Example 492 from N-(2-fluoro-4-[(6-cyano-7-[(2R)-(oxiran-2-yl)methoxy]-4 - quinolinyl)oxy]phenyl)-indole-cyclopropanamide gave the title compound. NMR (DMSO-d6) 5 (ppm): 0.37-0.44 (2H, m), 0.62-0.69 (2H, m),1.63-1.75 (4H,m),2·45-2·60 (6H,m),2·65-2·77 _- 594 -_____ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)

裝 訂Binding

k 1304061 A7 ___B7 五、發明説明（589) (1H, m), 3.98-4.08 (1H, m), 4.22 (1H, dd5 J=10, 5.2 Hz), 4.31 (1H，dd，J=l〇，3.6 Hz)，5·〇4 (1H，br s)，6·59 (1H，d， J=5.6 Hz), 6.82-6.85 (1H, m), 7.08-7.13 (1H, m)3 7.32-7.38 (1H，m)，7·63 (1H，s)，8.20-8.28 (2H，m)，8.72-8.76 (2H， m) 〇 起始物質用下述2步驟合成。 製造例530- 1 『2-氟-4-(「6-氰基二7- (「（2ΙΟ-Γ埽氡乙烷-2-某甲氣）-4-崦啤 基1氣）茉某1胺基甲酸笨酯 用製造例141-1記載之方法，從4-(4-胺基-3-氟-苯氧基）-7- [(2R)-環氧乙燒-2-基]甲氧η奎琳-6-甲腈合成。 ^-NMR (CDC13) 5 (ppm): 2.90-3.01 (2H, m), 3.44-3.55 (1H, m)，4.21-4.28 (1H，m)，4.47-4.54 (1H，m)，6·53 (1H, d，J=5.2 Hz)，7.00-7.06 (2H，m)，7.19-7.30 (4H，m)，7.40-7.46 (2H， m)，7·48-7·53 (1H，m)，8.27 (1H，br s)，8.65-8.73 (2H，m)。 製造例530-2 ίiΓ_(2-氟-4-「（6:氰基-7-Γ(2R)-(環氫乙烷-2-某、甲擎|卜4-邊啉基）氣1苯基）-Ν’-瑗丙Μ 將環丙胺（0·04 ml)加至二甲基亞颯（3 ml)中，然後將[2-氟-4_([6-氰基-7- ([(2R)-(環氧乙烷·2-基甲氧）-4-喹啉基] 氧）苯基]胺基甲酸苯酯（212 mg)溶解於其中並撥拌1〇分 鐘。在該反應溶液中加入水及乙酸乙酯以及濾取析出之結 晶，得到標題化合物（150 mg)。 1 H-NMR (DMSO-d6) 5 (ppm): 0.37-0.44 (2H, m), 0.61-0.69 ___ - 595 -__ 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 B7 五、發明説明（590) (2H，m)，2.50-2.60 (1H，m)，2.78-2.79 (2H，m)，3.45-3.50 (1H，m)，4·20 (1H，dd，J=12, 6·0 Ηζ)，4·73 (1H，dd，J=12, 2·4 Hz)，6.59 (1H，d，J=5.6 Hz)，6.82-6.85 (1H，m)，7.08-7.13 (1H，m)，7.32-7.38 (1H，m)，7_63 (1H，s), 8.20-8.28 (2H，m)， 8.72-8.78 (2H，m)。k 1304061 A7 ___B7 V. Description of invention (589) (1H, m), 3.98-4.08 (1H, m), 4.22 (1H, dd5 J=10, 5.2 Hz), 4.31 (1H, dd, J=l〇, 3.6 Hz),5·〇4 (1H,br s),6·59 (1H,d, J=5.6 Hz), 6.82-6.85 (1H, m), 7.08-7.13 (1H, m)3 7.32-7.38 (1H, m), 7.63 (1H, s), 8.20-8.28 (2H, m), 8.72-8.76 (2H, m) The starting material was synthesized in the following two steps. Production Example 530- 1 "2-Fluoro-4-("6-Cyano-di 7-("(2ΙΟ-Γ埽氡ethane-2-A gas)-4-崦 beer base 1 gas) Mo Mo 1 Ethyl carbamic acid ester was obtained from the method described in Production Example 141-1 from 4-(4-amino-3-fluoro-phenoxy)-7-[(2R)-epoxyethyl-2-yl]- Synthesis of oxy-n-quine-6-carbonitrile. ^-NMR (CDC13) 5 (ppm): 2.90-3.01 (2H, m), 3.44-3.55 (1H, m), 4.21-4.28 (1H, m), 4.47 -4.54 (1H,m),6·53 (1H, d,J=5.2 Hz), 7.00-7.06 (2H,m), 7.19-7.30 (4H,m),7.40-7.46 (2H, m),7 · 48-7·53 (1H, m), 8.27 (1H, br s), 8.65-8.73 (2H, m). Production Example 530-2 ίiΓ_(2-Fluoro-4-"(6:Cyano-7 -Γ(2R)-(cyclohydroethane-2-, 甲擎|卜4-porphyrin) gas 1 phenyl)-Ν'-瑗 Μ Μ Add cyclopropylamine (0·04 ml) to two In methyl sulfoxide (3 ml), then [2-fluoro-4_([6-cyano-7-([(2R)-(oxiran-2-ylmethoxy)-4-quinoline) The phenyl) phenyl] phenyl carbamate (212 mg) was dissolved in the mixture and stirred for 1 hr. Water and ethyl acetate were added to the reaction solution, and the crystals were separated by filtration to give the title compound (150 mg) 1 H-NMR (DMSO-d6) 5 (ppm): 0.37-0.44 (2H, m), 0.61-0.69 ___ - 595 -__ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 B7 V. Invention description (590) ( 2H,m), 2.50-2.60 (1H,m), 2.78-2.79 (2H,m), 3.45-3.50 (1H,m),4·20 (1H,dd,J=12, 6·0 Ηζ), 4·73 (1H, dd, J=12, 2·4 Hz), 6.59 (1H, d, J=5.6 Hz), 6.82-6.85 (1H, m), 7.08-7.13 (1H, m), 7.32 7.38 (1H, m), 7_63 (1H, s), 8.20-8.28 (2H, m), 8.72-8.78 (2H, m).

實施例5U 氰基-7-(「（2R)-2-蕤某-3-Π-六 i.吡啶某） 喳啉基1氣）笨基卜Ν’ -瑷丙甚Μ 用實施例496記載之方法，從Ν-(2-氟-4-[(6-氰基-7-[(2R)-(環氧乙烷-2-基）甲氧]-4-喹啉基）氧]苯基）-Ν’-環丙 膽’传到標題化合物。 ^-NMR (DMSO-d6) &lt;5 (ppm): 0.38-0.44 (2H, m), 0.62-0.69 (2H, m), 1.33-1.54 (6H, m), 2.30-2.70 (7H, m), 4.00-4.09 (1H, m), 4.21 (1H, dd, J=10.4, 5.6 Hz), 4.32 (1H, dd? J=10.4, 3.2 Hz), 4.95 (1H, d, J=4.4 Hz), 6.59 (1H, d, J=5.6 Hz), 6.83-6,85 (1H, m), 7.08-7.13 (1H, m), 7.32-7.38 (1H, m), 7·64 (1H，s)，8.20-8.28 (2H，m)，8.72-8.78 (2H，m)。 實施例532 N-『2-氣-4-(『6-氰基-7- (「3- ( 1 -六藍,T7比咬基）丙基1氣）-4- g奎 啉基1氫）茉某唑基）月尿 用實施例495記載之方法，從2-氟-4-([6-氰基-7- ([3-(卜 六氫批淀基）丙基]氧）-4-0奎琳基]氧）苯胺，得到標題化合 物。 .·- ^-NMR (DMSO-d6) (5 (ppm): 1.30-1.53 (6H, m), 1.92-2.00 _____- 596 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（591) (2H, m)5 2.30-2.50 (6H, m), 4.28-4.35 (2H, m), 6.62 (1H, d, j==5.6 Hz), 7.12-7.20 (2H, m), 7.36-7.47 (2H, m), 7.60 (1H, s)，8·20-8·28 (1H, m)，8·72-8·77 (2H，m)。 起始物質用下述方法合成。 life 例 532- 1 氰幕J-Hd -六氤吡啶某）丙某1氳崦啉 羞丄乳）笨胺 在4-(4-胺基-3-氟苯氧基）_6_氰基·7_羥基喹啉（2〇〇 mg) 中加入二甲基甲酿胺（4 ml)，氯丙基六氫吡啶）鹽酸鹽 (268 mg)及碳酸鉀（374 mg)，並於60°C加熱8小時。在該反 應溶液中加入水及用乙酸乙酯萃取，將有機層用水及飽和 食鹽水依次洗淨後，用無水硫酸鈉乾燥及減壓餾去溶媒。 將得到之粗生成物用矽凝膠管柱層析（乙酸乙酯）精製，得 到為淡黃色結晶之標題化合物（80 mg)。 'H-NMR (CDCl3)5(ppm): 1.38-1.64 (6H, m), 2.07-2.18 (2H, m)，2·37-2·48 (6H，m)，3.79 (2H，br s)，4.24-4.34 (2H，m)， 6.47 (1H, d3 J=5.6 Hz), 6.77-6.92 (3H, m), 7.46 (1H, s), 8.63-8.67 (2H, m) 〇 實施例533 土『2-氟-4- (f 6-氰基-3- Π -吡咯啶基）丙某n) · 4· 4 4 基1氣）茉某岫華、a年 用實施例495記載之方法，從2-氟-4-([6-氰基-7· ([3-(卜 叶匕咯啶基·.）丙基J氧）-4-喹啉基]氧）苯胺，得到標題化合 物0 -597 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) A7 B7 1304061 五、發明説明（592) 'H-NMR (DMSO-d6) 5 (ppm): 1.65-1.72 (4H, m)3 1.94-2.02 (2H, m), 2.40-2.50 (4H, m), 2.56-2.62 (2H, m), 4.30-4.36 (2H，m)，6.63(lH，d，J=5.6Hz)，7.13-7.20(2H，m)，7.37-7·47 (2H，m)，7.60 (1H，s)，8.20-8.27 (1H，m)，8.72-8.76 (2H， m) o 起始物質用下述方法合成。 製造例533-1 氟-4-(f6_氨基-7-(f3-(l -口比洛淀基）丙基1晕口套g株某1 氣）笨胺 在4-(4 -胺基-3-氟苯乳基）-6-乱基-7-經基峻p林（300 mg) 中加入二甲基甲醯胺（4 ml)，1-(3-氯丙基吡咯啶）鹽酸鹽 (376 mg)及碳酸却（553 mg)，並於60°C加熱8小時。在該反 應溶液中加入水及用乙酸乙酯萃取，將有機層用水及飽和 食鹽水依次洗淨後，用無水硫酸鈉乾燥及減壓餾去溶媒。 將得到之粗生成物用矽凝膠管柱層析（乙酸乙酯）精製’得 到為淡黃色結晶之標題化合物（200 mg)。 ^-NMR (DMSO-d6) 5 (ppm): 1.62-1.72 (4H, m), 1.93-2.03 (2H, m), 2.40«2.49 (4H, m), 2.55-2.61 (2H, m), 4.28-4.35 (2H, m), 5.22-5.25 (2H, m)5 6.51 (1H, d, J=4.8 Hz), 6.82- 6·90 (2H，m)，7.06-7.12 (1H，m)，7.56 (1H，s)，8·68-8·72 (2H， m) ° 實施例534 N-(2-氯-5-氨某-7-(2-(1-吡咯啶某）乙氣 氧）笨基）-N’-茉某脈 ___- 598 -_ -一-— 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）Example 5U Cyano-7-("(2R)-2-蕤 some-3-Π-hexa.pyridine) porphyrin group 1 gas) stupid base Ν '- 瑷 Μ Μ Μ Μ Μ Μ Μ A method from Ν-(2-fluoro-4-[(6-cyano-7-[(2R)-(oxiran-2-yl)methoxy]-4-quinolinyl)oxy)benzene The title compound is passed to the title compound. ^-NMR (DMSO-d6) &lt;5 (ppm): 0.38-0.44 (2H, m), 0.62-0.69 (2H, m), 1.33- 1.54 (6H, m), 2.30-2.70 (7H, m), 4.00-4.09 (1H, m), 4.21 (1H, dd, J=10.4, 5.6 Hz), 4.32 (1H, dd? J=10.4, 3.2 Hz), 4.95 (1H, d, J=4.4 Hz), 6.59 (1H, d, J=5.6 Hz), 6.83-6,85 (1H, m), 7.08-7.13 (1H, m), 7.32-7.38 (1H, m), 7·64 (1H, s), 8.20-8.28 (2H, m), 8.72-8.78 (2H, m). Example 532 N-"2-gas-4-("6-cyanide Base-7- ("3-(1-hexa-blue, T7-bite) propyl 1 gas)-4-g quinolinyl 1 hydrogen) jazozolyl) monthly urine using the method described in Example 495, from 2-Fluoro-4-([6-cyano-7-([3-(ihexahydrobenzyl)propyl]oxy)-4-0 quinolinyl]oxy)aniline afforded the title compound. - ^-NMR (DMSO-d6) (5 (ppm): 1.30-1.53 (6H, m), 1.92-2.00 _____- 596 - paper ruler Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (591) (2H, m)5 2.30-2.50 (6H, m), 4.28-4.35 (2H, m), 6.62 (1H, d, j==5.6 Hz), 7.12-7.20 (2H, m), 7.36-7.47 (2H, m), 7.60 (1H, s), 8·20-8·28 (1H, m) , 8·72-8·77 (2H, m). The starting material was synthesized by the following method. Life Example 532- 1 Cyanide J-Hd - Hexapyridine pyridine) C propyl 1 porphyrin shy milk) Stupid Amine in 4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (2 〇〇mg) with dimethyl ketoamine (4 ml), chloropropyl hexa Hydropyridine) hydrochloride (268 mg) and potassium carbonate (374 mg) were heated at 60 °C for 8 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate and evaporated. The obtained crude product was purified by EtOAc EtOAc (EtOAc) 'H-NMR (CDCl3) 5 (ppm): 1.38-1.64 (6H, m), 2.07-2.18 (2H, m), 2·37-2·48 (6H, m), 3.79 (2H, br s) , 4.24-4.34 (2H, m), 6.47 (1H, d3 J=5.6 Hz), 6.77-6.92 (3H, m), 7.46 (1H, s), 8.63-8.67 (2H, m) 〇Example 533 『2-Fluoro-4-(f 6-cyano-3-indolyl-pyrrolidinyl)-propyl-n) · 4· 4 4-based 1 gas) Momo, and a method described in Example 495, From 2-fluoro-4-([6-cyano-7·([3-()) propyl J oxy)-4-quinolinyl]oxy)aniline, the title compound -597 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 1304061 V. Description of invention (592) 'H-NMR (DMSO-d6) 5 (ppm): 1.65-1.72 (4H, m)3 1.94-2.02 (2H, m), 2.40-2.50 (4H, m), 2.56-2.62 (2H, m), 4.30-4.36 (2H, m), 6.63 (lH,d,J=5.6Hz) , 7.13-7.20(2H,m),7.37-7.47 (2H,m), 7.60 (1H,s), 8.20-8.27 (1H,m),8.72-8.76 (2H, m) o for starting materials The following method was synthesized. Preparation Example 533-1 Fluoro-4-(f6-amino-7-(f3-(l-perylpyroxy)propyl) 1 halo sleeve g strain 1 gas) stupid amine in 4-(4-amino group -3-fluorophenyllactyl)-6-ranyl-7-yl-dimethylpyridinamine (4 ml), 1-(3-chloropropylpyrrolidine) salt The acid salt (376 mg) and the carbonic acid (553 mg) were heated at 60 ° C for 8 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The title compound (200 mg) was obtained as a pale yellow crystals. DMSO-d6) 5 (ppm): 1.62-1.72 (4H, m), 1.93-2.03 (2H, m), 2.40«2.49 (4H, m), 2.55-2.61 (2H, m), 4.28-4.35 (2H , m), 5.22-5.25 (2H, m)5 6.51 (1H, d, J=4.8 Hz), 6.82- 6.90 (2H,m), 7.06-7.12 (1H,m),7.56 (1H,s ), 8·68-8·72 (2H, m) ° Example 534 N-(2-chloro-5-ammonia-7-(2-(1-pyrrolidine)ethane gas) stupid) N'-茉脉脉___- 598 -_ -一-- This paper scale applies to Chinese national standards (CNS ) A4 size (210 X 297 mm)

裝 訂Binding

1304061 A7 B7 五、發明説明（593) 用與實施例11同樣之方法，從4-(3-胺基-4-氯苯氧基）-6-氰基-7-(2-( 1-吡咯啶基）乙氧基）喹啉（44.5 mg，0.109 mmol)及異氰酸苯酯，得到為白色結晶之標題化合物（19.8 mg，0.038 mmol，34.5%) 〇 1H-NMR 光譜（DMSO-d6)5(ppm): 1.69 (4H，m)，2.59 (4H，m)， 2·91 (2H，t，J=5.6 Hz)，4·38 (2H，t，J=5.6 Hz)，6·66 (1H，d， J=5.2 Hz)，6.97-7.01 (2H，m)，7.24-7.28 (2H，m)，7·41 (2H，d， J=7.2 Hz), 7.60-7.63 (2H, m), 8.20 (1H, m), 8.51 (1H, s)5 8·74-8·76 (2H，m)，9·53 (1H，d，J=4.4 Hz)。 起始物質用下述方法合成。 製造例534-1 7-(芊氣基）-4-(4-氣-3-硝基笨氣基）-6-氰基4啉 藉由與製造例11同樣之手法，從7-(苄氧基）-4-氯-6-氰基 峻4 ( 5.462 g，1 8.53 mmol)及4-氯-3 -硝基紛，得到為淡褐 色結晶之標題化合物（4.794 g，11.10 mmol，59.9%)。 iH-NMR 光譜（CDCl3)5(Ppm): 5.74 (2H，s)，6·57 (1H，d， J=5.2 Ηζ)，7·34-7·55 (6H，m)，7·58 (1H，s)，7·70 (1H，d， J=8.8 Hz)，7·76 (1H，d，J=2.8 Hz)，8.64 (1H，s)，8·76 (1H，d， J=5.2 Hz)。 製造例534-2 4- (4-氣-3-硝基苯氣某）_ 6-氰基-7-羥基崦啉 藉由與實施例83同樣之手法，從7-(芊氧基）-4-(4-氣-3-硝基苯氧基）-6-氰基喹啉（1.00 g，2.32 mmol)，得到為淡黃 色結晶之標題化合物（743 mg，2.17 mmol，93.9%)。 _- 599 -_ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X297公釐）. A7 B7 1304061 立、發明説明（594) iH-NMR 光譜（DMSO-d6)5(ppm): 6·73 (1H，d，J=5.2 Hz), 7.45 (1H，s)，7·69 (1H, dd，J=2.8, 8.8 Hz)，7·91 (1H，d，J=8.8 Hz), 8.14 (1H, d, J=2.8 Hz), 8.67 (1H, s), 8.71 (1H, d, J=5.2 Hz)，11·71 (1H，br)。 f造例534-3 ^-(3 -胺基-4-氣苯乳基）-6 -亂基- 7-¾基p奎淋 藉由與製造例6同樣之手法，從4-(4-氯-3-硝基苯氧基）-6-氰基-7-羥基喹啉（743 mg，2.17 mmol)，得到為淡黃色結 晶之標題化合物（464 mg，1.49 mmol，68·5%)。 1H-NMR 光譜（DMSO-d6) 5 (ppm): 5.62-5.65 (2H，m)，6·43 (1H, dd, J=2.8, 8.8 Hz), 6.54 (1H, d, J=5.2 Hz), 6.63 (1H, d, J-2.8 Hz), 7.30 (1H, d, J=8.8 Hz), 7.41 (1H, s), 8.62 (1H, s), 8.65 (1H, d5 J=5.2 Hz) 〇 製造例534-4 $-(3 -胺基-4-氣苯·氧基）-6-亂基- 比啥淀）乙氣基） 口奎淋 藉由與實施例7同樣之手法，從4-(3-胺基-4-氯苯氧基）-6-氰基-7-經基口奎淋（200 mg，0.642 mmol)及1-(2-氯乙基） 吡咯啶鹽酸鹽，得到為白色結晶之標題化合物（143 mg， 0.350 mmo卜 54.5%) ° iH-NMR 光譜（CDCl3)5(ppm): 1.84 (4H，m)，2.74 (4H，m)， 3.08 (2H, t, J=5.6 Hz), 4.20-4.24 (2H, m), 4.37 (2H, t, 1=5.6 Hz), 6.50 (1H, dd, J=2.8, 8.8 Hz), 6.54 (1H, d, J=5.2 Hz), 6.59 (1H, d, J=2.8 Hz), 7.33 (1H, d, J=8.8 Hz), 7.46 (1H, s), ___ '600 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（595 8·64 (1H，s)，8·68 (1H，d，J=5.2 Hz)。 實施例535 1.(2-氣'_[(( 6-氰基- 7-(2-( 1-吡咯啶基）乙氣某4-4啉基） 氪）苯基）-Ν·-(1,3唑-2-其、B年 用與實施例131同樣之方法，從4-(3-胺基-4-氯苯氧基）-6-氰基-7-(2_( Ι-p 比咯啶）乙氧基）喹啉（46.6 mg , 0.114 mmol) 及N-(l，3-嘍唑-2-基）胺基甲酸苯酯，得到為白色結晶之標 題化合物（5.7 mg，0.011 mmol，9.35%)。 iH-NMR光譜（DMSO-d6)5(ppm): 1.69 (4H，m)，2.61 (4H，m)， 2.93 (2H, m), 4.39 (2H, m)5 6.65 (1H, d, J=5.2 Hz), 7.06 (1H, dd，J=2.8，8.8 Hz)，7.13-7.14 (2H，m)，7.38-7.40 (2H，m)， 7.63 (1H, s), 7.66 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=3.2 Hz), 8.75 (1H，d，J=5.2 Hz), 8·77 (1H，s) 〇 實施例536 羞-5-((6-氰某-7-(2-(1-吡咯啶基）乙1甚14-4毗真、 氧）苯基）-Ν〜環丙篡胧 將4-(3-胺基-4-乳表氧^基）-6-氨基- 7- (2-(1-p比嘻唉）乙氧 基）p奎淋（47.9 mg，0· 117 mmol)於氮蒙氣下溶於二甲基甲酿 胺（1 ml)，以及於室溫下滴入吡啶（〇·〇ι9 ml，0.234 mmol) 及氯甲酸苯酯（0.030 ml，0.234 mmol)，並攪拌1小時。滴 入環丙胺（0.1 ml)，然後再攪拌一夜。將反應液分溶於乙酸 乙酯及水中，用飽和食鹽水洗淨及用無水硫酸鈉乾燥。餘 去溶媒後滤取從乙酸乙酯中析出之結晶，然後藉由通風 乾燥，得到為淡褐色結晶之標題化合物（12.6 mg，Q Q26 -601 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 B7 五、發明説明（1304061 A7 B7 V. Inventive Note (593) In the same manner as in Example 11, from 4-(3-amino-4-chlorophenoxy)-6-cyano-7-(2-(1-pyrrole) Iridinyl)ethoxy)quinoline (44.5 mg, 0.109 mmol) and phenyl isocyanate afforded the title compound as white crystals (19.8 mg, 0.038 mmol, 34.5%) 〇1H-NMR spectrum (DMSO-d6) 5 (ppm): 1.69 (4H, m), 2.59 (4H, m), 2·91 (2H, t, J = 5.6 Hz), 4·38 (2H, t, J = 5.6 Hz), 6.66 (1H,d, J=5.2 Hz), 6.97-7.01 (2H,m), 7.24-7.28 (2H,m),7·41 (2H,d, J=7.2 Hz), 7.60-7.63 (2H, m ), 8.20 (1H, m), 8.51 (1H, s)5 8·74-8·76 (2H, m), 9·53 (1H, d, J = 4.4 Hz). The starting materials were synthesized by the following method. Production Example 534-1 7-(Indolyl)-4-(4-Ga-3-nitro-hydrocarbyl)-6-cyano- 4 phenyl was obtained from 7-(benzyl) by the same procedure as in Production Example 11. The title compound (4.794 g, 11.10 mmol, 59.9%), m. ). iH-NMR spectrum (CDCl3) 5 (Ppm): 5.74 (2H, s), 6.57 (1H, d, J = 5.2 Ηζ), 7·34-7·55 (6H, m), 7·58 ( 1H, s), 7·70 (1H, d, J = 8.8 Hz), 7·76 (1H, d, J = 2.8 Hz), 8.64 (1H, s), 8.76 (1H, d, J= 5.2 Hz). Production Example 534-2 4-(4-Ga-3-nitrobenzene gas)_6-Cyano-7-hydroxyporphyrin In the same manner as in Example 83, from 7-(decyloxy)- 4-(4-Benzyl-3-nitrophenoxy)-6-cyanoquinoline (1.00 g, 2.32 mmol) _- 599 -_ This paper size applies to Chinese National Standard (CNS) A4 specification (210 X297 mm). A7 B7 1304061 Li, invention description (594) iH-NMR spectrum (DMSO-d6) 5 (ppm): 6· 73 (1H,d,J=5.2 Hz), 7.45 (1H, s), 7·69 (1H, dd, J=2.8, 8.8 Hz), 7.91 (1H, d, J=8.8 Hz), 8.14 (1H, d, J = 2.8 Hz), 8.67 (1H, s), 8.71 (1H, d, J = 5.2 Hz), 11·71 (1H, br). fExample 534-3 ^-(3-Amino-4-phenylphenoxy)-6-rangue- 7-3⁄4-based p-quinone by the same method as in Production Example 6, from 4-(4- Chloro-3-nitrophenoxy)-6-cyano-7-hydroxyquinoline (743 mg, 2.17 mmol) gave the title compound (464 mg, 1.49 mmol, 68.5%). 1H-NMR spectrum (DMSO-d6) 5 (ppm): 5.62-5.65 (2H, m), 6.43 (1H, dd, J = 2.8, 8.8 Hz), 6.54 (1H, d, J = 5.2 Hz) , 6.63 (1H, d, J-2.8 Hz), 7.30 (1H, d, J=8.8 Hz), 7.41 (1H, s), 8.62 (1H, s), 8.65 (1H, d5 J=5.2 Hz) 〇 Production Example 534-4 $-(3-Amino-4- phenoxy-oxy)-6-ranyl-pyridyl-ethylidene) Ethyl sulfonate The same procedure as in Example 7 was carried out from 4 -(3-Amino-4-chlorophenoxy)-6-cyano-7- via quinine (200 mg, 0.642 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride, The title compound (143 mg, 0.350 mmol, 54.5%) was obtained as white crystals. </ RTI> NMR spectrum (CDCl3) 5 (ppm): 1.84 (4H, m), 2.74 (4H, m), 3.08 (2H, t, J=5.6 Hz), 4.20-4.24 (2H, m), 4.37 (2H, t, 1=5.6 Hz), 6.50 (1H, dd, J=2.8, 8.8 Hz), 6.54 (1H, d, J=5.2 Hz), 6.59 (1H, d, J=2.8 Hz), 7.33 (1H, d, J=8.8 Hz), 7.46 (1H, s), ___ '600 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of the invention (595 8·64 (1H, s), 8.68 (1H, d, J = 5.2 Hz). Example 535 1. (2-gas '_ [(( 6-cyano-7-(2-() 1-pyrrolidinyl)ethyl 4- 4 phenyl phenyl) phenyl) phenyl) hydrazine - (1, 3 azole-2-, B, in the same manner as in Example 131, from 4-(3) -amino-4-chlorophenoxy)-6-cyano-7-(2_(Ι-p-pyridyl)ethoxy)quinoline (46.6 mg, 0.114 mmol) and N-(l,3- The title compound (5.7 mg, 0.011 mmol, 9.35%) was obtained as white crystals. mp NMR (d-d): 5 (ppm): 1.69 (4H, m ), 2.61 (4H, m), 2.93 (2H, m), 4.39 (2H, m)5 6.65 (1H, d, J=5.2 Hz), 7.06 (1H, dd, J=2.8, 8.8 Hz), 7.13 -7.14 (2H,m), 7.38-7.40 (2H,m), 7.63 (1H, s), 7.66 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=3.2 Hz), 8.75 ( 1H, d, J = 5.2 Hz), 8·77 (1H, s) 〇 Example 536 Shame-5-((6-cyanyl-7-(2-(1-pyrrolidinyl)ethyl 1 even 14- 4 contiguous, oxy)phenyl)-Ν~cyclopropene will be 4-(3-amino-4-milopoloxy)-6-amino-7- (2-(1-p 嘻唉Ethyloxy)p-quinone (47.9 mg, 0·117 mmol) was dissolved in dimethylamine (1 ml) under nitrogen atmosphere, and pyridine (〇·〇ι 9 ml) was added dropwise at room temperature. 0.234 mmol) and phenyl chloroformate (0.030 ml, 0.234 mmol) and stirred for 1 hour. Cyclopropylamine (0.1 ml) was added dropwise, followed by stirring overnight. The reaction solution was dissolved in ethyl acetate and water, washed with brine and dried over anhydrous sodium sulfate. After removing the solvent, the crystals precipitated from ethyl acetate were filtered, and then dried by air to give the title compound as pale brown crystals (12.6 mg, Q Q26 - 601 - the paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of invention (

mmol，21.9%) 0 iH-NMR光譜（DMSO-d6)5(ppm): 0·39 (2H，m)，〇.63 (2H 叫 1·70 (4H，m)，2·49-2·53 (1H，m)，2.60 (4H，m)，2·9ΐ (2H m) 4·40 (2H，m)，6.64 (1H，d，J=5.2 Hz)，6.93 (1H，dd，J==2 8’ 8.8 Hz), 7.33 (1H, d, J=2.8 Hz), 7.57 (1H, d, J-8.8 Hz), 7 64 (1H，s)，8.09 (1H，s)，8·19 (1H，d，J=2.8 Hz)，8.75.8.77 (2H m) 〇 ， 實施例537 N二(2-氣-5-((6-氰某 D-4·^奎啉基）氣）笨基環丙基脲 藉由與實施例11同樣之手法，從N-(2-氣-5-((l氨基7 ((2R) -2-捏基-3-(1-p比嘻淀基）丙氧基-4-p奎琳基）氧）苯羞^ 胺基甲酸苯酯）（107 mg，0.191 mmol)及環丙胺，得到為 色粉末之標題化合物（20·7 mg，0.040 mmol，20.7%)。 iH-NMR光譜（DMSO-d6)5(ppm): 0·40 (2H，m)，〇 65 η。 、化，m)， 1.69 (4H, m), 2.49-2.68 (6H, m), 2.72 (1H, m), 4.Ο3 n u ’ tn)5 4.23 (1H，dd，J=5.6, 10.4 Hz)，4·33 (1H，dd，J=4.4 1 〇 . 5 AU-4 Hz) 5.03 (1H，m)，6.64 (1H，d，J=5.2 Hz)，6.94 (1H，dd，j==2 8’ 8·4 Hz)，7·33 (1H，m)，7.56-7.93 (2H，m)，8·1〇 (1jj 0 ’ /1TT , v s)3 8.20 (1H，d，J=2.8 Hz)，8·71-8·77 (2H，m)。 起始物質用下述方法合成。 製造例 基-4-氳茇氧幕）-6-氨某-7-((2R: 氧喳啉 _— _- 602 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇χ 297公釐）M, 21.9%) 0 iH-NMR spectrum (DMSO-d6) 5 (ppm): 0·39 (2H, m), 〇.63 (2H is 1.70 (4H, m), 2·49-2· 53 (1H,m), 2.60 (4H,m),2·9ΐ (2H m) 4·40 (2H,m), 6.64 (1H,d,J=5.2 Hz), 6.93 (1H,dd,J= =2 8' 8.8 Hz), 7.33 (1H, d, J=2.8 Hz), 7.57 (1H, d, J-8.8 Hz), 7 64 (1H, s), 8.09 (1H, s), 8.19 (1H, d, J = 2.8 Hz), 8.75.8.77 (2H m) 〇, Example 537 N bis (2-a-5-((6-cyanyl D-4·^ quinolyl) gas) stupid The cyclopropyl propyl urea was obtained by the same procedure as in Example 11 from N-(2- gas-5-((l-amino 7((2R)-2- yl)-3-(1-p-pyridyl) </RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 20.7%) iH-NMR spectrum (DMSO-d6) 5 (ppm): 0·40 (2H, m), 〇65 η., m, m), 1.69 (4H, m), 2.49-2.68 (6H, m), 2.72 (1H, m), 4.Ο3 nu ' tn)5 4.23 (1H,dd,J=5.6, 10.4 Hz),4·33 (1H,dd,J=4.4 1 〇. 5 AU-4 Hz) 5.03 (1H, m), 6.64 (1H, d, J = 5.2 Hz), 6.94 (1H, dd, j==2 8' 8·4 Hz),7·33 (1H,m), 7.56-7.93 (2H,m),8·1〇(1jj 0 ' /1TT , vs)3 8.20 (1H,d,J=2.8 Hz), 8·71-8·77 (2H, m) The starting material was synthesized by the following method: Production example: 4-oxime curtain)-6-Ammonia-7-((2R: oxyporphyrin_- _- 602 - This paper size applies to China National Standard (CNS) A4 specification (21〇χ 297 mm)

裝 訂Binding

k 1304061 A7 ___ B7 五、發明説明（印7) 藉由與實施例7同樣之手法，從4-(3-胺基-4-氣苯氧基 6 -氰基_ 7 - #呈基p奎淋（264 mg，0.847 mmol)及4-甲基-1 -苯石黃 酸（2R)環氧乙烷-2-基甲酯，得到為淡黃色結晶之標題化合 物（201 mg，0.547 mmol，64.6%) ° H-NMR 光譜（CDCl3)5(ppm): 2·93 (1H，dd，J=2.4，4.8 Hz)， 2.98 〇H，dd，J=4.0, 4.8 Hz)，3·50 (1H，m)，4.21-4.24 (3H， m), 4.50 (1H, dd, J=3.2, 11.2 Hz), 6.50 (1H, dd, J=2.8, 8.8k 1304061 A7 ___ B7 V. Description of the Invention (Ink 7) By the same procedure as in Example 7, 4-(3-amino-4-phenoxy 6-cyano-7-#-based p-quinion The title compound (201 mg, 0.547 mmol, 64.6) was obtained as a pale yellow crystal. %) ° H-NMR spectrum (CDCl3) 5 (ppm): 2·93 (1H, dd, J=2.4, 4.8 Hz), 2.98 〇H, dd, J=4.0, 4.8 Hz), 3·50 (1H , m), 4.21-4.24 (3H, m), 4.50 (1H, dd, J=3.2, 11.2 Hz), 6.50 (1H, dd, J=2.8, 8.8

Hz), 6.5.6 (1H，d，J=5.2 Hz)，6.59 (1H，d，J=2.8 Hz)，7·33 (1H， d, J=8.8 Hz), 7.48 (1H, s), 8.67 (1H, s), 8.69 (1H, d, J=5.2 Hz) 〇 製造例537-7 4二(3-胺某_4-氣苯氧基）-6-氨某-7-(((210-2-鞀華-1(1_口比 查咬基）丙基）氯V奎啉 將4-(3-胺基-4-氯苯氧基）-6-氰基- 7-(((2R) -環氧乙燒· 2-基）甲氧喹啉）（201 mg，0.547 mmol)於氮蒙氣下溶於四氫 呋喃（5.0 ml)，加入吡咯啶（0.456 ml)並於室溫攪拌一夜。 將反應液減壓漠縮，付諸於梦凝膠管柱層析（溶出液：乙酸 乙酯），將包含目的物之溶出份濃縮，懸浮於乙酸乙酿，將 其用己烷稀釋’濾取結晶及通風乾燥，得到為淡黃色結晶 之標題化合物（235 mg，0.535 mmol，98.0%)。 iH-NMR 光譜（CDCl3)5(ppm): 1·82 (4H，m)，2.59 (2H，m)， 2·65 (1H，dd, J=4.0，12·0 Hz)，2·74 (2H，m)，2·94 (1H，dd J=5.2, 12.0 Hz), 4.19-4.27 (5H, m), 6.50 (1H, dd, J=2.85 8.8Hz), 6.5.6 (1H,d,J=5.2 Hz), 6.59 (1H,d,J=2.8 Hz), 7·33 (1H, d, J=8.8 Hz), 7.48 (1H, s), 8.67 (1H, s), 8.69 (1H, d, J = 5.2 Hz) 〇Production Example 537-7 4 bis (3-amine _4- phenoxy)-6-ammonia -7-((( 210-2-鼗华-1(1_口比查咬)propyl)chloro-V-quinoline 4-(3-amino-4-chlorophenoxy)-6-cyano-7-(( (2R)-Ethylene bromide·2-yl)methoxyquinoline (201 mg, 0.547 mmol) was dissolved in tetrahydrofuran (5.0 ml) under nitrogen atmosphere, pyrrolidine (0.456 ml) was added and stirred at room temperature One night. The reaction solution was decompressed under reduced pressure, and applied to a gel column chromatography (eluent: ethyl acetate), and the fraction containing the target was concentrated, suspended in acetic acid, and diluted with hexane. 'Filtered by crystallization and ventilated to give the title compound (235 mg, 0.535 mmol, 98.0%) as pale yellow crystals. iH-NMR spectrum (CDCl3) 5 (ppm): 1·82 (4H, m), 2.59 ( 2H,m), 2·65 (1H,dd, J=4.0,12·0 Hz), 2·74 (2H,m), 2·94 (1H,dd J=5.2, 12.0 Hz), 4.19-4.27 (5H, m), 6.50 (1H, dd, J=2.85 8.8

Hz)，6·55 (1H，d，J=5.2 Hz)，6·59 (1H，d，J=2.8 Hz)，7.33 (1h， _______- 603 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061Hz),6·55 (1H,d,J=5.2 Hz),6·59 (1H,d,J=2.8 Hz),7.33 (1h, _______- 603 - This paper scale applies to Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) 1304061

d, J=8.8 Hz), 7.50 (1H, s), 8.65 〇H, s), 8.68 (1H, d, J=5.2 Hz) 〇 實施例537-3 基-)-4_^g林基）氣）茉某）脖其 藉由與製造例17同樣之手法，從心（3_胺基氯苯氧基）_ 6-氰基-7-(((2R)-2-羥基-3-(1-吡咯啶基）丙基）氧）喹啉 (23 5 mg，0.53 5 mmol),得到為白色結晶之標題化合物（1〇7 mg，0.191 mmol，35.7%)。 h-NMR 光譜（CDCl3)5(ppm): 2·20 (4H，m)，3.39-3.48 (5H， m)，4·11 (1H，m)，4·25 (1H，m)，4.44 (1H，dd，J=4.8, 9.2 Hz)， 4.67 (1H，m)，6·'50 (1H，m)，6.57-6.60 (2H，m)，6.91 (1H，m)， 7.17-7.49 (6H, m), 8.17 (1H, s), 8.66 (1H, d, J=5.2 Hz), 8.71 (1H, d，J=5.6 Hz) 〇 實施例538 MA-甲基-4-14-氯-3-(((4-氟苯胺某）羱篡）胺某）茉氫基）-7-甲乳基-6-p奎淋基藉酿胺 藉由與實施例11同樣之手法，從N6-甲基-4-(3-胺基-4-乳麥氧基）-7-甲氧基-6-峻淋基幾龜胺（72 mg，0.2 mmol)及 異氰酸4-氟苯酯，得到為白色結晶之標題化合物（77.6 mg， 0.157 mmol，77·9%) 〇 iH-NMR 光譜（DMSO-d6)c5(ppm): 2·82 (3Η，d，J=4.4 Ηζ)， 4.01 (3H, s), 6.62 (1H, d, J=5.2 Hz), 6.96 (1H, dd, J=2.8, 8.8 Hz), 7.10 (2H, m), 7.40 (2H, m), 7.51 (1H, s), 7.60 (1H, d, -604 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)d, J=8.8 Hz), 7.50 (1H, s), 8.65 〇H, s), 8.68 (1H, d, J=5.2 Hz) 〇Example 537-3 Base-)-4_^g林基) The same method as in Production Example 17, from the heart (3_Aminochlorophenoxy)_ 6-cyano-7-((2R)-2-hydroxy-3-(1) -Pyrrolidinyl)propyl)oxy)quinoline (23 5 mg, 0.53 5 mmol) afforded the title compound (1,7 mg, 0.191 mmol, 35.7%) as white crystals. h-NMR spectrum (CDCl3) 5 (ppm): 2·20 (4H, m), 3.39-3.48 (5H, m), 4·11 (1H, m), 4·25 (1H, m), 4.44 ( 1H, dd, J=4.8, 9.2 Hz), 4.67 (1H, m), 6·'50 (1H, m), 6.57-6.60 (2H, m), 6.91 (1H, m), 7.17-7.49 (6H , m), 8.17 (1H, s), 8.66 (1H, d, J = 5.2 Hz), 8.71 (1H, d, J = 5.6 Hz) 〇 Example 538 MA-Methyl-4-14-chloro-3 -(((4-fluoroaniline))))))))))))))))) 4-(3-Amino-4-bromoxy)-7-methoxy-6-aryl-leuroamine (72 mg, 0.2 mmol) and 4-fluorophenyl isocyanate The title compound is white crystals (77.6 mg, 0.157 mmol, 77.9%) 〇iH-NMR spectrum (DMSO-d6) c5 (ppm): 2·82 (3Η, d, J=4.4 Ηζ), 4.01 (3H , s), 6.62 (1H, d, J=5.2 Hz), 6.96 (1H, dd, J=2.8, 8.8 Hz), 7.10 (2H, m), 7.40 (2H, m), 7.51 (1H, s) , 7.60 (1H, d, -604 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂Binding

線 1304061 A7 B7Line 1304061 A7 B7

五、發明説明（599) J=8.8 Hz), 8.15 (1H, d5 J=2.8 Hz), 8.35 (1H, d, J=4.4 Hz), 8.47 (1H, s), 8.54 (1H, s), 8.68 (1H, d, J=5.2 Hz), 9.56 (1H, s) ° 起始物質用下述方法合成。 製造例538-1V. Description of the invention (599) J=8.8 Hz), 8.15 (1H, d5 J=2.8 Hz), 8.35 (1H, d, J=4.4 Hz), 8.47 (1H, s), 8.54 (1H, s), 8.68 (1H, d, J = 5.2 Hz), 9.56 (1H, s) ° The starting materials were synthesized in the following manner. Manufacturing Example 530-1

4-M-氯-3-硝某茉氣基）-7-甲氳某-6-喳啉羧酸甲ML 藉由與製造例11同樣之手法，從4-氯-7-甲氧基-6-喹啉羧 酸甲酯（.2.5 17 g，10.0 mmol)及4-氯-3-硝基酚，得到為淡黃 色結晶之標題化合物（2.114 g，5.44 mmol，54.4%)。 iH-NMR 光譜（CDCl3)5(ppm): 3.97 (3H，s)，4·06 (3H，s)， 6.54 (1H, d, J=5.2 Hz), 7.38 (1H, dd, J=2.8, 8.8 Hz), 7.53 (1H, s), 7.66 (1H, d, J=8.8 Hz), 7.75 (1H, d, J=2.8 Hz), 8.70 (1H，s)，8·73 (1H, d, J=8.8 Hz) 〇 M造例53 8-2 4-(4-氣-3-确基笨乳基）-7-甲氣基-6-休藏酸 在4-(4-氯3-硝基苯氧基）-7-甲氧基-6-峻淋幾酸甲酯 (1.00 g，2·57 mmol)中，加入甲醇（3〇 mi)及2當量氫氧化鈉 水i液（10 ml) ’並於60 C攪摔1小時。將反應液放冷至室 溫，加入2N鹽酸中和後，餾去甲醇，濾取析出之淡褐色結 晶’用水充分洗淨後’於70t乾燥，得到標題化合物（89W7 mg，2.39 mmol，93.1%) 〇 h-NMR 光譜（DMS〇-d6)5(Ppm): 3.97 (3H，s)，6 76 (1H d J=5.2 Hz); 7.53 (1H，s)，7·70 (1H’ dd，J=2 8, μ Hz)，7’ 91’ (1H, d, J=8.8 Hz), 8.16 (1H, d, J=2.8 Hz), 8.49 (1H, s), 8.73 -605 -4-M-Chloro-3-nitroxanthyl)-7-methylhydrazine-6-porphyrincarboxylic acid methyl ML By the same procedure as in Production Example 11, from 4-chloro-7-methoxy- Methyl 6-quinolinecarboxylate (.2.517 g, 10.0 mmol) and 4-chloro-3-nitrophenol afforded the title compound (21.14 g, 5.44 mmol, 54.4%). iH-NMR spectrum (CDCl3) 5 (ppm): 3.97 (3H, s), 4·06 (3H, s), 6.54 (1H, d, J = 5.2 Hz), 7.38 (1H, dd, J = 2.8, 8.8 Hz), 7.53 (1H, s), 7.66 (1H, d, J=8.8 Hz), 7.75 (1H, d, J=2.8 Hz), 8.70 (1H, s), 8.73 (1H, d, J=8.8 Hz) 〇M Example 53 8-2 4-(4-Ga-3-Acid-based Lacto)-7-Methane-6-Retention Acid in 4-(4-Chlorine 3-Nitrate To a solution of methanol (3 〇mi) and 2 equivalents of sodium hydroxide water (10 ml) in methylphenoxy)-7-methoxy-6-furanic acid methyl ester (1.00 g, 2.57 mmol) ) 'And fell for 1 hour at 60 C. The reaction mixture was cooled to room temperature, and then neutralized with 2N hydrochloric acid, and the mixture was evaporated to dryness. 〇h-NMR spectrum (DMS〇-d6)5(Ppm): 3.97 (3H, s), 6 76 (1H d J=5.2 Hz); 7.53 (1H, s), 7·70 (1H' dd, J=2 8, μ Hz), 7' 91' (1H, d, J=8.8 Hz), 8.16 (1H, d, J=2.8 Hz), 8.49 (1H, s), 8.73 -605 -

1304061 A7 _ B7 五、發明説明（~' (1H，d，J=5.2 Hz)，13.13 (1H，br)。 製造例538-3 N6-甲基-4-(4-蓊-3-硝基苯氣基）-7-甲氫某-6-&lt;生身酿胺 將4-(4-氯-3-硝基苯氧基）_7_甲氧基-6·^奎琳幾酸（897 mg ’ 2 ·3 9 mmol)於氮蒙氣下溶於二甲基甲醯胺（1〇如），以 及於室溫下依次加入40%甲胺-甲醇溶液（2·〇 mi)，三乙胺 (1·〇 ml)，（1H-1，2,3-苯并三唑-1-基氧）（三（二甲胺基））鱗 六氟磷酸鹽（1.27 g，2.87 mmol)後，攪拌4小時。將反應液 分溶於乙酸乙酯及水中，將有機層用水及飽和食鹽水洗淨 及用無水硫酸鈉乾燥。餾去溶媒後，懸浮於乙酸乙酯中， 將其用己燒稀釋’然後〉慮取結晶及通風乾燥，得到為白色 結晶之標題化合物（928 mg，定量的）。 iH-NMR 光譜（DMSO-d6)5(ppm): 2·82 (3H，d，J=4.4 Hz)， 4.01 (3H, s), 6.77 (1H, d, J=5.2 Hz), 7.54 (1H, s), 7.68 (1H, dd, J=2.8, 8.8 Hz), 7.90 (1H, d, J=8.8 Hz), 8.13 (1H, d, J=2.8 Hz), 8.35 (1H, d, J=4.4 Hz), 8.53 (1H, s), 8.72 (1H, d, J=5.2 Hz)。 製造例53S-4 胺基-4-氯苯氧基）-7-甲氣某二杏啉某藉醯 藉由與製造例6同樣之手法，從N6-甲基-4-(4-氯-3-石肖基 私氧基）-7-甲氧基-6-峻淋叛酿胺（92 8 mg，2.39 mmol)，得 到為灰色結晶之標題化合物（614 mg，1 72 mmol， 71.7%) 〇 _— _- 606 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 x 297公釐）1304061 A7 _ B7 V. Description of the invention (~' (1H, d, J = 5.2 Hz), 13.13 (1H, br). Production example 538-3 N6-methyl-4-(4-indole-3-nitro Benzene gas)-7-methylhydrogen-6-&lt;Bistly amine 4-(4-chloro-3-nitrophenoxy)_7_methoxy-6·^ quinal acid (897 mg ' 2 · 3 9 mmol) was dissolved in dimethylformamide (1 〇) under nitrogen atmosphere, and 40% methylamine-methanol solution (2·〇mi), triethylamine was added sequentially at room temperature. (1·〇ml), (1H-1,2,3-benzotriazol-1-yloxy)(tris(dimethylamino))sodium hexafluorophosphate (1.27 g, 2.87 mmol), stirred The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated. 'then' crystallization and venting to give the title compound (928 mg, quantitative) as white crystals. iH-NMR spectrum (DMSO-d6) 5 (ppm): 2·82 (3H, d, J=4.4 Hz), 4.01 (3H, s), 6.77 (1H, d, J=5.2 Hz), 7.54 (1H, s), 7.68 (1H, dd, J=2.8, 8.8 Hz), 7.90 (1H, d, J =8.8 Hz), 8.13 ( 1H, d, J = 2.8 Hz), 8.35 (1H, d, J = 4.4 Hz), 8.53 (1H, s), 8.72 (1H, d, J = 5.2 Hz). Production Example 53S-4 Amino-4 -Chlorophenoxy)-7-Methane, a dimethyl porphyrin, by the same method as in Production Example 6, from N6-methyl-4-(4-chloro-3-stone succinyloxy)-7 -Methoxy-6-Junline Acetoamine (92 8 mg, 2.39 mmol) gave the title compound ( 614 mg, 1 72 mmol, 71.7%) as crystals as crystals 〇 __ _- 606 - This paper size applies China National Standard (CNS) Α4 Specifications (210 x 297 mm)

線 1304061 A7 _ B7 __ 五、發明説明（6〇1) j-NMR 光譜（CDCl3)5(ppm): 3·08 (3H, d，J=5.2 Hz)，4.12 (3H，s)，4·17-4·21 (2H，m)，6.49-6.54 (2H，m)，6·59 (1H，d， J=2.8 Hz)，7.30 (1H，d，J=8.8 Hz)，7.51 (1H，s)，7·86 (1H，br)， 8.64 (1H，d，J=5.2 Hz)，9·23 (1H，s) 〇 實施例539 N6-甲-基-4-Γ4-氣唑-2-基胺某）羱某）座 氧基）-7-甲氣某-6-4啉基燊醯胺 藉由與實施例131同樣之手法，從N6-甲基-4-(3-胺基-4-鼠丰氧基）-7-甲氧基- 6-0奎淋基幾酿胺（143 mg，0·4 mmol) 及N-(l，3-噻唑-2-基）胺基甲酸苯酯，得到為白色結晶之標 題化合物（170.4 mg，0.352 mmol，88.0%)。 j-NMR 光譜（DMSO-d6)5(ppm): 2·82 (3H，d，J=4.8 Hz)， 4.01 (3H, s), 6.62 (1H, d, J=5.2 Hz), 7.03 (1H, dd, J=2.8, 8.8 Hz), 7.13 (1H, d, J=3.6 Hz), 7.39 (1H, d, J=3.6 Hz), 7.52 (1H, s), 7.64 (1H, d, J=8.8 Hz), 8.16 (1H, d, J=2.8 Hz), 8.35 (1H, d, J=4.8 Hz), 8.55 (1H, s), 8.68 (1H, d, J=5.2 Hz), 11.30 (1H, br) 0 實施例540Line 1304061 A7 _ B7 __ V. Description of the invention (6〇1) j-NMR spectrum (CDCl3) 5 (ppm): 3·08 (3H, d, J=5.2 Hz), 4.12 (3H, s), 4· 17-4·21 (2H,m), 6.49-6.54 (2H,m),6·59 (1H,d, J=2.8 Hz), 7.30 (1H,d,J=8.8 Hz),7.51 (1H, s), 7·86 (1H, br), 8.64 (1H, d, J = 5.2 Hz), 9·23 (1H, s) 〇 Example 539 N6-methyl-4-yl-4-oxazole-2 -N-methyl-4-(3-amino group) from the same method as in Example 131 -4-murtoxy)-7-methoxy- 6-0 quinolylamine (143 mg, 0.4 mmol) and N-(l,3-thiazol-2-yl)aminocarboxylic acid The title compound (170.4 mg, 0.352 mmol, 88.0%) was obtained as white crystal. j-NMR spectrum (DMSO-d6) 5 (ppm): 2·82 (3H, d, J = 4.8 Hz), 4.01 (3H, s), 6.62 (1H, d, J = 5.2 Hz), 7.03 (1H , dd, J=2.8, 8.8 Hz), 7.13 (1H, d, J=3.6 Hz), 7.39 (1H, d, J=3.6 Hz), 7.52 (1H, s), 7.64 (1H, d, J= 8.8 Hz), 8.16 (1H, d, J=2.8 Hz), 8.35 (1H, d, J=4.8 Hz), 8.55 (1H, s), 8.68 (1H, d, J=5.2 Hz), 11.30 (1H , br) 0 Example 540

Ni-甲基-4-(4-氪-3-(((環丙胺某）羰基）胺某）芡氫某）-7-甲 乳基-6-p奎淋藉酿胺 將N6-甲基-4-(3-胺基-4-氯苯氧基）-7-甲氧基-6-喹啉羧 醯胺（179 mg，0.50 mmol)於氮蒙氣下溶於二甲基甲醯胺（2 ml)，以及於室溫下滴入吡啶（〇_〇61 ml，0.75 mmol)及氯甲 酸苯酯（0.094 ml，0.75 mmol)，並攪摔1小時。滴入環丙胺 _ 607 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（6〇2) (0·2 ml)，並再攪拌一夜。將反應液分溶於乙酸乙酯及水 中，用飽和食鹽水洗淨及用無水硫酸鈉乾燥。餾去溶媒 後，濾取從乙酸乙酯析出之結晶及通風乾燥，得到為白色 結晶之標題化合物（163.9 mg，0.372 mmol，74.3%)。 ^-NMR 光譜（DMSO-d6)5(ppm): 0·39 (2H，m)，0·62 (2H，m)， 2.49-2.53 (1H, m), 2.83 (3H, d, J=4.8 Hz), 4.02 (3H, s), 6.60 (1H, d3 J=5.2 Hz), 6.90 (1H, dd, J=3.2, 8.8 Hz), 7.32 (1H, d, J=2.8 Hz), 7.52-7.56 (2H, m), 8.07 (1H, s), 8.16 (1H, d, J=3.2 Hz), 8.37 (1H, d, J=4.8 Hz), 8.54 (1H, s), 8.67 (1H, d? J=5.2 Hz)。 實施例541 甲基-4-(4-氩-3-(((甲胺某）蕤基）胺基）茉氣基）-7-甲氣 基-6-4^林基藉ailfe 藉由與實施例540同樣之手法，從N6-甲基-4-(3-胺基-4-鼠苯氧基）-7-甲氧基--6 _ p奎淋基幾酿胺（108 mg，0.30 mmol)，得到為白色結晶之標題化合物（71.9 mg，0.173 mmol » 57.4%) ° W-NMR 光譜（DMSO-d6)5(Ppm): 2·60 (3H，d，J=4.4 Hz)， 2.81 (3H, d, J=4.8 Hz), 4.00 (3H, s), 6.59 (1H, d, J=5.2 Hz), 6.87 (1H, dd, J-2.8, 8.4 Hz), 7.14 (1H, t, 1=7.6 Hz), 7.50-7.54 (2H, m), 8.13 (1H, d, J=2.8 Hz), 8.19 (1H, s), 8.35 (1H, d, J=4.4 Hz)，8·53 (1H，s)，8·67 (1H，d，J=5.2 Hz)。 實施例542&quot; N6-甲基-4-(4-氟-3-(((乙胺某）羰某）脖某）茉氫某）-7-甲氯 __- 608 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 裝 訂Ni-methyl-4-(4-indol-3-(((cyclopropylamine))carbonyl)amine)))))) 4-(3-Amino-4-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide (179 mg, 0.50 mmol) dissolved in dimethylformamide under nitrogen atmosphere (2 ml), and pyridine (〇_〇 61 ml, 0.75 mmol) and phenyl chloroformate (0.094 ml, 0.75 mmol) were added dropwise at room temperature and stirred for 1 hour. Instillation of cyclopropylamine _ 607 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (6〇2) (0·2 ml), and stir for another night. The reaction solution was dissolved in ethyl acetate and water, washed with brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the crystals were crystallized from ethyl acetate (yield: EtOAc) ^-NMR spectrum (DMSO-d6) 5 (ppm): 0·39 (2H, m), 0·62 (2H, m), 2.49-2.53 (1H, m), 2.83 (3H, d, J=4.8 Hz), 4.02 (3H, s), 6.60 (1H, d3 J=5.2 Hz), 6.90 (1H, dd, J=3.2, 8.8 Hz), 7.32 (1H, d, J=2.8 Hz), 7.52-7.56 (2H, m), 8.07 (1H, s), 8.16 (1H, d, J=3.2 Hz), 8.37 (1H, d, J=4.8 Hz), 8.54 (1H, s), 8.67 (1H, d? J = 5.2 Hz). Example 541 methyl-4-(4-argon-3-((methylamine) sulfhydryl))amino)methyl-)-carbyl-6-4^-based ailfe by means of Example 540, in the same manner, from N6-methyl-4-(3-amino-4-murolyloxy)-7-methoxy--6-p-quinolidylamine (108 mg, 0.30 The title compound (71.9 mg, 0.173 mmol, 57.4%) was obtained as white crystals. W-NMR spectrum (DMSO-d6) 5 (Ppm): 2·60 (3H, d, J = 4.4 Hz), 2.81 (3H, d, J=4.8 Hz), 4.00 (3H, s), 6.59 (1H, d, J=5.2 Hz), 6.87 (1H, dd, J-2.8, 8.4 Hz), 7.14 (1H, t, 1=7.6 Hz), 7.50-7.54 (2H, m), 8.13 (1H, d, J=2.8 Hz), 8.19 (1H, s), 8.35 (1H, d, J=4.4 Hz), 8·53 ( 1H, s), 8.67 (1H, d, J = 5.2 Hz). Example 542&quot; N6-methyl-4-(4-fluoro-3-(((ethylamine)))))))))))))))) National Standard (CNS) A4 Specification (210X 297 mm) Binding

線 1304061 A7 B7 五、發明説明（6〇3) 基-6-p备呲某勒醯胺 藉由與實施例540同樣之手法，從N6-甲基-4-(3-胺基-4-氯苯氧基）-7-甲氧基-6- 4:淋基幾醯胺（1〇7邮，0.30 mmol)，得到為白色結晶之標題化合物（9〇·6 mg，0·211 mmol，70.6%) 0 1H-NMR 光譜（DMSO-d6)5(ppm): K〇2 (3H，t，j=7.2 Hz)， 2·81 (3H，t，J=4.4 Hz)，3.06 (2H，m)，4 〇〇 (3H，s)，6 58 (1H， d, J=5.2 Hz), 6.87 (1H, dd, J=3.2, 8.8 Hz), 7.13 (1H, m)5 7.50-7.54 (2H，m)，8.14-8.15 (2H，m)，8 35 (1H，d，J=4 4 HZ)， 8.53 (1H，s)，8·67 (1H，d，J=5.2 Hz)。 實施例543 R- (2-毚.-4_ ( 6纏氰基_ 7- ((( 2R)環氧乙檢-2·莘甲氫某）-4_ 口奎 也基）氣)茉基W-環丙基脲 藉由與實施例7同樣之手法，從N-(4-(6-氰基-7-羥基-4-喹啉基）氧-2-氯苯基）-N，-環丙脲（873 mg，2.21 mmol)及4-甲基-1-苯磺酸[(2R)環氧乙烷-2-基甲基]酯，得到為淡黃 色結晶之標題化合物（663 mg，1.47 mmol，66.5%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 0·42 (2H，m)，0.65 (2H，m)， 2.56 (1H, m), 2.83 (1H, m), 2.93 (1H, m), 3.48 (1H, m), 4.18 (1H, dd, J=6.4, 12.0 Hz), 4.72 (1H, m), 6.61 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.27 (1H, dd, J=2.4, 9.2 Hz), 7.51 (1H, d, J=2.8 Hz), 7.65 (1H, s), 8.00 (1H, s), 8.29 (1H, dd，J=4.0, 9.2 H2)，8.75 (1H, d，J=5.2 Hz)，8.78 (1H，s)。 實施例544 ___ - 609 - 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐）Line 1304061 A7 B7 V. Description of the invention (6〇3) Group 6-p prepared a certain amount of carbamide by the same procedure as in Example 540, from N6-methyl-4-(3-amino-4- Chlorophenoxy)-7-methoxy-6- 4: decyl decylamine (1 〇 7 gram, 0.30 mmol) 70.6%) 0 1H-NMR spectrum (DMSO-d6) 5 (ppm): K〇2 (3H, t, j = 7.2 Hz), 2·81 (3H, t, J = 4.4 Hz), 3.06 (2H, m),4 〇〇(3H,s),6 58 (1H, d, J=5.2 Hz), 6.87 (1H, dd, J=3.2, 8.8 Hz), 7.13 (1H, m)5 7.50-7.54 ( 2H, m), 8.14 - 8.15 (2H, m), 8 35 (1H, d, J = 4 4 HZ), 8.53 (1H, s), 8.67 (1H, d, J = 5.2 Hz). Example 543 R-(2-毚.-4_(6 entangled cyano-7-(((2R) epoxicone-2·莘甲氢)-4_ 口奎基)))))) Cyclopropyl urea by the same procedure as in Example 7 from N-(4-(6-cyano-7-hydroxy-4-quinolinyl)oxy-2-chlorophenyl)-N,-cyclopropane Urea (873 mg, 2.21 mmol) and 4-methyl-1-benzenesulfonic acid [(2R) oxiran-2-ylmethyl] ester as the title compound (663 mg, 1.47 mmol , 66.5%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 0·42 (2H, m), 0.65 (2H, m), 2.56 (1H, m), 2.83 (1H, m), 2.93 (1H, m), 3.48 (1H, m), 4.18 (1H, dd, J=6.4, 12.0 Hz), 4.72 (1H, m), 6.61 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.27 (1H, dd, J=2.4, 9.2 Hz), 7.51 (1H, d, J=2.8 Hz), 7.65 (1H, s), 8.00 (1H, s), 8.29 ( 1H, dd, J=4.0, 9.2 H2), 8.75 (1H, d, J=5.2 Hz), 8.78 (1H, s). Example 544 ___ - 609 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x 297 mm)

訂Order

線 1304061 A7 B7 五、發明説明（604) (2 -羞- 4- ((6-^基-7-(((2R)-2 -拜某- 3- (1-六氣 p比啥華） 西基）氧）-4-α奎啉某）氣）茉某璜丙某脲 在N-(2-氣-4-(6-氰基- 7-(((2R)環氧乙烷-2-基甲氧基）_ 4-喹啉基）氧）苯基）-N，-環丙脲（113 mg，0.25 mmol)中，加 入四氫吱喃（2.5 ml)及六氫吡啶（〇·25 ml)，並於室溫撥拌一 夜。將反應液減壓濃縮，付諸於矽凝膠管柱層析（溶出液： 乙酸乙酯），將包含目的物之溶出部分濃縮，懸浮於乙酸乙 酯中，將其用己烷稀釋，濾取結晶及通風乾燥，得到為白 色結晶之標題化合物（57.7 mg，0· 1 〇8 mmol，43· 1 %)。 iH-NMR光譜（DMSO-d6)5(ppm): 0·42 (2H，m)，0.65 (2H，m)， 1.35 (2H, m), 1.48 (4H, m), 2.34-2.51 (6H, m), 2.56 (1H, m), 4.02 (1H, m), 4.19 (1H, dd, J=6.0, l〇.4 Hz), 4.29 (1H, dd, J=3.6, 10.4 Hz), 4.93 (1H, d, J=4.0 Hz), 6.57 (1H, d, J=5.2 Hz), 7.19 (1H, d, J=2.8 Hz), 7.25 (1H, dd, J=2.8, 8.8 Hz), 7.50 (1H, d, J=2.8 Hz), 7.62 (1H, s), 7.98 (1H, s), 8.27 (1H, d，J=8.8 Hz)，8.71-8.73 (2H，m) « 實施例545 M卜甲基-(4-LLL4:i苯胺基),幾棊上L甲基）胺基）茇氧其卜 7-甲氣基-6-4啉基羧醯胺 藉由與實施例435同樣之手法，從4-(4-(((4-氟苯胺基）羰 基）（甲基）胺基）苯氧基）-7-甲氧基-6·^奎淋基幾酸（115 mg , 0·2 5 mmol)及40%甲胺-甲醇溶液，得到為白色結晶之標題 化合物（89·4 mg，0.188 mmol，75.6%)。 iH-NMR 光譜（DMSO-d6)5(Ppm): 2.83 (3H，d，J=4.8 Hz)， -610 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公董)Line 1304061 A7 B7 V. Description of invention (604) (2 - Shame - 4- ((6-^基-7-(((2R)-2 - 拜某- 3- (1-六气的比比啥) West-based)Oxy)-4-α-quinoline (a) gas in the presence of N-(2- gas-4-(6-cyano-7-((2R)) oxide -Methyloxy)-4-cycloquinolyloxy)phenyl)-N,-cyclopropanil (113 mg, 0.25 mmol), tetrahydrofuran (2.5 ml) and hexahydropyridine (〇· 25 ml), and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and applied to a gel column chromatography (eluent: ethyl acetate), and the fractions containing the desired material were concentrated and suspended in acetic acid. The title compound (57.7 mg, 0·1 〇8 mmol, 43·1 %) was obtained as white crystals. ) 5 (ppm): 0·42 (2H, m), 0.65 (2H, m), 1.35 (2H, m), 1.48 (4H, m), 2.34-2.51 (6H, m), 2.56 (1H, m ), 4.02 (1H, m), 4.19 (1H, dd, J=6.0, l〇.4 Hz), 4.29 (1H, dd, J=3.6, 10.4 Hz), 4.93 (1H, d, J=4.0 Hz) ), 6.57 (1H, d, J=5.2 Hz), 7.19 (1H, d, J=2.8 Hz), 7.25 (1H, dd, J=2.8, 8.8 Hz), 7.50 (1H, d, J=2.8 Hz), 7.62 (1H, s), 7.98 (1H, s), 8.27 (1H, d, J=8.8 Hz), 8.71-8.73 (2H, m) « Example 545 M-methyl-(4-LLL4:i-anilino), a few hydrazines of L-methyl)amino) oxime bromide 7-carbazyl-6-4 phenylcarbenylamine by the same method as in Example 435 From 4-(4-(((4-fluoroanilinyl)carbonyl))(methyl)amino)phenoxy)-7-methoxy-6·^ quinolate (115 mg, 0· The title compound (89·4 mg, 0.188 mmol, 75.6%) was obtained as white crystals. iH-NMR spectrum (DMSO-d6) 5 (Ppm): 2.83 (3H, d, J = 4.8 Hz), -610 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 DON)

裝 訂Binding

線 1304061 A7 B7 五、發明説明（6〇5) 3.28 (3H, s)5 4.01 (3H, s), 6.65 (1H, d, J=5.2 Hz), 7.08 (2H, m), 7.32 (2H, m), 7.42-7.48 (4H, m), 7.51 (1H, s), 8.23 (1H, s), 8.35 (1H, d, J=4.8 Hz), 8.60 (1H, s), 8.69 (1H, d, J=5.2 Hz) 〇 實施例546 M·：·乙基氣茉胺基）羰基甲某）胺某）芡攀幕v U氧基4啉某淼醯胺 藉由與實施例435同樣之手法，從4-(4-(((4-氟苯胺基）羰 基）（甲基）胺基）苯氧基）-7-甲氧基-6-喳啉基羧酸（ i15 mg， 0·25 mmol)及2·〇Μ乙胺-四氫呋喃溶液，得到為白色結晶之 標題化合物（87.0 mg，0.178 mmol，71.5%)。 W-NMR 光譜（DMSO-d6)5(ppm): 1·13 (3H，t，J=7.2 Hz)， 3.28 (3H, s), 3.28-3.36 (2H, m), 4.01 (3H, s), 6.64 (1H, d, J=5.2 Hz), 7.06 (2H, m), 7.31 (2H, m), 7.42-7.48 (4H, m), 7.51 (1H, s), 8.23 (1H, s), 8.39 (1H, t, 1=5.2 Hz), 8.55 (1H, s)，8.68 (1H, d，J=5.2 Hz)。 實施例547 116-(2-(1-吡咯畦）乙某）-4-(3-氯-4-(((：環丙择^^^1^ 基）苯氧基）-7-甲氳基-6·崦啉某羧醯胺 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙苯胺 基）羰基）胺基）苯氧基）-7-甲氧基-6-喹啉基幾酸（43 mg , 0.10 mmol)及1-(2-胺基乙基）外t；哈症，得到為白色結晶之標 題化合物（42.9 mg，0.082 mmol，81.9%)。 W-NMR光譜（DMSO-d6)(5(ppm): 0·41 (2H，m)，〇·65 (2H，m)Line 1304061 A7 B7 V. Description of invention (6〇5) 3.28 (3H, s)5 4.01 (3H, s), 6.65 (1H, d, J=5.2 Hz), 7.08 (2H, m), 7.32 (2H, m), 7.42-7.48 (4H, m), 7.51 (1H, s), 8.23 (1H, s), 8.35 (1H, d, J=4.8 Hz), 8.60 (1H, s), 8.69 (1H, d , J=5.2 Hz) 〇Example 546 M·:·Ethyl oleylamino)carbonylmethyl)Amine 芡Climb v U oxy 4 oxan a certain guanamine by the same method as Example 435 From 4-(4-(((4-fluoroanilinyl)carbonyl))(methyl)amino)phenoxy)-7-methoxy-6-carbolinylcarboxylic acid (i15 mg, 0·25 The title compound (87.0 mg, 0.178 mmol, 71.5%) was obtained as white crystals. W-NMR spectrum (DMSO-d6) 5 (ppm): 1·13 (3H, t, J = 7.2 Hz), 3.28 (3H, s), 3.28-3.36 (2H, m), 4.01 (3H, s) , 6.64 (1H, d, J=5.2 Hz), 7.06 (2H, m), 7.31 (2H, m), 7.42-7.48 (4H, m), 7.51 (1H, s), 8.23 (1H, s), 8.39 (1H, t, 1 = 5.2 Hz), 8.55 (1H, s), 8.68 (1H, d, J = 5.2 Hz). Example 547 116-(2-(1-pyrrole)ethyl)-4-(3-chloro-4-(((:: Cyclopropionide)^^^^^yl)phenoxy)-7-carboxamidine Benzyl-6-carboline a carboxamide was used in the same manner as in Example 438 from 4-(3-chloro-4-((cyclopropylanilinyl)carbonyl)amino)phenoxy)-7- Methoxy-6-quinolinyl acid (43 mg, 0.10 mmol) and 1-(2-aminoethyl)-m. %) W-NMR spectrum (DMSO-d6) (5 (ppm): 0·41 (2H, m), 〇·65 (2H, m)

裝 訂Binding

線 -611 -Line -611 -

1304061 A7 B7 五、發明説明（6〇6) 1.70 (4H，m)，2.48-2.61 (7H，m)，3·43 (2H，m)，4.01 (3H，s)， 6·52 (1H，d，J=5.2 Hz), 7.18 (1H，s)，7·22 (1H，dd，J=2.4, 8.8 Hz)，7.47 (1H，d，J=2.4 Hz)，7.51 (1H，s)，7·97 (1H，s)，8.26 (1H, d, J=8.8 Hz), 8.50 (1H, m), 8.64 (1H, s), 8.65 (1H, d5 J=5.2 Hz) 〇 實施例548 N6-(2-(l -六氤吡啶基）乙基）-4-(3-氣-4-(((環而脸某）羱某） 胺基）茉氫某）-7-甲氫基-6-4啉基羧醯胺 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙苯胺 基）羰基）胺基）苯氧基）-7_甲氧基-6-喹啉基羧酸（43 mg， 0·10 mmol)及1-(2-胺基乙基）六氫吡啶，得到為白色結晶之 標題化合物（44.6 mg，0.083 mmol，82.9%)。 iH-NMR光譜（DMSO-d6) 5(ppm): 0·41 (2H，m)，〇·65 (2H，m)， 1·39 (2Η，m)，1·51 (4Η，m), 2·39 (4Η，m)，2·43-2·49 (2Η，m)， 2.56 (1Η, m), 3.39 (2H, m), 4.05 (3H, s), 6.52 (1H, d, J=5.2 Hz), 7.18 (1H, s), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J-2.8 Hz), 7.53 (1H, s), 7.96 (1H, s), 8.26 (1H, d5 J=8.8 Hz), 8·48 (1H，m)，8·66 (1H，d，J=5.2 Hz)，8.70 (1H，s)。 實施例549 M6- (2-丙基）-4-(3 -氣- 4-(((環丙胺基）複基）胺基）苯氫基）_ 7-甲氣某-6〃杏呲基羧醯胺 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙苯胺 基）羰基）胺基）苯氧基）-7-甲氧基-6-喹啉基羧酸（43 mg， 0.10 mmol)及2-丙胺，得到為白色結晶之標題化合物（15.2 • 612 -_. _________ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 __— 〜 五、發明説明（607) ， mg，0.032 mmol，32.4%)。 iH-NMR光譜（DMSO-d6)5(ppm): 0.41 (2H，m)，〇·65 (2H，m)， 1.17 (6H, d, J=6.8 Hz), 2.56 (1H, m), 3.99 (3H, s), 4.08 (1H, m)，6.51 (1H，d，J=5.2 Hz)，7·19 (1H，s)，7.22 (1H，dd，J=2.8， 8.8 Hz)，7·46 (1H，d，J=2.8 Hz)，7·49 (1H，s)，7.97 (1H，s)， 8.15 (1H，d，J=8.0 Hz)，8.26 (1H，d，J=8.8 Hz)，8·43 (1H，s)， 8.64 (1H，d，J=5.2 Hz)。 實施例550 . N6-環戍某-4-(3-氣-4-(G瑗丙胺基_)羰-基立胺基!蓋氧基）-7-甲氧基-6-4啉基羧醯胺 藉由與實施例438同樣之手法，從4-(3-氯-4-(((環丙胺基X -· 羰基）胺基）苯氧基）-7-甲氧基-6-4啉基羧酸（43 mg，0.10 -___ - - mmol)及環戊胺，得到為白色結晶之標題化合物（34.3 mg， 0.069 mmol » 69.3%) 0 h-NMR 光譜（DMSO-d6)(5(ppm): 0·41 (2H，m)，〇·65 (2H，m)， 1.53 (4Η, m), 1.67 (2H, m), 1.89 (2H, m), 2.56 (1H, m), 4.00 (3H，s)，4·23 (1H，m)，6·51 (1H，d，J=5.2 Hz)，7.18 (1H，s)， 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.46 (1H, d, J=2.8 Hz), 7.48 (1H，s)，7·97 (1H，s)，8.23-8.27 (2H，m)，8.41 (1H，s), 8.64 (1H，d，J=5.2 Hz)。 實施例551 U 4-( 6-胺基嘧啶-4-某氫）苯基Ν’-茉某胧 一 將6-(4-胺基笨氧基）σ密淀-4·基胺（88.9 mg，0.440 mmol) 及異氰酸苯酿（52.4 mg，0.440 mmol)在二甲基甲酿胺（2 ml) — __- 613 -____ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A71304061 A7 B7 V. INSTRUCTIONS (6〇6) 1.70 (4H, m), 2.48-2.61 (7H, m), 3.43 (2H, m), 4.01 (3H, s), 6.52 (1H, d, J = 5.2 Hz), 7.18 (1H, s), 7.22 (1H, dd, J = 2.4, 8.8 Hz), 7.47 (1H, d, J = 2.4 Hz), 7.51 (1H, s), 7·97 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8.50 (1H, m), 8.64 (1H, s), 8.65 (1H, d5 J=5.2 Hz) 〇Example 548 N6 -(2-(l-hexa-pyridinyl)ethyl)-4-(3-carb-4-(((环)))))))))))) 6-4 phenylcarbamate was obtained from 4-(3-chloro-4-((cyclopropylanilinyl)carbonyl)amino)phenoxy)-7-methoxy by the same procedure as in Example 438. The title compound (44.6 mg, 0.083 mmol, 82.9%) was obtained as white crystals. . iH-NMR spectrum (DMSO-d6) 5 (ppm): 0·41 (2H, m), 〇·65 (2H, m), 1·39 (2Η, m), 1·51 (4Η, m), 2·39 (4Η,m),2·43-2·49 (2Η,m), 2.56 (1Η, m), 3.39 (2H, m), 4.05 (3H, s), 6.52 (1H, d, J =5.2 Hz), 7.18 (1H, s), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J-2.8 Hz), 7.53 (1H, s), 7.96 (1H, s ), 8.26 (1H, d5 J=8.8 Hz), 8·48 (1H, m), 8.66 (1H, d, J = 5.2 Hz), 8.70 (1H, s). Example 549 M6-(2-propyl)-4-(3- gas-4-((cyclopropylamino)-based)amino)phenylhydro)-7-methyl--6-apricot Carboxylamidine from 4-(3-chloro-4-((cyclopropylanilinyl)carbonyl)amino)phenoxy)-7-methoxy-6-quinidine by the same procedure as in Example 438 The title compound is obtained as white crystals (15.2 • 612 -_. _________) The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1304061 A7 B7 __- ~ V. Description of the invention (607), mg, 0.032 mmol, 32.4%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.41 (2H, m), 〇·65 (2H, m), 1.17 (6H, d, J = 6.8 Hz), 2.56 (1H, m), 3.99 (3H, s), 4.08 (1H, m), 6.51 (1H, d, J = 5.2 Hz), 7·19 (1H, s), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7· 46 (1H,d,J=2.8 Hz),7·49 (1H,s),7.97 (1H,s), 8.15 (1H,d,J=8.0 Hz), 8.26 (1H,d,J=8.8 Hz) ), 8·43 (1H, s), 8.64 (1H, d, J = 5.2 Hz). Example 550. N6-cycloindole-4-(3- gas-4-(G瑗propylamino)carbonyl)-capryloxy!-7-methoxy-6-4-phenylcarboxyl The indoleamine was obtained from 4-(3-chloro-4-(((cyclopropylamino)carbonyl)))) The title compound (34.3 mg, 0.069 mmol, 69.3%) was obtained as white crystals (yield: EtOAc (d) Ppm): 0·41 (2H, m), 〇·65 (2H, m), 1.53 (4Η, m), 1.67 (2H, m), 1.89 (2H, m), 2.56 (1H, m), 4.00 (3H, s), 4·23 (1H, m), 6·51 (1H, d, J = 5.2 Hz), 7.18 (1H, s), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.46 (1H, d, J=2.8 Hz), 7.48 (1H, s), 7.97 (1H, s), 8.23-8.27 (2H, m), 8.41 (1H, s), 8.64 (1H, d, J = 5.2 Hz). Example 551 U 4-(6-Aminopyrimidine-4-hydrogen)phenylhydrazine--jammanium 6-(4-aminophenyloxy) sigma-4 · Amine (88.9 mg, 0.440 mmol) and benzene isocyanate (52.4 mg, 0.440 mmol) in dimethyl amide (2 ml) — __- 613 -____ This paper scale applies to Chinese National Standard (CNS) A 4 gauge (210 X 297 mm) 1304061 A7

中’於室溫攪拌3小時。將反應液分溶於乙酸乙酯及水中， 然後將有機層用水及飽和食鹽水洗淨及用無水硫酸鎂乾 燥。滤去乾燥劑及將濾液減壓蒸餾。將得到之粗生成物懸 浮於乙酸乙酯中，將其用己烷稀釋，濾取結晶及用己烷洗 淨後’通風乾燥，得到為無色結晶之標題化合物（98〇 mg， 0.305 mmol，69%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): 5·6ό (1H，s)，6·81 (2H，br s)，6·94,6·99 (1H，m)，7.03-7.08 (2H，m)，7.25-7.32 (2H，m)， 7.43-7.52 (4H，m)，8.07 (1H，s)，8·74 (1H，s)，8.80 (1H，s)。 中間體如下述合成。 製造例551-1 - 4-氯_-_6- (4-確某笨氣某）喊读 將 2,4-二氯嘧啶（2.98 g，20.0 mmol)，4-硝基酚（2.78 g， 20·0 mmol)及碳酸鉀（4.15 g，30.0 mmol)在二甲基甲醯胺 (20 ml)中，於室溫攪拌15小時。將反應液分溶於乙酸乙酯 及水中，將有機層用水及飽和食鹽水洗淨及用無水硫酸鎂 乾燥。濾去乾燥劑及將濾液減壓蒸餾。將得到之粗生成物 付諸於矽凝膠管柱層析（溶出液，乙酸乙酯：己烷=1 : 4)， 將包含目的物之溶出部分濃縮，得到為無色結晶之標題化 合物（3.89 g，15.5 mmol，77%)。 W-NMR 光譜（00&lt;：13)5(??111):7.08(111，（1，&gt;0.6 112)，7.32-7.37 (2H，m)，8.32-8.37 (2H，m)，8.60 (1H，d，J=0.6 Hz)。 iH 5 5Ί~- ϊ 硝基笨氣基）嘧啶-4-某胺 -614 - 本紙 中國國家標準(CNS) A4規格（210X297公釐） 1304061 A7 B7 五、發明説明（6〇9) 了 將4-氣- 6-(4-硝基苯氧基）嘧啶（1 ·〇4 g，4.00 mm〇i)在氨_ 乙醇溶液（14%，10 ml)中，用壓熱器sU(rc加熱攪拌15小 時。將反應液分配於乙酸乙酯及水中，將有機層用1N氫氧 化鈉水溶液，水及飽和食鹽水洗淨，用無水硫酸鎂乾燥， 滤除乾燥劑及及減壓蒸館滤液。將得到之粗生成物付諸於 矽凝膠管柱層析（溶出液，乙酸乙酯：己烷=1:1),將包含 目的物之溶出部分濃縮，得到為無色結晶之標題化合物 (306 mg，1.32 mmol，33%) 0 iH-NMR 光譜（CDCl3)5(ppm): 5.00 (2H，br s)，6·03 (1H，s)， 7·25-7·32 (2H，m)，8·26_8·33 (3H，m) 〇 製造例551-3 - 6- (4-胺基笨氣基）嘧啶-4-某胺 乂 將6-(4-硝基苯氧基）p密淀-4-基胺（306 mg，1 ·32 mmol)， 鐵粉（369 mg，6.60 mmol)及氯化銨（706 mg，13.2 mmol)懸 浮於乙醇（20 ml)-水（5 ml)之混合溶媒中，並於8〇cc加熱攪 摔20分鐘。反應終了後，將反應混合物經矽藻土過遽，及 用乙酸乙酯沖洗。將有機層用飽和食鹽水沖洗，用無水疏 酸鍰乾燥，濾除乾燥劑，將濾液濃縮，得到為淡黃色結晶 之標題化合物（266 mg，1.32 mmol，100%)。 W-NMR 光譜（DMSO-d6)5(Ppm): 5·05 (2H，br s)，5.55 (1H， s), 6.57-6.62 (2H, m), 6.73 (2H, br s), 6.77-6.82 (2H, m), 8.04 (1H，s) 〇 實施例55T” 一 生（6“4“3-茉某服）笨氳某）嘧啶-4-基）乙醯脸 ___ - 615 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇X 297公釐）The medium was stirred at room temperature for 3 hours. The reaction mixture was dissolved in ethyl acetate and water. The desiccant was filtered off and the filtrate was distilled under reduced pressure. The obtained crude product was suspended in ethyl acetate. EtOAc (EtOAc m.) %) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 5·6ό (1H, s), 6.81 (2H, br s), 6.94, 6·99 (1H, m), 7.03 -7.08 (2H, m), 7.25-7.32 (2H, m), 7.43-7.52 (4H, m), 8.07 (1H, s), 8.74 (1H, s), 8.80 (1H, s). The intermediate was synthesized as follows. Production Example 551-1 - 4-Chloro_-_6- (4- indeed some stupid) shouted 2,4-dichloropyrimidine (2.98 g, 20.0 mmol), 4-nitrophenol (2.78 g, 20 0 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in dimethylformamide (20 ml). The reaction mixture was dissolved in ethyl acetate and water. The desiccant was filtered off and the filtrate was distilled under reduced pressure. The obtained crude product was subjected to hydrazine gel column chromatography (eluent, ethyl acetate:hexane = 1 : 4), and the eluted portion of the desired material was concentrated to give the title compound (3.89) as colorless crystals. g, 15.5 mmol, 77%). W-NMR spectrum (00 &lt;: 13) 5 (?? 111): 7.08 (111, (1, &gt; 0.6 112), 7.32 - 7.37 (2H, m), 8.32 - 8.37 (2H, m), 8.60 ( 1H,d,J=0.6 Hz). iH 5 5Ί~- 硝基 nitro stupid base) pyrimidine-4-an amine-614 - paper Chinese national standard (CNS) A4 specification (210X297 mm) 1304061 A7 B7 V. Description of the invention (6〇9) 4-Gas-6-(4-nitrophenoxy)pyrimidine (1·〇4 g, 4.00 mm〇i) in ammonia-ethanol solution (14%, 10 ml) The mixture was heated and stirred for 15 hours with an autoclave sU (rc). The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1N aqueous sodium hydroxide, water and brine, dried over anhydrous magnesium sulfate The desiccant and the filtrate were evaporated under reduced pressure, and the obtained crude product was subjected to hydrazine gel column chromatography (eluent, ethyl acetate: hexane = 1:1), and the dissolved portion containing the target substance was concentrated. The title compound (306 mg, 1.32 mmol, 33%) was obtained as colorless crystals (yield: </ br> </ br> </ br </ br> 25-7·32 (2H,m),8·26_8·33 (3H,m) 〇Production Example 551-3 - 6- (4-Amine-based gas group) Pyrimidine-4-an amine oxime 6-(4-nitrophenoxy)p-denyl-4-ylamine (306 mg, 1.32 mmol), iron powder (369 mg, 6.60 mmol) and ammonium chloride (706 mg, 13.2 mmol) was suspended in a mixed solvent of ethanol (20 ml)-water (5 ml), and stirred for 20 minutes under heating at 8 cc. After the reaction was completed, the reaction mixture was passed through diatomaceous earth. The organic layer was washed with EtOAc. EtOAc (EtOAc m. W-NMR spectrum (DMSO-d6) 5 (Ppm): 5·05 (2H, br s), 5.55 (1H, s), 6.57-6.62 (2H, m), 6.73 (2H, br s), 6.77 -6.82 (2H, m), 8.04 (1H, s) 〇 Example 55T" Life (6 "4" 3-Moxa) Awkward) Pyrimidine-4-yl) Erythral Face ___ - 615 - Ben The paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇X 297 mm)

裝 訂Binding

線 1304061 A7 B7 五、發明説明（61〇) 將N-(4-(6-胺基嘧啶-4-基氧）苯基）-N，-苯基脲（6〇.〇 mg，0.187 mmol)在無水乙酸（1 ml)-吡啶（1 ml)之混合溶媒 中’於60 °C加熱攪摔1 8小時。使反應液回到室溫後，注入 水中’滤取析出之結晶，用水及甲醉洗淨後，藉由通風乾 燥得到微無色結晶之標題化合物（35.0 mg，0.096 mmol， 52%) 〇 H-NMR光 if (DMSO-d6) 5 (ppm): 2.11 (3Η，s)，6.94-7.00 (1Η， m)，7·10,7·15 (2H，m)，7.25-7.31 (2H，m)，7.44-7.54 (5H，m)， 8.49 (1H, d, J=0.4 Hz), 8.72 (1H, s), 8.80 (1H, s), 10.94 (1H, s)。 實施例553 - K4-(6-胺基嘧啶-4-某氧）苯基）-Nf“4-氪1某、Μ 藉由與實施例551同樣之手法，從6-(4-胺基苯氧基）嘧啶-4-基胺（88·9 mg，0.440 mmol)及異氰酸 4-氟苯酯（60.3 mg， 〇·440 mmol)，得到為無色結晶之標題化合物（10〇 mg， 0.295 mmol，65%) 〇 iH-NMR 光譜（DMSO-d6)(5(ppm): 5.66 (1H，d，J=0.6 Hz)， 6.81 (2H，br s)，7.04-7.15 (4H，m)，7·44-7·52 (4H，m)，8.07 (1H，d，J=〇.6 Hz)，8·84 (1H，s)，8.85 (1H，s)。 實施例554 U6-(4-(3-(4-氣苯基）脲）笨氣某）嘧啶-4_某）乙醯胺 藉由與實施例552同樣之手法，從4-(6-胺基嘧啶-4-基乳）笨塞氟苯基脉）（60.0 mg，0.176 mmol)，得 到為操色結晶之標題化合物（56 mg，〇· 147 mmol，79%)。 ___- 616 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（611) 二 k-NMR光譜（DMSO-d6) 5(ppm): 2·11 (3H，s)，7.09-7.16 (4H， m)，7.44-7.54 (5Η，m)，8·49 (1Η，s)，8·80 (1Η，s)，8.83 (1Η， s)，10.94 (1H，s) 〇 實施例555 士（4-(6-腹羞，密啶-4-表直）苯基^“3_甲磺醯茉某）月展 將6-(4-胺基苯氧基）嘧啶-4_基胺（88 9 mg , 〇·44〇 mm〇1) 及（3-甲磺醯苯基）胺基甲酸苯酯（128 mg，〇·44〇 mm〇1)在二 甲基亞颯（2 ml)中，於85t：攪拌18小時。將反應液分溶於 乙酸乙醋及水中，將有機層用i當量氫氧化鈉水溶液，水及 飽和食鹽水洗淨及用無水硫酸鎂乾燥，然後濾去乾燥劑及 將濾液減壓蒸餾。將得到之粗生成物付諸於矽凝膠管柱層… 析（溶出液，乙酸乙酯：甲醇= 30: 1),將包含目的物之溶：?义 出部分濃縮，懸浮於乙酸乙酯中，將其用己烷稀釋，濾取 結晶及用己烷洗淨後，通風乾燥，得到為無色結晶之標題 化合物（75.0 mg，0.188 mmol，43%)。 iH-NMR 光譜（DMS〇-d6)3 (ppm): 3.20 (3H，s)，5.67 (1H，s)， 6.82 (2H, br s), 7.04-7.12 (2H, m), 7.44-7.59 (4H, m), 7.65-7.70 (1H, m), 8.07 (1H, s), 8.16-8.19 (1H, m), 8.92 (1H, br s), 9·19 (1H, br s)。 實施例556 1-(6-(4-(3-(3-甲磺醯笨基）脲）笨氫某）嘧啶-4-某）乙醯脉 藉由與實施例552同樣之手法，從N-(4-(6-胺基嘧啶-4-基氧）苯基）-以’-(3-甲基磺醯苯基）脲（50.0 mg，0.125 mmol) ’得到為無色結晶之標題化合物（π mg，0.029 . ____- 617 - __ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（612) mmol，24%) 0 iH-NMR 光譜（DMSO-d6)5(ppm): 2.11 (3H，s)，3·20 (3H，S)， 7.11-7.17 (2Η，m)，7.50-7.59 (5Η，m)，7.66-7.70 (1Η，m)， 8.16-8.19 (1H，m)，8.50 (1H，s)，9·01 (1H，bi* s)，9.28 (1H，br s)，10·95 (1H，s) 〇 實施例557 N-(4-(2-胺某嘧淀-4-基氧）茉某）-N，_ y荼曰午 藉由與實施例551同樣之手法，從4-(4-胺基苯氧基），密淀_ 2-基胺（101 mg，〇·5〇〇 mmol)及異氰酸苯酯（59 6 mg，〇 5〇〇 mmol)，得到為無色結晶之標題化合物（1〇5 mg , ο υ? mmol，65%)。 _ h-NMR 光譜（DMSO-d6)5(ppm): 6·07 (1H，d，J=5.8 Hz)， 6.61(2H，brs)，6.94-6.99 (lH，m)，7.05-7.10(2H，m)，7.25- 7.31 (2H, m), 7.43-7.51 (4H, m), 8.08 (1H, d, J=5.8 Hz), 8·74 (1H，br s), 8·79 (1H，br s) 〇 中間體如下述合成。 製造例557- 1 ii一氣-( 4·碲·基笨氣基）嘧啶-華脸 將2-胺基-4,6-二氯嘧啶（3.28 g，20.0 mmol)，4-硝基酚 (2·78 g ’ 20·0 mm〇i)及碳酸卸（4g，30·0 mmol)在二甲基 甲酿胺（20 ml)中，於i〇〇°C加熱攪拌3小時。使反應液回到 室溫後，注入冰水（100 ml),濾取析出之結晶及用水洗淨 後’藉由通風乾燥，得到為無色結晶之標題化合物（4·93 g ’ 18·5 mmol，92%) 〇 •τ---—-- m 本紙張尺度適财國®家標準X 297公|「 装 訂Line 1304061 A7 B7 V. Description of the invention (61〇) N-(4-(6-Aminopyrimidin-4-yloxy)phenyl)-N,-phenylurea (6〇.〇mg, 0.187 mmol) It was stirred and heated at 60 ° C for 18 hours in a mixed solvent of anhydrous acetic acid (1 ml)-pyridine (1 ml). After the reaction mixture was returned to room temperature, it was poured into water to remove the crystals which were crystallized, washed with water and water, and the title compound (35.0 mg, 0.096 mmol, 52%). NMR light if (DMSO-d6) 5 (ppm): 2.11 (3Η, s), 6.94-7.00 (1Η, m), 7·10, 7·15 (2H, m), 7.25-7.31 (2H, m) , 7.44 - 7.54 (5H, m), 8.49 (1H, d, J = 0.4 Hz), 8.72 (1H, s), 8.80 (1H, s), 10.94 (1H, s). Example 553 - K4-(6-Aminopyrimidin-4-oxooxy)phenyl)-Nf "4-indole-1, hydrazine from 6-(4-aminobenzene) by the same procedure as in Example 551 Oxy)pyrimidin-4-ylamine (88·9 mg, 0.440 mmol) and 4-fluorophenyl isocyanate (60.3 mg, 440·440 mmol) afforded the title compound (10 〇mg, 0.295 M, i, NMR, spectroscopy (DMSO-d6) (5 (ppm): 5.66 (1H, d, J = 0.6 Hz), 6.81 (2H, br s), 7.04-7.15 (4H, m), 7·44-7·52 (4H,m), 8.07 (1H,d,J=〇.6 Hz), 8.84 (1H, s), 8.85 (1H, s). Example 554 U6-(4) -(3-(4-Phenylphenyl)urea) succinyl) pyrimidine-4_one) acetamidine 4-(6-aminopyrimidin-4-yl milk) by the same procedure as in Example 552 The title compound (56 mg, 〇·147 mmol, 79%) was obtained as the color of crystals. ___- 616 - This paper scale applies to the Chinese National Standard (CNS) A4 size (210X 297 mm) 1304061 A7 B7 V. Description of invention (611) Diluted k-NMR spectrum (DMSO-d6) 5 (ppm): 2·11 (3H, s), 7.09-7.16 (4H, m ),7.44-7.54 (5Η,m),8·49 (1 Η, s), 8·80 (1Η, s), 8.83 (1Η, s), 10.94 (1H, s) 〇 Example 555 士(4-(6-腹腹,密啶-4-直直)Benzene Base ^"3_Methanesulfonate Mosquito" monthly exhibition of 6-(4-aminophenoxy)pyrimidin-4-ylamine (88 9 mg, 〇·44〇mm〇1) and (3-methylsulfonate) Phenylphenyl) phenyl carbamate (128 mg, 〇·44〇mm〇1) was stirred in dimethyl hydrazine (2 ml) at 85t: for 18 hours. The reaction liquid was dissolved in ethyl acetate and water, and the organic layer was washed with water, aqueous sodium chloride, and brine, and dried over anhydrous magnesium sulfate. The obtained crude product was applied to a column of a gel column (eluate, ethyl acetate:methanol = 30:1), and the solution containing the desired product was partially concentrated and suspended in ethyl acetate. The title compound (75.0 mg, 0.188 mmol, 43%) was obtained as crystals. iH-NMR spectrum (DMS〇-d6) 3 (ppm): 3.20 (3H, s), 5.67 (1H, s), 6.82 (2H, br s), 7.04-7.12 (2H, m), 7.44-7.59 ( 4H, m), 7.65-7.70 (1H, m), 8.07 (1H, s), 8.16-8.19 (1H, m), 8.92 (1H, br s), 9·19 (1H, br s). Example 556 1-(6-(4-(3-(3-methylsulfonyl)carbazide) phenoxy-pyrimidine-4-yl) oxime was carried out in the same manner as in Example 552 from N. -(4-(6-Aminopyrimidin-4-yloxy)phenyl)--[-(3-methylsulfonylphenyl)urea (50.0 mg, 0.125 mmol). π mg,0.029 . ____- 617 - __ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (612) mmol, 24%) 0 iH-NMR spectrum ( DMSO-d6)5 (ppm): 2.11 (3H, s), 3·20 (3H, S), 7.11-7.17 (2Η, m), 7.50-7.59 (5Η, m), 7.66-7.70 (1Η, m ), 8.16-8.19 (1H, m), 8.50 (1H, s), 9·01 (1H, bi* s), 9.28 (1H, br s), 10.95 (1H, s) 〇 Example 557 N -(4-(2-Amine-pyrimidin-4-yloxy)-m-)-N, _ y 荼曰 藉 藉 藉 藉 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- , _ 2-ylamine (101 mg, 〇·5 〇〇 mmol) and phenyl isocyanate (59 6 mg, 〇 5 〇〇 mmol), the title compound (1 〇 5 mg, ο υ? mmol, 65%). _ h-NMR spectrum (DMSO-d6) 5 (ppm): 6·07 (1H, d, J = 5.8 Hz), 6.61 (2H, brs), 6.94-6.99 (lH, m), 7.05-7.10 (2H , m), 7.25- 7.31 (2H, m), 7.43-7.51 (4H, m), 8.08 (1H, d, J=5.8 Hz), 8·74 (1H, br s), 8·79 (1H, Br s) The hydrazine intermediate was synthesized as follows. Production Example 557- 1 ii-gas-(4·碲·yl stupyl)pyrimidine-Huawei 2-amino-4,6-dichloropyrimidine (3.28 g, 20.0 mmol), 4-nitrophenol (2) · 78 g '20·0 mm〇i) and carbonic acid unloading (4 g, 30·0 mmol) in dimethyl amide (20 ml), and stirred under heating at i ° ° C for 3 hours. After returning the reaction mixture to room temperature, it was poured into ice water (100 ml), and the crystals which were crystallized and washed with water were evaporated to give the title compound (4·93 g ' 18·5 mmol ,92%) 〇•τ------ m This paper size is suitable for the country of the country® standard X 297 || Binding

線 1304061 A7 ______ B7 __ 五、發明説明（613) : 1- NMR 光譜（DMSO-d6)5(ppm): 6·43 (1H，s)，7.25 (2H，br s)’ 7·46-7·52 (2H，m)，8.28-8.34 (2H，m)。 製造例557-9 K4·胺某苯氧基）嘧珐_2·某胺 將心氯- 6-(4-硝基苯氧基）嘧啶-2-基胺（1.60 g，1.32 mmol)懸浮於甲醇（3〇 ml)-四氫呋喃（30 ml)之混合溶媒 中’加入氫氧化鈀/碳（3〇〇 mg)，並於氫氣氛圍及室溫下攪 拌1 8小時。經由矽藻土過濾濾去觸媒，用乙醇洗淨後，減 壓館去濾液。將得到之粗生成物付諸於矽凝膠管柱層析（溶 出液：乙酸乙酯：己烷=3 : 1)，然後將包含目的物之溶出 部分濃縮’得到為無色結晶之標題化合物（91〇111§，4.5-〇 \ mmol，75%)。 '， W-NMR光譜（DMSO-d6)5(PPm)·· 5.01 (2H，br s)，5·93 (1H，」 d, J=5.4 Hz), 6.50-6.60 (4H, m), 6.76-6.82 (2H, m), 8.03 (1H, d, J=5.4 Hz) 〇 實施例558 K4-(2-胺某嘧哈-心基氲）茉篡氣茉某、月辱 藉由與實施例551同樣之手法，從4-(各胺基苯氧基）嘧啶_ 2- 基胺（101 mg , 〇·500 mmol)及異氰酸氟苯酯（68 6 mg，0.500 mmol)，得到為無色結晶之標題化合物（1〇5 mg，0.309 mmol，62%) 〇 ifi-NMR 光譜（DMSO-d6)6(ppm): 6·〇6 (1H，d，J=5.6 Hz)， 6.61 (2H, br s), 7.05-7.15 (4H, m)5 7.44-7.52 (4H, m), 8.08 一 (1H，d，J=5.6 Hz)，8.75-8.79 (2H，m) 〇 -619 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1304061 A7 B7 五、發明説明（614 實施例559 1- (4-(2-胺基嘧啶-4-基氧）苯基)-_ΝΌ-甲礒醯苯某）服 藉由與實森例555同樣之手法’從4- (4-胺基苯氧基）喊淀― 2- 基胺（101 mg，〇·500 mmol)及（3 -甲續醯苯基）胺基甲酸苯 酯（146 mg，0.500 mmol)，得到為無色結晶之標題化合物 (96 mg，0.240 mmol，48%) 〇 iH-NMR 光譜（DMSO-d6)5 (ppm): 3.20 (3H，s)，ό.07 (1H，d， J=5.8 Hz), 6.61 (2H, br s), 7.06-7.12 (2H, m), 7.46-7.59 (4H,- m)，7.65-7.70 (1H，m)，8.09 (1H，d，J=5 8 Hz)，8.16-8.19 (1H， m)，8·89 (1H，br s)，9.18 (1H，br s) 〇 實施例560 - 土l(3-氟-4-(環丙胺羰基）胺基苯氧^甲氣乙最某卜 4:淋羧蝰腰 從以與實施例11同樣之手法由4-(4·胺基氟苯氧基）-7-(2-甲氧乙氧基）-6-喹淋羧酿胺（1〇〇 mg)得到之N/(4-(6-胺 甲酿基-7-(2-甲氧乙氧基）-4〃奎琳基）氧氟苯基）胺基甲 酸苯醋及環丙胺’得到為淡黃色結晶之標題化合物（22 mg) 〇 WNMR 光譜（DMSO-d6)5(PPm): 0·39 (2H，叫，〇·63 (2H，m)， 2.49 (1H，m)，3·30 (3H，s)，3·79 (2H，m)，4 39 (2h，m)，6.51 (1H，d，J=5.2 Hz)，6.79 (1H，s)，7·〇6 (iH，m)，7 31 (1H，蛛 7.54 (1H, s), 7.79 (1H, s), 7.83 (1H, s), 8.18-8.22 (2H, m),— 8·65 (1H，d，J=5:2 Hz)，8·74 (1H，s)。 ’ 實施例561 -620 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 B7 五、發明説明（615) 二 氮基-6-氨基g套啦-4-基乳）-2-甲幕笨基Ί-3 -環丙 霞 以與製造例17同樣地，從4-(4-胺基· 2-甲基苯氧基）-7-甲 氧基喹啉-6-羧醯胺（2g)及氯碳酸苯酯，得到為固體之胺基 甲酸酯（1.73 g)。繼而，以與實施例11同樣地，將胺基甲酸 酉旨（I·7 g)在二甲基亞观中，於室溫用環丙胺處理，得到為 固體之標題化合物（1.4 g)。 !H-NMR 光譜（DMSO-d6) 5 (ppm): 0.37-0.41 (2H，m)，〇·59· 0·64 (2Η，m)，2·23 (3Η，s)，2.50-2.56 (1Η，m)，5·42 (2Η，s)， 6.49 (1H, d3 J=5.2 Hz), 6.73-6.75 (1H, m), 7.02 (1H, dd ， J=2.8 Hz, J=8.8 Hz), 7.08 (1H, d, J=2.8 Hz), 7.32-7.53 (5¾ m), 7.60 (1H, s), 7.66 (1H, s), 7.89 (1H, d, 1=8.8 Hz), 8.68 - v (1H，d，J=5.2 Hz)，8·73 (1H，s)。 — —:?z 中間體如下述合成。 製造例561-1 4-M-胺某-3-甲基茉氣基）-7-芊氧喹啉-6-甲腈 以與製造例395-1同樣之方法，從7-芊氧基-4-氯喹啉-心 甲腈（5 g)及4-胺基-3-甲基酚，得到為固體之標題化合物 (3·6 g) 〇 W-NMR 光譜（DMSO-d6)5(ppm): 2·07 (3H，s)，4·94 (2H，s)， 5.43 (2Η, s), 6.46 (1H, d, J=5.2 Hz), 6.69 (1H, d, J=8.8 Hz), 6.82 (1H, dd, J=2.8 Hz, J=8.8 Hz), 6.87 (1H, d, J=2.8 Hz)3 7.36 (1Η，υ=7·2 Hz), 7·44 (2H，t，J=7.2 Hz), 7·53 (2H, d，， J=7.2 Hz), 7.66 (1H, s), 8.67 (1H, d, J=5.2 Hz), 8.73 (lfj -621 -Line 1304061 A7 ______ B7 __ V. Description of invention (613) : 1- NMR spectrum (DMSO-d6) 5 (ppm): 6·43 (1H, s), 7.25 (2H, br s)' 7·46-7 · 52 (2H, m), 8.28-8.34 (2H, m). Production Example 557-9 K4·amine phenoxy)pyrimidine_2·an amine The suspension of heart chlorine-6-(4-nitrophenoxy)pyrimidin-2-ylamine (1.60 g, 1.32 mmol) was Palladium hydroxide/carbon (3 〇〇 mg) was added to a mixed solvent of methanol (3 〇ml)-tetrahydrofuran (30 ml), and stirred under a hydrogen atmosphere at room temperature for 18 hours. The catalyst was filtered through a diatomaceous earth filter, washed with ethanol, and the filtrate was depressurized. The obtained crude product was subjected to hydrazine gel column chromatography (eluent: ethyl acetate:hexane = 3:1), and then the eluted fraction containing the objective substance was concentrated to give the title compound as colorless crystals. 91〇111§, 4.5-〇\ mmol, 75%). ', W-NMR spectrum (DMSO-d6) 5 (PPm) · · 5.01 (2H, br s), 5.93 (1H, "d, J = 5.4 Hz), 6.50-6.60 (4H, m), 6.76 -6.82 (2H, m), 8.03 (1H, d, J = 5.4 Hz) 〇Example 558 K4-(2-Amine-Mupira-Heartyl) 篡 篡 、 、 、 、 、 、 、 、 551, in the same manner, from 4-(Ethylaminophenoxy)pyrimidine-2-ylamine (101 mg, 〇·500 mmol) and fluorophenylisocyanate (68 6 mg, 0.500 mmol) to give colorless Crystalline title compound (1〇5 mg, 0.309 mmol, 62%) 〇ifi-NMR spectrum (DMSO-d6) 6 (ppm): 6·〇6 (1H, d, J=5.6 Hz), 6.61 (2H, Br s), 7.05-7.15 (4H, m)5 7.44-7.52 (4H, m), 8.08 one (1H,d,J=5.6 Hz),8.75-8.79 (2H,m) 〇-619 - the paper scale Applicable to China National Standard (CNS) A4 Specification (210X297 mm) 1304061 A7 B7 V. Description of Invention (614 Example 559 1- (4-(2-Aminopyrimidin-4-yloxy)phenyl)--ΝΌ-A礒醯 某 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Phenylphenyl) phenyl carbamate (146 mg, 0.500 mm The title compound (96 mg, 0.240 mmol, 48%) eluted eluted eluted eluted eluted eluted eluted eluted J=5.8 Hz), 6.61 (2H, br s), 7.06-7.12 (2H, m), 7.46-7.59 (4H,- m), 7.65-7.70 (1H,m), 8.09 (1H,d,J= 5 8 Hz), 8.16-8.19 (1H, m), 8.89 (1H, br s), 9.18 (1H, br s) 〇 Example 560 - Soil l (3-fluoro-4-(cyclopropylaminecarbonyl) Aminophenoxyl, methyl, ethane, ethane, ketone, ketone, ketone, ketone, ketone, ketone, ketone, ketone, ketone, ketone, ketone, ketone N-(4-(6-Amino-mercapto-7-(2-methoxyethoxy)-4 quinaclinyl) oxyfluoride obtained by 6-quinonecarboxamide (1 〇〇mg) The title compound (22 mg) was obtained as pale yellow crystals. NMR spectrum (DMSO-d6) 5 (PPm): 0·39 (2H, called, 〇·63 (2H) , m), 2.49 (1H, m), 3·30 (3H, s), 3·79 (2H, m), 4 39 (2h, m), 6.51 (1H, d, J = 5.2 Hz), 6.79 (1H, s), 7·〇6 (iH, m), 7 31 (1H, spider 7.54 (1H, s), 7.79 (1H, s), 7.83 (1H, s), 8.18-8.22 (2H, m ), — 8·65 (1H, d, J = 5: 2 Hz), 8.74 (1H, s). 'Example 561 -620 - This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of invention (615) Diazo-6-aminog-la-4-yl Milk)-2-methyl succinyl hydrazone-3-cyclopropane was the same as in Production Example 17, from 4-(4-amino-2-methylphenoxy)-7-methoxyquinoline- 6-Carboxylimidamine (2 g) and phenyl chlorocarbonate gave a solid urethane (1.73 g). Then, in the same manner as in Example 11, the title compound (1.4 g) was obtained as a solid. !H-NMR spectrum (DMSO-d6) 5 (ppm): 0.37-0.41 (2H, m), 〇·59· 0·64 (2Η, m), 2·23 (3Η, s), 2.50-2.56 ( 1Η,m),5·42 (2Η,s), 6.49 (1H, d3 J=5.2 Hz), 6.73-6.75 (1H, m), 7.02 (1H, dd, J=2.8 Hz, J=8.8 Hz) , 7.08 (1H, d, J=2.8 Hz), 7.32-7.53 (53⁄4 m), 7.60 (1H, s), 7.66 (1H, s), 7.89 (1H, d, 1=8.8 Hz), 8.68 - v (1H, d, J = 5.2 Hz), 8.73 (1H, s). — —?z The intermediate was synthesized as follows. Production Example 561-1 4-M-Amine Some 3-methyl-methyl-l-yl)-7-anthranquinoline-6-carbonitrile In the same manner as in Production Example 395-1, from 7-methoxy- 4-Chloroquinoline-cardacarbonitrile (5 g) and 4-amino-3-methylphenol gave the title compound (3·6 g) as a solid. 〇W-NMR spectrum (DMSO-d6) 5 (ppm) : 2·07 (3H, s), 4·94 (2H, s), 5.43 (2Η, s), 6.46 (1H, d, J=5.2 Hz), 6.69 (1H, d, J=8.8 Hz), 6.82 (1H, dd, J=2.8 Hz, J=8.8 Hz), 6.87 (1H, d, J=2.8 Hz)3 7.36 (1Η,υ=7·2 Hz), 7·44 (2H,t,J =7.2 Hz), 7·53 (2H, d,, J=7.2 Hz), 7.66 (1H, s), 8.67 (1H, d, J=5.2 Hz), 8.73 (lfj -621 -

本紙張尺度適用中S S家職CNS) A4規格_&gt;&lt;挪公I) 1304061 A7 B7 五、發明説明（616) 實施例562 1-「4-(6-氰基-7-羥基4啉-4-基最.U2-甲基笨基1-3-環丙月尿 以與製造例301-2同樣之方式，將i-[4-(7-芊氧基-6-氰基 π奎淋-4-基乳）-2-甲基本基]-3 -環丙膽（〇·8 g)在四氫咬喃 中，Μ鈀/碳脫芊基化，得到為固體之標題化合物（0.5 g)。 iH-NMR S.(DMSO-d6)5(ppm):0,36-0.41(2H，m)，0.59-0·65 (2H，m)，2·17 (3H，s)，2.49-2.56 (1H，m)，6·32 (lH，_d， J=5.2 Hz), 6.74 (1H, d, J=2.8 Hz), 7.01 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.07 (1H, d, J=2.4 Hz), 7.30 (1H, s), 7.59 (1H, s), 7.90 (1H, d, J=8.8 Hz), 8.56 (1H, d, J=5.2 Hz), 8.57 (lHv s)。 實施例563 l-「4-(6-氨某“2RV7-環氣乙烷某甲氫墓4啉-4-某％ 甲基苯某1-3-環丙脲 以與製造例284- 1同樣之方式，從1-[4-(6-氰基-7-羥基峻 琳-4-基氧）-2-甲基苯基]-3-環丙脲（500 mg)，得到為固體 之標題化合物（312 mg)。 iH-NMR 光譜（DMSO-d6)5(ppm): 0·37-0·42 (2H，m)，〇·59· 〇·65 (2Η，m)，2.18 (3Η，s)，2.49-2.56 (1Η，m)，2.78-2.81 (1Η， m)，2.89 (1H，t，J=4.8 Hz)，3.42-3.47 (1H，m)，4·14 (1H，dd， J=6.4 Hz, J=11.6 Hz), 4.68 (1H, dd, J=2.4 Hz, J=11.6 Hz), 6·49 (1Η，Ί=5·2 Hz)，6·74 (1H，d，J=2.4 Hz), 7.03 (1H，dd， J=2.4 Hz，J=8.4 Hz)，7.09 (1H，d，J=2.4 Hz)，7·59 (1H，s)， _ - 622 -__ 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（~~) ~~7 7.61 (1H, s), 7.92 (1H, d, J=8.4 Hz), 8.70 (1H, d, J=5.2 Hz), 8.74 (1H，s) 〇 實施例564 1- { 4-「6-奢·某-7- ((2R) -2-經基-3- ^比洛淀，1-某j氣基）岭 琳-4-基氫1-2-甲甚茇某卜3二5袤丙脲 以與實施例284同樣之方式，從1-[4-(6-氰基_7-(2R)-環 乳乙燒甲氧基峻淋-4-基乳）-2-甲基表基]_3_環丙膽（55 mg)，得到為固體之標題化合物（11 mg)。 iH-NMR 光譜（〇1^0-(16)(5(??111):0.37-0.41(211，111)，〇.58-0.65 (2H, m), 2.26 (3H, s), 1.62-1.69 (4H, m), 2.44-2.56 (6H, m), 2.68 (1H, dd, J=6.4 Hz, J=12 Hz), 3.96-4.03 (1H, m),… 4.18 (1H, dd, J=5.6 Hz, J=10.4 Hz), 4.28 (1H, dd, J=3.6 Hz,--J=10.4 Hz), 5.00 (1H, d, J=5.2 Hz), 6.48 (1H, d, J=5.2 Hz), 6.75 (1H, d, J=2.4 Hz), 7.03 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.09 (1H, d, J=2.4 Hz), 7.58 (1H, s), 7.60 (1H, s), 7.91 (1H, d，J=8.8 Hz)，8·68 (1H，d, J=5.2 Hz)，8·71 (1H，s)。 實施例565 氨基- 7- ((2R)-2 -經基- 3- ττ 比症-1-基丙氣基）p套 啉-4-某氣1-2-甲某茇某卜3-環丙月尿 以與實施例284同樣之方式，從[1-[4-(6-氰基-(2R)-7-環 氧乙烷甲氧基喳啉-4-基氧）-2-甲基苯基]-3-環丙脲（1〇〇 mg) 及六氫吡啶，得到為固體之標題化合物（8 mg)。 1H-NMR 光一譜（01^30-(16)5(??111):0.37-0.41(211，111)，0.59-0.66 (2H, m), 1.31-1.38 (2H, m)5 1.43-1.53 (4H, m), 2.20 __- 623 ___ 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 B7 五、發明説明（618) (3H，s)，2.33-2.58 (7H, m), 3.99-4.06 (1H, m)，4.19 (1H，dd， J=5.6 Hz，J=10.4 Ηζ)，4·29 (1H，dd，J=3.2 Hz，j=1〇 4 Hz)， 4.94 (1H, br), 6.49 (1H, d, J=5.2 Hz), 6.75-6.79 (1H, m),This paper scale applies to the SS home job CNS) A4 specification _&gt;&lt;Novogong I) 1304061 A7 B7 V. Inventive Note (616) Example 562 1-"4-(6-Cyano-7-hydroxyl porphyrin) -4-based most. U2-methyl stupyl 1-3-cyclopropanyl urea i-[4-(7-decyloxy-6-cyano-π-quinion in the same manner as in Production Example 301-2)淋-4-yl milk)-2-methylbenzyl]-3-cyclopropylcholine (〇·8 g) in tetrahydroanthracene, deuterated palladium/carbon decarboxylation afforded the title compound as a solid (0.5 g). iH-NMR S. (DMSO-d6) 5 (ppm): 0, 36-0.41 (2H, m), 0.59-0.65 (2H, m), 2·17 (3H, s), 2.49 -2.56 (1H,m),6·32 (lH,_d, J=5.2 Hz), 6.74 (1H, d, J=2.8 Hz), 7.01 (1H, dd, J=2.4 Hz, J=8.8 Hz) , 7.07 (1H, d, J=2.4 Hz), 7.30 (1H, s), 7.59 (1H, s), 7.90 (1H, d, J=8.8 Hz), 8.56 (1H, d, J=5.2 Hz) , 8.57 (lHv s). Example 563 l-"4-(6-Ammonia "2RV7-cycloethane, a toluene, 4 toluene-4-%, methylbenzene, 1-3-cyclopropanone In the same manner as in Production Example 284-1, 1-[4-(6-cyano-7-hydroxy-juphenan-4-yloxy)-2-methylphenyl]-3-cyclopropanil (500 mg) The title compound (312 mg) was obtained as a solid. iH-NMR Spectrum (DMSO-d6) 5 (ppm): 0·37-0·42 (2H, m), 〇·59· 〇·65 (2Η, m), 2.18 (3Η, s), 2.49-2.56 (1Η, m), 2.78-2.81 (1Η, m), 2.89 (1H, t, J=4.8 Hz), 3.42-3.47 (1H, m), 4·14 (1H, dd, J=6.4 Hz, J=11.6 Hz ), 4.68 (1H, dd, J=2.4 Hz, J=11.6 Hz), 6·49 (1Η, Ί=5·2 Hz), 6.74 (1H, d, J=2.4 Hz), 7.03 (1H ,dd, J=2.4 Hz, J=8.4 Hz), 7.09 (1H,d,J=2.4 Hz),7·59 (1H,s), _ - 622 -__ This paper scale applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) 1304061 A7 B7 V. Description of invention (~~) ~~7 7.61 (1H, s), 7.92 (1H, d, J=8.4 Hz), 8.70 (1H, d, J= 5.2 Hz), 8.74 (1H, s) 〇Example 564 1- { 4-"6-Luxury·-7-((2R)-2-Phenyl-3-^Biluo, 1-Yu gas In the same manner as in Example 284, from 1-[4-(6-cyano-7-(2R)), in the same manner as in Example 284. - Cyclopropylidene methoxylated 4-mercapto)-2-methylexyl]_3_cyclopropylcholine (55 mg) gave the title compound (11 mg). iH-NMR spectrum (〇1^0-(16)(5(??111):0.37-0.41(211,111), 〇.58-0.65 (2H, m), 2.26 (3H, s), 1.62- 1.69 (4H, m), 2.44-2.56 (6H, m), 2.68 (1H, dd, J=6.4 Hz, J=12 Hz), 3.96-4.03 (1H, m),... 4.18 (1H, dd, J =5.6 Hz, J=10.4 Hz), 4.28 (1H, dd, J=3.6 Hz, --J=10.4 Hz), 5.00 (1H, d, J=5.2 Hz), 6.48 (1H, d, J=5.2 Hz), 6.75 (1H, d, J=2.4 Hz), 7.03 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.09 (1H, d, J=2.4 Hz), 7.58 (1H, s) , 7.60 (1H, s), 7.91 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 5.2 Hz), 8.71 (1H, s). Example 565 Amino - 7- ((2R)-2 - thiol- 3- ττ -1--1-ylpropyl) pylostane-4-one gas 1-2-A 茇 茇 3- 3- 3- 3- 3- 3- 3- 以 以 以In the same manner, from [1-[4-(6-cyano-(2R)-7-oxiranylmethoxyphthaloline-4-yloxy)-2-methylphenyl]-3- Cyclopropaneurea (1 mg) and hexahydropyridine gave the title compound (8 mg) as a solid. 1H-NMR photo spectrum (01^30-(16)5 (?? 111): 0.37-0.41 (211 , 111), 0.59-0.66 (2H, m), 1.31-1.38 (2H, m)5 1.43-1.53 (4H, m), 2.20 __- 623 ___ This paper scale applies to Chinese national standards (C NS) A4 size (210 x 297 mm) 1304061 A7 B7 V. Description of invention (618) (3H, s), 2.33-2.58 (7H, m), 3.99-4.06 (1H, m), 4.19 (1H, dd , J=5.6 Hz, J=10.4 Ηζ), 4·29 (1H, dd, J=3.2 Hz, j=1〇4 Hz), 4.94 (1H, br), 6.49 (1H, d, J=5.2 Hz ), 6.75-6.79 (1H, m),

7.02-7.08 (1H，m)，7.09-7.13 (1H，m)，7.60 (1H，s)，7 62 (1H s), 7.93 (1H, d, J=9.2 Hz), 8.70 (1H, d, J=5.2 Hz), 8.71 (1H, s) ° 實施例566 4-基氳1-2-甲某茉基卜3-環丙脲 以與實施例284同樣之方式，從[1-[4-(6-氰基-(2R)-7-環 氧乙烷甲氧基喹啉-4-基氧）-2-甲基苯基]-3-環丙脲（55 mg). 及二乙胺，得到為固體之標題化合物（21 mg)。 1H-NMR光譜（〇]^3〇-(16)5(??111):0.37-0.41(211，111)，0.59-0.65 (2H, m), 0.91-1.00 (6H, m), 2.18 (3H, s), 2.43-2.69 (7H, m)，3.91-4.00 (1H，m)，4.17-4.22 (1H，m)，4.26-4.31 (1H，m)， 6·48 (1H，d，J=5.2 Hz)，6·76 (1H，d，J=2.8 Hz)，7.03 (1H，dd， J=2.8 Hz, J=8.8 Hz), 7.09 (1H, d, J=2.4 Hz), 7.58 (1H, s), 7.60 (1H, s), 7.91 (1H, d, J=8.8 Hz), 8.68 (1H, d, J=5.2 Hz), 8.71 (1H，s)。 實施例567 氨基- 7- (3-p比哈邊-1-基丙氣基）林-4-基氣1-2-—甲基表基丨-3 -環雨月尿 以與實施彳列7同樣之方式，從1 - [4 - ( 6 -氨基-7 -备基峻11 林-4-基氧）-2-甲基苯基]-3-環丙脲（60 mg)及1-(3-氯丙基）吡 _____ - 624 - _ I紙張尺度適财® s轉準(CNS) A4&amp; (謂~_ 1304061 A7 B7 五、發明説明（619) 二 咯啶，得到為固體之標題化合物（23 mg)。 ifi-NMR 光譜（〇^18〇-(16)(5(卩0111):〇.37-〇.41(2^1，111)，〇.59-0.65 (2H, m), 1.62-1.69 (4H, m), 1.93-2.01 (2H, m), 2.18 (3H，s)，2.39-2.45 (4H，m)，2.49-2.55 (1H，m)，2.57 (2H，t， J=7.2 Hz), 4.30 (2H, t, 1=6.4 Hz), 6.48 (1H, d, J=5.2 Hz), 6.75 (-1H, d, J=2.8 Hz), 7.03 (1H, dd, J=2.8 Hz, J=8.8 Hz), 7.08 (1H, d, J=2.8 Hz), 7.55 (1H, s), 7.60 (1H, s), 7.91 (1H, d，J=8.8 Hz)，8.68 (1H，d，J=5.2 Hz)，8.71 (1H，s)。 實施例5687.02-7.08 (1H,m), 7.09-7.13 (1H,m), 7.60 (1H,s),7 62 (1H s), 7.93 (1H, d, J=9.2 Hz), 8.70 (1H, d, J = 5.2 Hz), 8.71 (1H, s) ° Example 566 4-Based 1-2-A methyl mosyl 3-cyclopropanil in the same manner as in Example 284, from [1-[4- (6-Cyano-(2R)-7-oxirane methoxyquinolin-4-yloxy)-2-methylphenyl]-3-cyclopropanil (55 mg). and diethylamine The title compound (21 mg) was obtained as a solid. 1H-NMR spectrum (〇]^3〇-(16)5(??111):0.37-0.41(211,111),0.59-0.65 (2H, m), 0.91-1.00 (6H, m), 2.18 ( 3H, s), 2.43-2.69 (7H, m), 3.91-4.00 (1H, m), 4.17-4.22 (1H, m), 4.26-4.31 (1H, m), 6·48 (1H, d, J =5.2 Hz),6·76 (1H,d,J=2.8 Hz), 7.03 (1H,dd, J=2.8 Hz, J=8.8 Hz), 7.09 (1H, d, J=2.4 Hz), 7.58 ( 1H, s), 7.60 (1H, s), 7.91 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 5.2 Hz), 8.71 (1H, s). Example 567 Amino - 7- (3-p than haha-1-ylpropenyl) lin-4-yl 1-2-methyl-formyl 丨-3 - circumfluent urination in the same manner as in the implementation of 彳7, from 1 - [4 - (6-Amino-7-predominyl 11 -4-yloxy)-2-methylphenyl]-3-cyclopropanil (60 mg) and 1-(3-chloropropyl) P-_____ - 624 - _ I Paper Scale Optimum® s Alignment (CNS) A4&amp; (Preparation ~_ 1304061 A7 B7 V. Inventive Note (619) Dibromopyridine, the title compound (23 mg) was obtained as a solid. Ifi-NMR spectrum (〇^18〇-(16)(5(卩0111):〇.37-〇.41(2^1,111),〇.59-0.65 (2H, m), 1.62-1.69 ( 4H, m), 1.93-2.01 (2H, m), 2.18 (3H, s), 2.39-2.45 (4H, m), 2.4 9-2.55 (1H, m), 2.57 (2H, t, J = 7.2 Hz), 4.30 (2H, t, 1 = 6.4 Hz), 6.48 (1H, d, J = 5.2 Hz), 6.75 (-1H, d, J=2.8 Hz), 7.03 (1H, dd, J=2.8 Hz, J=8.8 Hz), 7.08 (1H, d, J=2.8 Hz), 7.55 (1H, s), 7.60 (1H, s) , 7.91 (1H, d, J = 8.8 Hz), 8.68 (1H, d, J = 5.2 Hz), 8.71 (1H, s).

Kv苯基-N、（4-(6-苯胺基嘧啶-4-某氣）宏某）脲 將N-(6-(4-胺基苯氧基）嘧啶-4-基）苯胺（55.6 mg，0.200 mmol)及異戴酸苯酯（26·1 mg，0.220 mmol)在二甲基甲酿-胺（1 ml)中，於室溫攪拌12小時。將反應液分溶於乙，酸乙 酯及水中，將有機層用水及飽和食鹽水洗淨及用無水硫酸 鎂乾燥，然後濾去乾燥劑及將濾液減壓蒸餾。將得到之粗 生成物懸浮於乙酸乙酯中，將其用己烷稀釋，滤取結晶及 用己燒洗淨後，藉由通風乾燥，得到為無色結晶之標題化 合物（69.0 mg，0.174 mmol，87%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 6·06 (1H，d，J=1.6 Hz) 6.95-7.02 (2H，m)，7.11-7.16 (2H，m)，7·25-7.34 (4H，m)， 7.44-7.50 (2H, m), 7.50-7.56 (2H, m), 7.58-7.63 (2H m)Kv phenyl-N, (4-(6-anilinopyrimidin-4-one) macro) urea N-(6-(4-aminophenoxy)pyrimidin-4-yl)aniline (55.6 mg , 0.200 mmol) and isophthalic acid phenyl ester (26.1 mg, 0.220 mmol) were stirred in dimethyl methyl-amine (1 ml) at rt for 12 h. The reaction mixture was dissolved in ethyl acetate, ethyl acetate and water. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The obtained crude product was suspended in ethyl acetate, EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 87%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 6·06 (1H, d, J = 1.6 Hz) 6.95-7.02 (2H, m), 7.11-7.16 (2H, m), 7·25-7.34 (4H,m), 7.44-7.50 (2H, m), 7.50-7.56 (2H, m), 7.58-7.63 (2H m)

8.35 (1H, d, J=1.6 Hz), 8.71 (1H, s), 8.79 (1H, s), 9.54 (1H s)。 、·_-，--， 中間體如下述合成。 -625 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 _ B7 五、發明説明： 製造例568-k 硝基茉氫某）嘧啶-4-基）苽胺 將4-氣- 6-(4 -硝基苯氧基）ρ密症（508 mg，2 ·00 mmol)及苯8.35 (1H, d, J=1.6 Hz), 8.71 (1H, s), 8.79 (1H, s), 9.54 (1H s). ,·_-,--, the intermediate was synthesized as follows. -625 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 _ B7 V. Description of invention: Manufacturing example 568-k Nitro-mosquito-) Pyrimidine-4-yl) decylamine 4-Gas-6-(4-nitrophenoxy) phenolism (508 mg, 2·00 mmol) and benzene

胺（559 mg，6·00 mmol)在 1-甲基吡咯啶（5 ml)中，於 90°C 加熱攪拌3小時。將反應液分溶於乙酸乙酯及水中，將有機 層用永及飽和食鹽水洗淨及用無水硫酸鎂乾燥，然後滤去 乾燥劑及將瀘液減壓蒸餾。將得到之粗生成物付諸於硬凝 膠管柱層析（溶出液··乙酸乙酯：己烷=1 : 3)，然後將包含 目的物之溶出部分濃縮，得到為無色結晶之標題化合物 (508 mg ’1.65 mmol，82 %) 〇 iH-NMR 光譜（CDCl3)5(ppm): 6·34 (1H，s)，7·03 (1H，br s)， 7.21-7.35 (5H, m), 7.40-7.46 (2H, m), 8.26-8.32 (2H, m), ：-； 8.35 (1H，s)。 — ：ϊ 製造例568-2 N-(6-(4-胺基笨氣基）喊淀-4-某）笨胺 將N-(6-(4-硝基苯氧基）嘧啶-4-基）苯胺（508 mg，1 65 mmol),鐵粉（461 mg，8.25 mmol)及氯化銨（882 mg , 16 5 mmol)懸浮於乙醇（16 ml)-水（4 ml)之混合溶媒中，並於8〇 °(：加熱攪拌20分鐘。反應終了後，將反應混合物經矽藻土 過濾及用乙酸乙酯沖洗。將有機層用飽和食鹽水沖洗，用 無水硫酸鎂乾燥，濾除乾燥劑，將濾液減壓蒸餾，然後將一 得到之粗生成物懸浮於乙酸乙酯中，將其用己烷稀釋，滤 取結晶反用己境洗淨後，藉由通風乾燥，得到為無色、纟士晶 — 之標題化合物（387 mg，1.39 mmol，84%)。 _ - 626 - 本紙張尺度適用巾gj @家標準(CNS) Μ規格(21GX 297公董) ' -------- 1304061 A7 _ B7 五、發明説明（621) 二 W-NMR光譜（CDC13) 5 (PPm): 3.64 (2H，br s)，6·17 (1H，d， J=0.8 Hz), 6.67-6.73 (2H, m), 6.77 (1H, br s), 6.89-6.95 (2H, m)，7.14-7.20 (1H，m)，7.26-7.32 (2H，m)，7.35-7.41 (2H，m)， 8.37 (1H, d, J=0.8 Hz) 〇 實施例569 N- ( 3 - f績醯一苯基）-N、（ 4- ( 6-苯胺某嘧啶-4-某氣）茉某）脲 將N-(6-(4-胺基苯氧基）嘧啶-4-基）苯胺（55·6 mg，0.200 mmol)及（3-甲基續醯苯基）胺基甲酸苯酯（63.8 mg，0·22〇 . mmol)在二甲基亞鐵（1 ml)中，於85°C加熱揽拌2小時。將 反應液分溶於乙酸乙酯及水中，將有機層用1N氫氧化鈉水 溶液，水及飽和食鹽水洗淨及用無水硫酸鎂乾燥，然後濾-· 去乾燥劑及將濾液減壓蒸餾。將得到之粗生成物懸浮於乙 酸乙酯中，將其用己烷稀釋，濾取結晶及用己烷洗淨後， 精由通風乾’仔到為播色結晶之標題化合物（77.0 mg， 0· 162 mmol，8 1 %) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): 3.20 (3H，s)，6.07 (1H，s)， 6.98-7.03 (1H，m)，7.12-7.17 (2H，m)，7.28-7.34 (2H，m)， 7.50-7.63 (6H, m), 7.66-7.72 (1H, m), 8.17-8.20 (1H, m), 8·34 (1H，s)，8·93 (1H，br s)，9·19 (1H，br s)，9.54 (1H，s” 實施例570The amine (559 mg, 6·00 mmol) was stirred and heated at 90 ° C for 3 hours in 1-methylpyrrolidine (5 ml). The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then filtered and evaporated. The obtained crude product was subjected to hard gel column chromatography (eluent ethyl acetate:hexane = 1:3), and then the eluted fraction containing the objective compound was concentrated to give the title compound as colorless crystals. (508 mg '1.65 mmol, 82 %) 〇iH-NMR spectrum (CDCl3) 5 (ppm): 6·34 (1H, s), 7·03 (1H, br s), 7.21-7.35 (5H, m) , 7.40-7.46 (2H, m), 8.26-8.32 (2H, m), :-; 8.35 (1H, s). — :ϊ 例 568-2 N-(6-(4-Amino-based)---------------------------N-(6-(4-nitrophenoxy)pyrimidine-4- Aniline (508 mg, 1 65 mmol), iron powder (461 mg, 8.25 mmol) and ammonium chloride (882 mg, 16 5 mmol) suspended in a mixed solvent of ethanol (16 ml)-water (4 ml) And the mixture was heated and stirred for 20 minutes. After the reaction was completed, the reaction mixture was filtered over EtOAc (EtOAc)EtOAc. The filtrate is distilled under reduced pressure, and the obtained crude product is suspended in ethyl acetate, diluted with hexane, filtered, washed with hexanes, and then dried by air.纟士晶 - the title compound (387 mg, 1.39 mmol, 84%). _ - 626 - This paper size applies towel gj @家标准(CNS) ΜSpecifications (21GX 297 DON) ' ------- - 1304061 A7 _ B7 V. DESCRIPTION OF THE INVENTION (621) Di-W-NMR spectrum (CDC13) 5 (PPm): 3.64 (2H, br s), 6.17 (1H, d, J = 0.8 Hz), 6.67-6.73 (2H, m), 6.77 (1H, br s), 6.89-6.95 (2H, m), 7.14-7.20 ( 1H, m), 7.26-7.32 (2H, m), 7.35-7.41 (2H, m), 8.37 (1H, d, J = 0.8 Hz) 〇 Example 569 N- ( 3 - f 醯 phenyl) -N, (4-(6-aniline-pyrimidine-4-one) methane) urea N-(6-(4-aminophenoxy)pyrimidin-4-yl)aniline (55·6 mg, 0.200 mmol) and (3-methyl phenyl phenyl) phenyl carbamate (63.8 mg, 0·22 〇. mmol) in dimethyl ferrous (1 ml), heated at 85 ° C The reaction solution was dissolved in ethyl acetate and water, and the organic layer was washed with 1N aqueous sodium hydroxide, water and brine, and dried over anhydrous magnesium sulfate. Distillation. The obtained crude product was suspended in ethyl acetate, diluted with hexanes, filtered and washed with hexanes, and then purified by air-dried to the title compound (77.0 mg). , 0· 162 mmol, 8 1 %) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 3.20 (3H, s), 6.07 (1H, s), 6.98-7.03 (1H, m), 7.12 7.17 (2H,m), 7.28-7.34 (2H,m), 7.50-7.63 (6H, m), 7.66-7.72 (1H, m), 8.17-8.20 (1H, m), 8·34 (1H,s ), 8·93 (1H, br s), 9·19 (1H, br s), 9.54 (1H, s) Example 570

Mz__(4-(6-(4-甲硫基笨胺基）嘧啶基氫）宏基W-l其月尿 將N-( 6-(4-胺基苯氧基）嘧啶-4-基）-4-甲硫基苯胺（194 mg，OJOtmmol)及異氰酸苯酯（78.6 mg，0.660 mmol)在二 甲基甲醯胺（2 ml)中，於室溫攪拌18小時。將反應液分溶 _____- 627 - __ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 _______B7 __ 五、發明説明（622) ， 於乙酸乙醋及水中，將有機層用水及飽和食鹽水洗淨及用 無水硫酸鍰乾燥，然後濾去乾燥劑及將濾液減壓蒸餾。將 得到之粗生成物懸浮於乙酸乙酯中，將其用己烷稀釋，濾 取結晶及用己燒洗淨後，藉由通風乾燥，得到為無色結晶 之標題化合物（250 mg，〇·564 mm〇卜94%)。 W-N舰光譜（DMSO-d6)5(ppm): 2.44 (3H，s)，6·〇3 (1H，d， J=1.6 Hz), 6.95-7.00 (1H, m), 7.10-7.15 (2H, m), 7.22-7.32 (4H, m), 7.44-7.50 (2H, m), 7.50-7.60 (4H, m), 8.34 (lH,.d? J=1.6 Hz)，8.73 (1H，br s), 8.81 (1H，br s)，9·56 (1H，s)。 中間體如下述合成。 製造例570- 1 _ ϋζ.(6-(4-硝基笨氣基）哺啶-4-某）-4-甲硫基茉胺 :: • — 將4-氯-6-(4-硝基苯氧基）嘧啶（2·33 g，9.25 mmol)，4-: (甲硫基）苯胺（1.29 g，9.25 mmol)及二異丙基乙胺（1.79 g， 13.9 mmol)在1-甲基吡咯啶酮（1〇 ^1)中，於80°C加熱攪拌 18小時。將反應液分溶於乙酸乙酯及水中，將有機層用in 氫氧化鈉水溶液，水及飽和食鹽水洗淨及用無水硫酸鎂乾 燥，然後濾去乾燥劑及將濾液減壓蒸餾。將得到之粗生成 物付諸於矽凝膠管柱層析（溶出液：乙酸乙酯：己烷: 3)，然後將包含目的物之溶出部分濃縮，懸浮於乙酸乙酯 中，用己烷稀釋，濾取結晶及用己烷洗淨後，藉由通風乾 组’件到為無色結晶之標題化合物（620 mg ’ 1.75 mmol， 19%) 〇 '， W-NMR 光譜（CDCl3)5(Ppm)·· 2.51 (3H，s)，6.28 (1H，d， ____- 628 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）Mz__(4-(6-(4-methylthiophenylamino)pyrimidinyl)hydrogen alkyl Wl, its moon urine will be N-(6-(4-aminophenoxy)pyrimidin-4-yl)-4- Methyl thioaniline (194 mg, OJOtmmol) and phenyl isocyanate (78.6 mg, 0.660 mmol) in dimethylformamide (2 ml) were stirred at room temperature for 18 h. - 627 - __ This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 _______B7 __ V. Invention description (622), using organic layer with water and saturated brine in ethyl acetate and water Washing and drying with anhydrous barium sulfate, then filtering off the desiccant and distilling the filtrate under reduced pressure. The crude product was suspended in ethyl acetate, diluted with hexane, filtered and washed with hexane. After that, the title compound (250 mg, 〇·564 mm 94 94%) was obtained as colorless crystals by air drying. WN ship spectrum (DMSO-d6) 5 (ppm): 2.44 (3H, s), 6· 〇3 (1H,d, J=1.6 Hz), 6.95-7.00 (1H, m), 7.10-7.15 (2H, m), 7.22-7.32 (4H, m), 7.44-7.50 (2H, m), 7.50 -7.60 (4H, m), 8.34 (lH,.d? J=1.6 Hz), 8.73 (1H, br s), 8.81 (1H , br s), 9·56 (1H, s). The intermediate was synthesized as follows. Production Example 570- 1 _ ϋζ. (6-(4-Nitrostyl) acetylene-4-)-4- Methylthiomosamine:: • — 4-chloro-6-(4-nitrophenoxy)pyrimidine (2·33 g, 9.25 mmol), 4-:(methylthio)aniline (1.29 g, 9.25 Methyl) and diisopropylethylamine (1.79 g, 13.9 mmol) in 1-methylpyrrolidone (1 〇^1), stirred at 80 ° C for 18 hours under heating. In the water, the organic layer was washed with aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then the desiccant was filtered off and the filtrate was distilled under reduced pressure. Hose column chromatography (eluent: ethyl acetate: hexane: 3), then the fractions containing the desired material were concentrated, suspended in ethyl acetate, diluted with hexane, filtered and washed with hexane. After that, the title compound (620 mg ' 1.75 mmol, 19%) 〇', W-NMR spectrum (CDCl3) 5 (Ppm)·· 2.51 (3H, s), 6.28 (1H,d, ____- 628 - This paper size applies to China National Standard (CNS) A4 Specification (210 x 297 mm)

裝 訂Binding

線 1304061 A7 B7 五、發明説明（623) 二 J=1.0 Hz), 6.99 (1H, br s)5 7.23-7.34 (6H, m), 8.26-8.32 (2H, m), 8·34 (1H，d，J=1.0 Hz) 〇 製造例570-2 N-(6-(4-胺基苯氧基）嘧啶-驭其）“-甲硫基茉胺 將N-(6-(4-硝基苯氧基）嘧啶-4-基）-4-甲硫基苯胺（620 mg，Γ.75 mmol)，鐵粉（489 mg，8.75 mmol)及氯化銨（936 mg，17·5 mmol)懸浮於乙醇（16 ml) -水（4 ml)之混合溶媒 中，並於80°C加熱攪拌1小時。反應終了後，將反應混舍 物經矽藻土過濾及用乙酸乙酯-四氫呋喃之混合溶媒沖洗。 將有機層用水及飽和食鹽水沖洗，用無水硫酸鎂乾燥，濾 除乾燥劑，將濾液減壓蒸餾，然後將得到之粗生成物懸浮—: 於乙酸乙酯中，然後將其用己烷稀釋，濾取結晶及用己烷，丨 ·· — : 洗淨後，藉由通風乾燥，得到為無色結晶之標題化'合物 (392 mg，1.21 mmol，69%) 〇 W-NMR 光譜（CDCl3)5(ppm): 2.49 (3H，s)，3·65 (2H，br s)， 6·10 (1H，d，J=1.0 Hz)，6·66-6·72 (2H，m)，6·76 (1H，br s)， 6.88-6.94 (2H, m), 7.21-7.30 (4H, m), 8.35 (1H, d, J=l.〇 Hz) 〇 實施例571 N-(3-甲磺醯苯基甲硫某i脖基）嘧啶-4_甚 氧）笨基）脲 &quot; 將N-(6-(4-胺基苯氧基）π密淀-4-基）_心甲硫基苯胺（194 mg，0.601T mmol)及（3-甲基磺醯苯基）胺基甲酸苯酯（192 mg，0.660 mmol)在二甲基亞颯（2 ml)中，於85 °C加熱攪拌 — · 629 - ^紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) '： &quot; ~ 1304061 A7 B7 五、發明説明（624) 1 8小時。將反應液分溶於乙酸乙酯及水中，將有機層用水 及飽和食鹽水洗淨及用無水硫酸鎂乾燥，然後濾去乾燥劑 及將濾液減磨蒸餾。將得到之粗生成物付諸於矽凝膠管柱 層析（溶出液：乙酸乙酯），然後將包含目的物之溶出部分 濃縮，懸浮於乙酸乙酯中，將其用己烷稀釋，濾取結晶及 用己烷洗淨後，藉由通風乾燥，得到為無色結晶之標題化 合物（297 mg，0.569 mmol，95%)。 rH-NMR 光譜（DMSO-d6)5(ppm): 2·44 (3H，s)，3·20 (3H，s)， 6.04 (1Η, d, J=〇.8 Hz), 7.12-7.17 (2H, m), 7.22-7.27 (2H, m), 7-50-7.63 (6H，m)，7.67-7.71 (1H，m)，8.17-8.20 (1H，m)， 8.34 (1H, d, J=〇.8 Hz), 8.92 (1H, s), 9.17 (1H, s), 9.56 (lHr S) 〇 一 · 實施例572 N-(4-( 6-(4-甲磺醯基苯胺基）嘧啶-4-某惫芡某）-N、茇其 m 將N-(4-(6-(4-甲硫基苯胺基）嘧啶-4-基氧）苯基）-N，-苯 基脲（180 mg，0·406 mmol)及3-氣過苯甲酸（200 mg，0.812 mmol)在二氯甲烷（6 ml)中，於室溫攪捽12小時。加入飽和 硫代硫酸鈉水溶液使反應停止後，將反應液分溶於乙酸乙 酯及水中，將有機層用1N氫氧化鈉水溶液，水及飽和食鹽 水洗淨及用無水硫酸鎂乾燥，然後濾去乾燥劑及將濾液減 壓蒸餾。將得到之粗生成物付諸於矽凝膠管柱層析（溶出 液，乙酸匕酿：己·坑=3 : 1)’然後將包含目的物之溶出部 分濃縮，懸浮於乙酸乙酯中，將其用己烷稀釋，濾取結晶 -630 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（625 ) ^ 及用己烷洗淨後，藉由通風乾燥，得到為無色結晶之標題 化合物（137 mg，0.288 mmol，71%)。 W-NMR 光譜（DMSO-d6)5(PPm): 3.16 (3H，s)，6.18 (1H，s)， 6.97-7.02 (1H, m), 7.13-7.19 (2H, m), 7.27-7.33 (2H, m), 7.46-7.51 (2H, m), 7.53-7.59 (2H, m), 7.81-7.87 (2H, m), 7.89-7.94 (2H, m), 8.47 (1H, s), 8.72 (1H, s), 8.81 (1H, s), 10.06 (1H，s)。 實施例573 N-(3-甲磺醯苯基）-Ν’-( 4-(6-(4-甲磺醯茉胺某）嘧啶-4-基 氣）笨基）脹 藉由與實施例572同樣之手法，從N-(3-甲磺醯苯基）-N、 . _ (4-(6-(4-甲硫苯胺基）嘧啶-4-基氧苯基）脲（230 mg，0.441 :: mmol)，得到為無色結晶之標題化合物㈠57 mg，0「284 : mmol，64%) 〇 iH-NMR光譜（DMSO-d6)5(ppm): 3·1ό (3H，s)，3.20 (3H，s)， 6·19 (1Η，d，J=1.0 Ηζ)，7.04-7.10 (2Η，m)，7·50-7·60 (4Η，m)， 7.66-7.70 (1H, m), 7.82-7.88 (2H, m), 7.88-7.94 (2H, m), 8.17-8.20 (1H, m), 8.47 (1H, d, J=l.〇 Hz), 8.95 (1H, s), 9.19 (1H，s)，10.06 (1H，s) 〇 實施例574 1^-(4-(6-(4-氟苯胺基）嘧啶-4-基氣.茱）茉基茉某脲 將N-(4-(6-$Lp密淀-4-基氧）苯基苯基膽（68.0 mg， 0.200 111111«〇4十及4-氟苯胺（111 mg，1·〇〇 mmol)在 1-甲基吡咯’ 啶酮（1 ml)中，於130°C下加熱攪拌3小時。將反應液分溶 -631 · 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂Line 1304061 A7 B7 V. Description of invention (623) II J=1.0 Hz), 6.99 (1H, br s)5 7.23-7.34 (6H, m), 8.26-8.32 (2H, m), 8·34 (1H, d, J=1.0 Hz) 〇Production Example 570-2 N-(6-(4-Aminophenoxy)pyrimidine- oxime) "-Methylthiomosamine" N-(6-(4-nitro) Phenoxypyrimidin-4-yl)-4-methylthioaniline (620 mg, Γ.75 mmol), iron powder (489 mg, 8.75 mmol) and ammonium chloride (936 mg, 17·5 mmol) suspended The mixture was heated and stirred at 80 ° C for 1 hour in a mixed solvent of ethanol (16 ml) - water (4 ml). After the reaction was completed, the reaction mixture was filtered through celite and mixed with ethyl acetate-tetrahydrofuran. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Diluted with hexane, filtered and crystallized from hexanes eluted with hexanes: EtOAc: EtOAc (EtOAc: EtOAc) Spectrum (CDCl3) 5 (ppm): 2.49 (3H, s), 3·65 (2H, br s), 6·10 (1H,d,J=1.0 Hz),6·66-6·72 (2H,m),6·76 (1H,br s), 6.88-6.94 (2H, m), 7.21-7.30 (4H, m ), 8.35 (1H, d, J = l. 〇 Hz) 〇 Example 571 N-(3-methylsulfonylphenylmethylthiol i-lyl)pyrimidine-4_hydrogen) stupid) Urea N-(6-(4-Aminophenoxy) π-amyl-4-yl)-m-methylthioaniline (194 mg, 0.601 T mmol) and (3-methylsulfonylphenyl) carbamic acid Phenyl ester (192 mg, 0.660 mmol) in dimethyl hydrazine (2 ml), heated and stirred at 85 °C - · 629 - ^ paper scale applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) ~: &quot; ~ 1304061 A7 B7 V. Inventive Note (624) 1 8 hours. Dissolve the reaction solution in ethyl acetate and water, wash the organic layer with water and saturated brine and dry over anhydrous magnesium sulfate. Desiccant and de-distillation of the filtrate. The obtained crude product was subjected to hydrazine gel column chromatography (eluent: ethyl acetate), and then the fraction containing the desired substance was concentrated and suspended in ethyl acetate. Diluted with hexane, filtered and washed with hexane, and dried by air. As colorless crystals of the title compound (297 mg, 0.569 mmol, 95%). rH-NMR spectrum (DMSO-d6) 5 (ppm): 2·44 (3H, s), 3·20 (3H, s), 6.04 (1Η, d, J=〇.8 Hz), 7.12-7.17 ( 2H, m), 7.22-7.27 (2H, m), 7-50-7.63 (6H, m), 7.67-7.71 (1H, m), 8.17-8.20 (1H, m), 8.34 (1H, d, J = 〇.8 Hz), 8.92 (1H, s), 9.17 (1H, s), 9.56 (lHr S) 实施1· Example 572 N-(4-( 6-(4-Methanesulfonylphenyl) Pyrimidine-4-one ))-N, 茇其m will be N-(4-(6-(4-methylthioanilino)pyrimidin-4-yloxy)phenyl)-N,-phenylurea (180 mg, 0·406 mmol) and 3-aeroperbenzoic acid (200 mg, 0.812 mmol) in dichloromethane (6 ml), stirred at room temperature for 12 hr. After the reaction was completed, the reaction mixture was dissolved in ethyl acetate and water. The organic layer was washed with 1N aqueous sodium hydroxide, water and brine, and dried over anhydrous magnesium sulfate. The obtained crude product was subjected to gel column chromatography (eluent, acetic acid brewing: hexane·3:1). Then, the dissolved fraction containing the target was concentrated and suspended in ethyl acetate. , will Diluted with hexane, filtered and crystallized -630 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304061 A7 B7 V. Description of invention (625 ) ^ and after washing with hexane, by The title compound (137 mg, 0.288 mmol, 71%) was obtained. -7.02 (1H, m), 7.13-7.19 (2H, m), 7.27-7.33 (2H, m), 7.46-7.51 (2H, m), 7.53-7.59 (2H, m), 7.81-7.87 (2H, m), 7.89-7.94 (2H, m), 8.47 (1H, s), 8.72 (1H, s), 8.81 (1H, s), 10.06 (1H, s). Example 573 N-(3-methane醯Phenyl)-Ν'-(4-(6-(4-methylsulfonyl)-pyrimidin-4-yl) gas) was expanded in the same manner as in Example 572, from N-(3) -Methanesulfonyl phenyl)-N, . _ (4-(6-(4-methylthioanilino)pyrimidin-4-yloxyphenyl)urea (230 mg, 0.441::mmol) afforded as colorless crystal Title Compound (I) 57 mg, 0 "284: mmol, 64%" 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 3·1ό (3H, s), 3.20 (3H, s), 6·19 ( 1Η, d, J=1.0 Ηζ), 7.04-7.10 (2Η, m), 7·50-7·60 (4 Η,m), 7.66-7.70 (1H, m), 7.82-7.88 (2H, m), 7.88-7.94 (2H, m), 8.17-8.20 (1H, m), 8.47 (1H, d, J=l .〇Hz), 8.95 (1H, s), 9.19 (1H, s), 10.06 (1H, s) 〇 Example 574 1^-(4-(6-(4-fluoroanilino)pyrimidin-4-yl茱.)) Methyl uranyl urea will be N-(4-(6-$Lp-dense-4-yloxy)phenyl phenyl choline (68.0 mg, 0.200 111111 «〇4 and 4-fluoroaniline (111 Mg, 1·〇〇mmol) was stirred and heated at 130 ° C for 3 hours in 1-methylpyrrole's ketone (1 ml). Dissolve the reaction solution -631 · This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm).

線 1304061 A7 - B7_ 五、發月(—— 於乙酸乙酯及水中，有機層用飽和碳酸氫鈉水溶液、水及 飽和食鹽水洗淨，用無水硫酸鎂乾燥，濾除乾燥劑，以及 將滤液減壓餾去。將得到之粗生成物懸浮於乙酸乙酯中， 再將其以己烷稀釋，濾取結晶及用己烷洗淨後，藉由通風 乾燥’得到為無色結晶之標題化合物（33.〇 mg，〇 ()79 mmol ·，40%) 〇 H-NMR 光 if(DMSO-d6)5(ppm): 6·00 (1H，d，J=〇,8 Hz) 6.95^7.00 (1H, m), 7.10-7.19 (4H, m), 7.26-7.32 (2H, m), 7.44-7.50 (2H, m), 7.50-7.56 (2H, m), 7.57-7.63 (2H, m), 8.33 (1H, d, J=0.8 Hz), 8.68 (1H, s), 8.76 (1H, s), 9.56 (1H s) 〇 ’ 中間體係以下述方法合成。 1造例 574- 1 一 iill&quot;氯嘧啶-4-基氣某）苯脉 將4-氯-6-(4-硝苯氧基）嘧啶（2·52 g，1〇 〇 mm〇i)、鐵粉 (2.79 g，50.0 mmol)及氯化銨（5·35 g，1〇〇 mm〇1)懸浮於乙 醇（100 ml)-水（25 ml)之混合溶媒中，在8〇它加熱攪拌“、 時。反應終了後，以矽藻土過濾反應混合物，用乙醇_乙酸 乙酯之混合溶媒清洗。將有機層用水及飽和食鹽水洗淨， 用無水硫酸鎂乾燥，濾除乾燥劑，以及將濾液減壓餾去。 將得到之粗生成物付諸於矽凝膠管柱層析（溶出液為乙酸乙 酯：己烷=2 ·· 3)，再將含有目的物之溶出份濃縮，得到為. 播色結晶之福題-化合物（1.74 mg , 7.85 mmo卜79%)。 lH-NMR^lf(CDCl3)5(ppm)： 3.71 (2H, br s)5 6.70-6.75 (2H,Line 1304061 A7 - B7_ V., the month of the month (- in ethyl acetate and water, the organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, filtered The title compound was obtained as a colorless crystals (yield of EtOAc). 33. 〇mg, 〇 () 79 mmol ·, 40%) 〇H-NMR light if (DMSO-d6) 5 (ppm): 6·00 (1H, d, J = 〇, 8 Hz) 6.95^7.00 ( 1H, m), 7.10-7.19 (4H, m), 7.26-7.32 (2H, m), 7.44-7.50 (2H, m), 7.50-7.56 (2H, m), 7.57-7.63 (2H, m), 8.33 (1H, d, J=0.8 Hz), 8.68 (1H, s), 8.76 (1H, s), 9.56 (1H s) 〇' The intermediate system is synthesized as follows: 1 574- 1 Iil&quot; Pyrimidine-4-yl gas) benzophenone 4-chloro-6-(4-nitrophenoxy)pyrimidine (2·52 g, 1〇〇mm〇i), iron powder (2.79 g, 50.0 mmol) and Ammonium chloride (5·35 g, 1〇〇mm〇1) was suspended in a mixed solvent of ethanol (100 ml)-water (25 ml), and it was heated and stirred at 8 °. After the reaction is completed, the reaction mixture is filtered with celite, and washed with a mixture of ethanol and ethyl acetate. The organic layer is washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated The obtained crude product was subjected to column chromatography on a gel column (ethyl acetate: hexane = 2 · · 3), and the fractions containing the desired product were concentrated to obtain a mixture. The so-called crystallization crystals - compound (1.74 mg, 7.85 mmo, 79%). lH-NMR^lf(CDCl3)5 (ppm): 3.71 (2H, br s)5 6.70-6.75 (2H,

1304061 A7 B71304061 A7 B7

m)，6·84 (1H，s)，6.90-6.95 (2H，m)，8·60 (1H，s)。 製造例574-2 ϋι·( 4- ( 6-氣嘧啶-4-基氣）茇某）-N，-茇其 將4-(6-氯嘧哫-4-基氧）苯胺（663 mg , 3.00 mmol)及異氰 酸苯酯（393 mg，3·30 mmol)在二甲基甲醯胺（5 ml)中，於 主溫下攪:拌18小時。將反應液注入水中，濾取析出之結 晶，用水及乙醇洗淨後，藉由通風乾燥，得到為無色結晶 之標題化合物（988 mg，2.91 mmol，97%)。 H-NMR 光譜（〇^480纏(16)5(??111):6.94-7.〇〇(111，111)，7.14- 7.20 (2H, m), 7.25-7.32 (2H, m), 7.33 (1H, d, J=0.8 Hz), 7.43-7.49 (2H, m), 7.50-7.56 (2H, m), 8.65 (1H, d, J=0.8 H^), 8.70 (1H, s)，8.78 (1H，s)。 實施例575 — K..4- ( 6- ( 3-氟苯胺基）嘧啶-4-基氣）茉某）-n，-芡甚輝 將N-(4-(6-^c喃淀-4-基乳）苯基）_N’_苯基膽（68.0 mg， 0·200 mmol)及3-氟苯胺（111 mg，ι·〇〇瓜则”在^甲基吡咯 淀酮（1 ml)中，於150°C下加熱攪拌90分鐘。將反應液分溶 於乙酸乙酯及水中，有機層用飽和碳酸氫鋼水溶液、水及 飽和食鹽水洗淨，用無水硫酸鎂乾燥，濾除乾燥劑，以及 將濾液減壓餾去。將得到之粗生成物懸浮於乙酸乙酯中， 再將其以己烷稀釋，濾取結晶及用己烷洗淨後，藉由通風 乾燥，得到為無色結晶之標題化合物（43.0 mg，0.104 mmol » 51%-) iH-NMR 光譜（DMSO-d6)5(ppm): 6.09 (1H，s)，6·77-6·83 (1H， I_____- 633 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 ___ B7 五、發明説明（628) 二、 m)，6.95-7.00 (1H，m)，7.11-7.17 (2H，m)，7.26-7.36 (4H，m)， 7.45- 7.50 (2H，m)，7.50-7.55 (2H，m)，7·71-7·77 (1H，m)， 8·42 (1H，s)，8.69 (1H，s)，8·77 (1H，s)，9.76 (1H，s)。 實施例576 氟苯胺基）喃淀·4_基氣某）笨基W -策某月辱 將N、（4-(6-氣嘧啶-4-基氧）苯基^Ν1-苯基脲（68.0 mg， 0.200 mmol)及 2 -氟苯胺（ill mg，1.00 mmol)在 1 -甲基峨嘻 啶酮（1 ml)中，於170°C下加熱攪拌3小時。將反應液分溶 於乙酸乙酯及水中，有機層用飽和碳酸氫鈉水溶液、水及： 飽和食鹽水洗淨，用無水硫酸鎂乾燥，濾除乾燥劑，以及 將濾液減壓館去。將得到之粗生成物付諸於矽凝膠管柱層 析（〉谷出液為乙酸乙S旨·己燒=3 : 2) ’再將含有目的物之溶 一 出份濃縮，懸浮於乙酸乙醋中，再將其以己燒稀釋，，歲取νΐ-結晶及用己烷洗淨後，藉由通風乾燥，得到為無色結晶之 標題化合物（26.0 mg，0·062 mmol，31%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 6.17 (1H，d，】=〇·8 Hz)， 6.95-7.00 (1H, m), 7.10-7.19 (4H, m), 7.22-7.32 (3H, m), 7.45- 7.50 (2H，m)，7.50-7.55 (2H，m)，7.86-7.93 (1H，m)， 8·29 (1H，d，J=0.8 Hz)，8.60 (1H，s)，8·76 (1H，s)，9.32 (1H， s) ° 實施例577 一、 N-(4-(6-(3,5-二氟苯胺基）嘧啶-4-基氣）苯某-苯岑脲 *N-(‘(合-氯成啶-4-基氧）苯基）-N’-苯基脲（68.0 mg， 一 0.200 mmol)及 3，5 -二氟苯胺（129 mg，1 ·00 mmol)在 1 -甲基 _- 634 -_______ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7m), 6.84 (1H, s), 6.90-6.95 (2H, m), 8.60 (1H, s). Production example 574-2 ϋι·(4-(6-amphetypyrimidin-4-yl) 茇)-N,-茇 which will be 4-(6-chloropyrimidin-4-yloxy)aniline (663 mg, 3.00 mmol) and phenyl isocyanate (393 mg, 3.30 mmol) in dimethylformamide (5 ml), stir at the main temperature: mix for 18 hours. The reaction mixture was poured into water, and the crystals crystals crystals crystals crystals crystals crystals crystal H-NMR spectrum (〇^480 entanglement (16) 5 (?? 111): 6.94-7. 〇〇 (111, 111), 7.14- 7.20 (2H, m), 7.25-7.32 (2H, m), 7.33 (1H, d, J=0.8 Hz), 7.43-7.49 (2H, m), 7.50-7.56 (2H, m), 8.65 (1H, d, J=0.8 H^), 8.70 (1H, s), 8.78 (1H, s). Example 575 - K..4-(6-(3-Fluoroanilino)pyrimidin-4-yl gas)Mothium)-n,-芡芡辉 will N-(4-(6 -^c 喃-4-yl milk)phenyl)_N'_phenyl choline (68.0 mg, 0·200 mmol) and 3-fluoroaniline (111 mg, ι·〇〇瓜则” in ^methylpyrrole The mixture was heated and stirred at 150 ° C for 90 minutes in the decyl ketone (1 ml). The reaction solution was dissolved in ethyl acetate and water, and the organic layer was washed with saturated aqueous solution of hydrogencarbonate, water and saturated brine. The magnesium is dried, the desiccant is filtered off, and the filtrate is distilled off under reduced pressure. The obtained crude product is suspended in ethyl acetate, and then diluted with hexane, filtered and washed with hexane. The title compound was obtained as a colorless crystals (43.0 mg, 0.104 mmol, 51%). NMR NMR (DMSO-d6) 5 (ppm): 6.09 (1H, s), 6.77-6·83 ( 1H, I_____- 633 - Ben The scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 ___ B7 V. Description of invention (628) II. m), 6.95-7.00 (1H, m), 7.11-7.17 (2H, m ), 7.26-7.36 (4H, m), 7.45- 7.50 (2H, m), 7.50-7.55 (2H, m), 7·71-7·77 (1H, m), 8·42 (1H, s) , 8.69 (1H, s), 8.77 (1H, s), 9.76 (1H, s). Example 576 fluoroanilinyl) sulphate · 4 _ qi a) stupid base W - policy a month will be N , (4-(6-amphazin-4-yloxy)phenyl)-phenylurea (68.0 mg, 0.200 mmol) and 2-fluoroaniline (ill mg, 1.00 mmol) in 1-methylacridine The ketone (1 ml) was stirred and heated at 170 ° C for 3 hours. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and brine. The magnesium is dried, the desiccant is filtered off, and the filtrate is depressurized. The obtained crude product is subjected to hydrazine gel column chromatography (> the effluent is acetic acid B S. hexane = 3: 2) 'The concentrate containing the target substance is concentrated and suspended in acetic acid The title compound (26.0 mg, 0.062 mmol, 31%) was obtained as a colorless crystals. . iH-NMR spectrum (DMSO-d6) 5 (ppm): 6.17 (1H,d,]=〇·8 Hz), 6.95-7.00 (1H, m), 7.10-7.19 (4H, m), 7.22-7.32 ( 3H, m), 7.45- 7.50 (2H, m), 7.50-7.55 (2H, m), 7.86-7.93 (1H, m), 8·29 (1H, d, J = 0.8 Hz), 8.60 (1H, s), 8.76 (1H, s), 9.32 (1H, s) ° Example 577 1. N-(4-(6-(3,5-difluoroanilino)pyrimidin-4-yl)benzene Benzylurea*N-('(-chloro-acridin-4-yloxy)phenyl)-N'-phenylurea (68.0 mg, a 0.200 mmol) and 3,5-difluoroaniline (129 Mg,1 ·00 mmol) at 1-methyl_- 634 -_______ This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304061 A7 B7

叶匕嘻啶酮（1 ml)中，於170°C下加熱攪拌3小時。將反應液 分溶於乙酸乙酯及水中，有機層用飽和碳酸氫鈉水溶液、 水及飽和食鹽水洗淨，用無水硫酸鎂乾燥，濾除乾燥劑， 以及將濾液減壓餾去。將得到之粗生成物付諸於矽凝膠管 柱層析（溶出液為乙酸乙g旨：己燒=1 : 1)，再將含有目的物 之溶出份濃縮，懸浮於乙酸乙酯中，再將其以己燒稀釋， 濾取結晶及用己烷洗淨後，藉由通風乾燥，得到為無色結 晶之標題化合物（17.5 mg，0.040 mmol，20%)。 H-NMR 光譜（DMSO-d6)5(ppm): 6·09 (1H，s)，6.77-6.85 (1H， m)，6.95-7.00 (1Η，m)，7.13-7.19 (2Η，m)，7·27·7·33 (2Η，m)， 7.38-7.50 (4H，m)，7.50-7.58 (2H，m)，8.46 (1H，s)，8·69 (1H， s)，8.78 (1H，s)，9·94 (1H，s)。 實施例578 — : 苯基-Ν·-(4-(6-Γ3,4,5-三甲氣笨胺基）嘧啶_4-基氲）茇甚、 脲鹽酸鹽 將N-(4-(6-氯嘧啶-4-基氧基）苯基）-N，-苯基脲（68.0 mg，0.200 mmol)及 3,4,5-三甲氧基苯胺（183 mg , 1.00 mmol)在1-甲基吡咯啶酮（1 ^1)中，於150°C下加熱攪拌2小 時。將反應液分溶於乙酸乙酯及水中，有機層用飽和碳酸 氫納水溶液、水及飽和食鹽水洗淨，用無水硫酸鍰乾燥， 濾除乾燥劑，以及將濾液減壓餾去。將得到之粗生成物付 諸於矽凝膠管柱層析（溶出液為乙酸乙酯：己烷=3:丨），再 將含有目·妁凇之溶出份濃縮，使用1N-鹽酸製成鹽酸鹽後， 懸浮於甲醇中，再將其以乙酸乙酯稀釋，濾取結晶及用乙 -635 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇 X 297公釐） 1304061 A7 B7 五、發明説明（63〇) 酸乙酯洗淨後，藉由通風乾燥，得到為淡綠色結晶之標題 化合物（50.0 mg，0.095 mmol，48%)。 H-：NMR 光請（DMSO-d6)5(ppm): 3·61 (3H，s)，3·74 (6H，s)， 6.03 (1Η，s)，6.90 (2Η，s)，6·95-7·00 (1Η，m)，7.10-7.16 (2Η， m)，7.27-7.33 (2H，m)，7.45-7.50 (2H，m)，7.50-7.55 (2H，m)， 8·36 (1H，s)，8.91 (1H，s)，9.02 (1H，S)，9·55 (1H，s)。 實施例579 將N-(4-(6-氧嘧啶_心基氧）苯基卜N、苯基脲（68 〇 mg 0.200 mmol)及N-甲基苯胺（1〇7 mg，1〇〇 _〇1)在丨甲基吡 洛淀酮（1 ml)中，於13(rc下加熱攪掉36小時。將反應液分 溶於乙酸乙酯及水中，有機層用水及飽和食鹽水洗淨，用V 無水硫酸鎂乾燥，濾除乾燥劑，以及將濾液減壓餾去^將-:妄 得到之粗生成物付諸於矽凝膠管柱層析（溶出液為乙酸乙 酯：己烷=1 : D，再將含有目的物之溶出份濃縮，懸浮於 乙酸乙酯巾，再將其以己烷稀釋，濾取結晶及用己烷洗淨 後，藉由通風乾燥，得到為無色結晶之標題化合物（38 mg，0.092 mmol，46%) 〇 H-NMR 光 if(DMSO-d6)5(ppm): 3.42 (3H，s)，5.75 (1H，s)， 6.95-7.03 (3H, m), 7.25-7.38 (5H, m), 7.41^.50 (6H, m), 8.27 (1H，s)，8·64 (1H，s)，8.68 (1H，s)。 實施例580 喹啉基）氧氯茇甚）fl尿 ____- 636 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 B7 五、發明説明（631) 藉由實施例145同樣之方法，從4-(4-胺基-3-氟苯氧基）-6 -氰基- 7-(2-甲氧乙氧基）峻淋（71.0 mg，0.200 mmol)，以 及由2-胺基-5-氯噻唑及氣甲酸苯酯調製之5-氯-2〃塞唑基 胺甲酸冬醋’得到為白色結晶之標題化合物（66.0 mg， 0·128 mmol，64%) 0 iH-NMR 光譜（DMSO-d6)5(ppm): 3.38 (3H，s)，3.80 (2H，m)， 4.43 (2H，m)，6.65 (1H，d，J=5.2 Hz)，7.20 (1H，m)，7.44 (1H， s)，7·47.(1Η，m)，7·66 (1H，s)，8.20 (1H，m)，8·76 (1H，d， J=5.2 Hz)，8.77 (1H，s)，9·02 (1H，s)，11.01 (ih，s)。 實施例581 N二.14-.(6-氰基-7-(2-甲氧k氧基）-4二^ P見基）氣-2_f芡篡v_ W 4-環丙基-2-違唑某）月展 藉由與貫施例145同樣之方法’從4-(4-胺基·3_氣苯氧 基）-6-氰基-7-(2-甲氧乙氧基）喹啉（71〇 mg , 〇 2⑼ mmol)，以及由2-胺基-4-環丙基嘍唑及氣甲酸苯酯調製之 4-環丙基-2-噻唑基胺甲酸苯醋，得到為白色結晶之標題化 合物（88·0 mg，0.169 mmol，85%)。 W-NMR 光譜（DMS〇-d6H(Ppm): 0.75 (2H，m)，〇 84 (2H，⑷， 1.95 (1H，m)，3·38 (3H，s)，3.80 (2H，m)，4·44 (2H 6·64 (1H，d，】=5·2 Hz)，6.72 (1H，s)，7·19 (1H，m)，7 46’（m，⑷， 7.66 (1H，s)，8.25 (1H，m)，8·76 (1H，d，j&gt;5 2 Hz) 8 77 (1H s)，10.84 (1H，br s)。 ’ 實施例582-” 4-(β-氣_4-(f胺羰某）胺苯氧棊）·7_甲杏啉斿醯胺 -637 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 ---- - B7 五、發明説明（啦） 二， 藉由與實施例1 1同樣之方法，從N- ( 4_ ( 6_胺甲醯基_ 7-甲 氧基-4-喹琳基）氧-2·氣苯基）胺甲酸苯酯（15〇 ，〇 324 mmol)及40%甲胺（甲醇溶液），得到為白色結晶之標題化合 物（65.0 mg，0.162 mmol，50%)。 h-nmr 光譜（DMSO-d6)5(ppm): 2 68 (3H，d，J=4 4 Hz)， 4·〇3 (3H，s)，6.53 (1H，d，J=5.0 Hz)，6.88 (1H，q，J=4.4 Hz)， 7.23 (1H, dd, J=2.8, 8.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.52 (1H，s)，7·74 (1H，s)，7·86 (1H，s)，8.12 (1H，s)，8·25 (1H，d， J=8.2 Hz)，8.67 (1H，s)，8·68 (1H，d，J=5.0 Hz)。 實施例583 氣-4-(乙胺羰基）胺苯氧基甲氣基奎啉羧醯胺 藉由與實施例11同樣之方法，從N-(4-(6-胺甲醯基-7-甲&lt; 氧基-4-喹啉基）氧-2-氯苯基）胺甲酸苯酯（150 mg，0V324 mmol)，及2M乙胺（四氫呋喃溶液），得到為白色結晶之標 題化合物（92.0 mg，0.221 mmol，68%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 1.08 (3H，t，J=7.2 Hz)， 3.14 (2H, m), 4.03 (3H, s), 6.53 (1H, d, J=5.2 Hz), 6.99 (1H, t，J=5.6 Hz), 7·23 (1H，dd，J=2.8, 8.8 Hz)，7.48 (1H，d，J=2.8 Hz)，7·52 (1H，s)，7.73 (1H，s)，7.85 (1H，s)，8·07 (1H，s)， 8.27 (1H, d, J=8.8 Hz), 8.66 (1H, s), 8.67 (1H, d, J=5.2 Hz) 〇 實施例584 4-(3-氣-HI，丙胺羰基）胺苯氣基）-7-甲氣基-6-喳啉藉醯 霞 -638 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公爱) 1304061 A7 ___ B7 五、發明説明(~~~) 藉由與實施例11同樣之方法，從N-(4-(6-胺甲醯基-7-甲 氧基-4-喹淋基）氧-2-氯苯基）胺甲酸苯酯（150 mg，0.324 mmol)及丙胺，得到為白色結晶之標題化合物（i i i mg， 0.258 mmol » 80%) 0 W-NMR 光譜（DMSO-d6)5(ppm): 0.91 (3H，t，J=7.4 Hz)， 1·47 (2H，m)，3.08 (2H，m)，4.03 (3H，s)，6.53 (1H，d，J=5.2 Hz)，7·03 (1H，t，J=5.6 Hz)，7.23 (1H，dd，J=2.8, 8.8 Hz)， 7.48 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.74 (1H, s), 7.85 (1H, s), 8.09 (1H, s), 8.28 (1H, d, J=8.8 Hz), 8.66 (1H, s), 8.67 (1H，d，J=5.2 Hz) o 實施例585The leaf acridone (1 ml) was stirred with heating at 170 ° C for 3 hours. The reaction mixture was dissolved in ethyl acetate and water, and then evaporated, evaporated, evaporated. The obtained crude product was subjected to column chromatography on a gel column (the eluate was acetic acid, hexane: 1:1), and the fraction containing the desired product was concentrated and suspended in ethyl acetate. The title compound (17.5 mg, 0.040 mmol, 20%) was obtained as a colorless crystals. H-NMR spectrum (DMSO-d6) 5 (ppm): 6·09 (1H, s), 6.77-6.85 (1H, m), 6.95-7.00 (1Η, m), 7.13-7.19 (2Η, m), 7·27·7·33 (2Η,m), 7.38-7.50 (4H,m), 7.50-7.58 (2H,m),8.46 (1H,s),8·69 (1H, s), 8.78 (1H , s), 9.94 (1H, s). Example 578 — : Phenyl-indole-(4-(6-Γ3,4,5-trimethylsulfamoylamino)pyrimidine-4-ylindole), uranyl hydrochloride, N-(4-( 6-chloropyrimidin-4-yloxy)phenyl)-N,-phenylurea (68.0 mg, 0.200 mmol) and 3,4,5-trimethoxyaniline (183 mg, 1.00 mmol) in 1-A The pyrrolidone (1 ^ 1) was stirred with heating at 150 ° C for 2 hours. The reaction mixture was dissolved in ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. The obtained crude product was subjected to hydrazine gel column chromatography (eluent is ethyl acetate: hexane = 3: hydrazine), and the dissolved fraction containing hydrazine was concentrated and made of 1N-hydrochloric acid. After the hydrochloride, it is suspended in methanol, and then diluted with ethyl acetate. The crystals are collected by filtration and applied to the standard of China National Standard (CNS) A4 (21〇X 297 mm) 1304061 A7. B7 V. Inventive Note (63 〇) After washing with ethyl acetate, the title compound (50.0 mg, 0.095 mmol, 48%) was obtained as pale green crystals. H-: NMR light (DMSO-d6) 5 (ppm): 3·61 (3H, s), 3.74 (6H, s), 6.03 (1Η, s), 6.90 (2Η, s), 6· 95-7·00 (1Η, m), 7.10-7.16 (2Η, m), 7.27-7.33 (2H, m), 7.45-7.50 (2H, m), 7.50-7.55 (2H, m), 8.36 (1H, s), 8.91 (1H, s), 9.02 (1H, S), 9·55 (1H, s). Example 579 N-(4-(6-oxopyrimidine-cardioyloxy)phenyl b N, phenylurea (68 mg mg 0.200 mmol) and N-methylaniline (1〇7 mg, 1〇〇_ 〇1) In 丨methylpyrrolidone (1 ml), it was stirred for 36 hours under heating at 13 (rc). The reaction solution was dissolved in ethyl acetate and water, and the organic layer was washed with water and saturated brine. Drying with V anhydrous magnesium sulfate, filtering off the desiccant, and distilling off the filtrate under reduced pressure. The crude product obtained by -: hydrazine was applied to a gel column chromatography (eluent was ethyl acetate: hexane = 1 : D, the concentrate containing the target substance was concentrated, suspended in an ethyl acetate towel, and diluted with hexane, and the crystals were collected by filtration and washed with hexane, and then dried by air to obtain colorless crystals. The title compound (38 mg, 0.092 mmol, 46%) 〇H-NMR light if (DMSO-d6) 5 (ppm): 3.42 (3H, s), 5.75 (1H, s), 6.95-7.03 (3H, m) , 7.25-7.38 (5H, m), 7.41^.50 (6H, m), 8.27 (1H, s), 8.64 (1H, s), 8.68 (1H, s). Example 580 quinolinyl) Oxychloride 茇 ) flu ____ _ 636 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 B7 V. INSTRUCTION DESCRIPTION (631) From the same procedure as in Example 145, from 4-(4-amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy) Base) (71.0 mg, 0.200 mmol), and 5-chloro-2 oxazolylamine carboxylic acid winter vinegar prepared from 2-amino-5-chlorothiazole and phenyl benzoate to give the title of white crystal (66.0 mg, 0·128 mmol, 64%). (1H,d,J=5.2 Hz), 7.20 (1H,m), 7.44 (1H, s),7·47.(1Η,m),7·66 (1H,s),8.20 (1H,m) , 8.76 (1H, d, J = 5.2 Hz), 8.77 (1H, s), 9·02 (1H, s), 11.01 (ih, s). Example 581 N.14-. (6- Cyano-7-(2-methoxykoxy)-4di^P-based) gas-2_f芡篡v_W 4-cyclopropyl-2-indiazole) monthly exhibition by means of 145 The same method 'from 4-(4-amino-3-phenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (71 mg, 〇2 (9) mmol), and 4-cyclopropyl-2-thiazolylamine benzene vinegar prepared from 2-amino-4-cyclopropylcarbazole and phenyl benzoate, obtained as white The title compound of color crystals (88·0 mg, 0.169 mmol, 85%). W-NMR spectrum (DMS 〇-d6H (Ppm): 0.75 (2H, m), 〇84 (2H, (4), 1.95 (1H, m), 3·38 (3H, s), 3.80 (2H, m), 4·44 (2H 6·64 (1H,d,]=5·2 Hz), 6.72 (1H, s), 7·19 (1H, m), 7 46'(m,(4), 7.66 (1H,s ), 8.25 (1H, m), 8.76 (1H, d, j &gt; 5 2 Hz) 8 77 (1H s), 10.84 (1H, br s). 'Example 582-' 4-(β-gas _4-(f-aminocarbonyl) phenoxy oxime)·7_methyl apricotine decylamine-637 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 --- - - B7 V. Inventive Note (2) Second, by the same method as in Example 11, from N-(4-(6-aminocarbamimidyl-7-methoxy-4-quinolinyl)oxy- The title compound (65.0 mg, 0.162 mmol, 50%) was obtained as white crystals. mp mp. (DMSO-d6) 5 (ppm): 2 68 (3H, d, J = 4 4 Hz), 4·〇3 (3H, s), 6.53 (1H, d, J = 5.0 Hz), 6.88 (1H, q, J=4.4 Hz), 7.23 (1H, dd, J=2.8, 8.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7·74 ( 1H, s), 7·86 (1H, s), 8.12 (1H, s), 8·25 (1H, d, J = 8.2 Hz), 8.67 (1H, s), 8.68 (1H, d, J = 5.0 Hz). Example 583 gas-4-(ethylamine carbonyl)amine phenoxymethyl quinolate carboxy oxime amide from N-(4-(6-amine) in the same manner as in Example 11. Phenylmethyl-7-methyl&lt;oxy-4-quinolinyl)oxy-2-chlorophenyl)carbamate (150 mg, 0 V 324 mmol), and 2M ethylamine (tetrahydrofuran) The title compound was crystallized (92.0 mg, 0.221 mmol, 68%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.08 (3H, t, J = 7.2 Hz), 3.14 (2H, m), 4.03 ( 3H, s), 6.53 (1H, d, J=5.2 Hz), 6.99 (1H, t, J=5.6 Hz), 7·23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d , J=2.8 Hz), 7·52 (1H, s), 7.73 (1H, s), 7.85 (1H, s), 8.07 (1H, s), 8.27 (1H, d, J=8.8 Hz) , 8.66 (1H, s), 8.67 (1H, d, J = 5.2 Hz) 〇 Example 584 4-(3-Gas-HI, propylamine carbonyl)amine benzene)-7-Methane-6-oxime Porphyrin by Xiaxia-638 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 public) 1304061 A7 ___ B7 V. Invention description (~~~) by Example 11 in the same manner as phenyl N-(4-(6-aminomethylamido-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (150 mg, 0.324 The title compound (iii mg, 0.258 mmol, 80%) was obtained as white crystals. mp NMR (DMSO-d6) 5 (ppm): 0.91 (3H, t, J = 7.4 Hz), 1 · 47 (2H, m), 3.08 (2H, m), 4.03 (3H, s), 6.53 (1H, d, J = 5.2 Hz), 7·03 (1H, t, J = 5.6 Hz), 7.23 ( 1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.74 (1H, s), 7.85 (1H, s), 8.09 (1H, s ), 8.28 (1H, d, J = 8.8 Hz), 8.66 (1H, s), 8.67 (1H, d, J = 5.2 Hz) o Example 585

藉由與實施例11同樣之方法，從N_(4_(6_胺甲醯基_7_甲 氧基-4-喹啉基）氧-2-氯苯基）胺甲酸苯酯（15〇 mg , 〇.324 mmol)，及2-胺基乙腈鹽酸鹽，得到為白色結晶之標題化合 物（107 mg，0.251 mmol，77%)。 iH-NMR光譜（DMSO-d6)5(Ppm): 4·03 (3H，s)，（22 (2h 丈 J=6.0 Hz), 6.56 (1H, d, J=5.2 Hz), 7.28 (1H, dd, J=2.8 8 8 Hz), 7.50 (1H, t, 1=6.0 Hz), 7.53 (lH, s), 7.54 (1H, d J=2 8From the same procedure as in Example 11, phenyl N-(4-(6-aminocarbazinyl-7-methoxy-4-quinolinyl)oxy-2-chlorophenyl)aminecarboxylate (15 mg) The title compound (107 mg, 0.251 mmol, 77%). iH-NMR spectrum (DMSO-d6) 5 (Ppm): 4·03 (3H, s), (22 (2h J = 6.0 Hz), 6.56 (1H, d, J = 5.2 Hz), 7.28 (1H, Dd, J=2.8 8 8 Hz), 7.50 (1H, t, 1=6.0 Hz), 7.53 (lH, s), 7.54 (1H, d J=2 8

Hz), 7.74 (1H, s), 7.86 (1H, s), 8.17 (1H, d, J=8.8 8.51 (1H，s)，8.66 (1H，s), 8.68 (1H，d，J=5.2 Hz)。 ’ 實施例58T5·-'·- U_3_-氣-4-(2-氣乙胺幾基）胺苯 __- 639 - I紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) &quot;' ________ 1304061 A7 ______ 57 五、發明説明（634) 醯胺— 藉由與實施例11同樣之方法，從N-(4-(6-胺甲醯基-7-甲 氧基-心喹啉基）氧-2-氯苯基）胺甲酸苯酯（150 mg，0.324 mmol)及3 -胺基丙腈，得到為白色結晶之標題化合物（1 〇9 mg，0.248 mmol，76%)。 iH-NMR 光譜（DMSO-d6)5(PPm): 2.72 (2H，t，J=6.4 Hz)， 3.41 (2H, m), 4.03 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.25 (1H, dd，J=2.8, 8·8 Hz)，7·37 (1H，t，J=6.0 Hz)，7.50 (1H，d，J=2.8Hz), 7.74 (1H, s), 7.86 (1H, s), 8.17 (1H, d, J=8.8 8.51 (1H, s), 8.66 (1H, s), 8.68 (1H,d,J=5.2 Hz Example 58T5·-'·- U_3_-Ga-4-(2-Acetoamine) Alkylbenzene__- 639 - I Paper scale applicable to China National Standard (CNS) A4 specification (210X 297 mm) &quot;' ________ 1304061 A7 _________ 57 V. INSTRUCTION DESCRIPTION (634) Indoleamine - N-(4-(6-aminocarbazinyl-7-methoxy-heart) by the same method as in Example 11. Benzyl quinolinyloxy-2-chlorophenyl)carbamate (150 mg, 0.324 mmol) and 3-aminopropionitrile as the title compound (1 〇9 mg, 0.248 mmol, 76%) iH-NMR spectrum (DMSO-d6) 5 (PPm): 2.72 (2H, t, J = 6.4 Hz), 3.41 (2H, m), 4.03 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.25 (1H, dd, J=2.8, 8·8 Hz), 7·37 (1H, t, J=6.0 Hz), 7.50 (1H, d, J=2.8

Hz), 7.52 (1H, s), 7.74 (1H, s), 7.86 (1H, s), 8.24 (1H? d, J=8.8 Hz)，8.31 (1H，s)，8.66 (lH，.s)，8.67 (1H，d，J=5.2 Hz) 〇 . 實施例589 izlir氯-4_ Γ順式-2-氟-環丙胺羰基）胺苯氳某[7-甲H L p奎淋# gil胺 藉由與實施例11同樣之方法，從N-(4-(6-胺甲醯基-7-甲 氧基-4-喹啉基）氧-2-氯苯基）胺甲酸苯酯（15〇 mg，0.324 mmol)，及順式-2·氟環丙胺甲苯磺酸鹽，得到為白色結晶 之標題化合物（39.0 mg，0.088 mmol，27%)。 ^-NMR 光譜（DMSO-d6)5(ppm): 0.82 (1H，m)，1.11 (1H，πι)， 2.68 (1H，m)，4.04 (3H，s)，4·78 (1H，m)，6·54 (1H，d，J=5.2 Hz)，7.25 (1H，dd，J=2.8，8·8 Hz)，7.32 (1H，d，J=3.6 Hz)， 7.50 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.74 (1H, s), 7.86 (1H, s), 8.25 (i-H； s), 8.29 (1H, d, J=8.8 Hz), 8.66 (1H, s), 8.67 (1H，d，J=5.2 Hz)。 _- 640 - 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐） 1304061 A7 B7 五、發明説明（635) : 實施例590 4- ( 3 -氯-4-(胺談基）胺笨氣基）-7-甲氣基_ 6- 4淋# g盘脖 藉由與貫施例11同樣之方法，從N-(4-(6 -胺甲醯基_7_甲 氧基-4- 4淋基）氧-2-氯苯基）胺甲酸苯酯（100 mg , 0.22 mmol)，及氨水（2毫升），得到為淡紅色結晶之標題化合物 (61.0 mg，79%)。 iH-NMR 光譜（DMSO-d6)(J (ppm): 4·01 (3H，s)，ό·41 (2H，s)， 6.51 (1H, d, J=5.2 Hz), 7.21 (1H, d5 J=9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.73 (1H, s), 7.84 (1H, s), 8.15 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.65 (1H, d, J=5.2 Hz), 8.66 (1H, s)。 — 實施例591 … (4-(6,7-二甲氧喹啉-4-基氣）茉基唑-2-基服一 —士 將4-(6,7-二甲氧峻淋-4-基氧）苯基胺甲酸苯酯（208 mg， 0.500 mmol)及 2 -胺基 p塞唆（1〇〇 mg，1 ·00 mmol)在二甲基亞 颯（1 ml)中，於85°C下加熱攪拌1小時。將反應液分溶於乙 酸乙酯及水中，有機層用1N氫氧化鈉水溶液、水及飽和食 鹽水洗淨，用無水硫酸鎂乾燥，濾除乾燥劑，以及將濾液 減壓餾去。將得到之粗生成物付諸於矽凝膠管柱層析（溶出 液為乙酸乙酯：甲醇=20 : 1)，再將含有目的物之溶出份濃 縮，懸浮於乙酸乙酯中，再將其以己烷稀釋，濾取結晶及 _ 用己烷洗淨後，藉由通風乾燥，得到為無色結晶之標題化 合物（150-m：g，0.355 mmol，71%)。 一 iH-NMR 光譜（CDCl3)5(ppm): 4.02-4.05 (6H，m)，6·46 (1H， _-641 -__ 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 _B7 五、發明説明（咖） 二 d, J=5.2 Hz), 6.92 (1H, d, J=3.6 Hz), 7.16-7.22 (2H, m), 7.40-7.44 (2H，m), 7·56 (1H，s)，7·61-7·67 (2H，m)，8·48 (1H， d，J=5.2 Hz) 〇 中間體係依以下述方法合成。 製造例591- 1 6,7_二甲氧述成-4-基一氧基）策甚胺甲酸苯酯 將藉由WO 97/ 17329之方法得到之4-(6,7-二甲氧喹啉-4-基氧）苯.胺（2.96 g，1〇·〇 mmol)及三乙胺〇 .21 g，12.0 mmol) -溶於二甲基甲醯胺（30 ml)中，冰冷下添加氯甲酸苯酯（ι·72 g，11 ·0 mmol)後，在室溫攪拌1小時。將反應液分溶於乙 酸乙酯及水中，有機層用水及飽和食鹽水洗淨，用無水硫-酸鎂乾燥，濾除乾燥劑，以及將濾液減壓餾去。將得到之 粗生成物付諸於矽凝膠管柱層析（溶出液為乙酸乙酯：己烷：一 ==3 : 1 )，再將含有目的物之溶出份濃縮，懸浮於乙酸乙酯 中，再將其以己烷稀釋，濾取結晶及用己烷洗淨後，藉由 通風乾燥，得到為無色結晶之標題化合物（2.50 g，6.00 mmol，60%) 〇 iH-NMR 光譜（CDCl3)5(ppm): 4·05 (3H，s)，4.06 (3H，s)， 6·46 (1H，d，J=5.2 Hz)，7.12 (1H，br s)，7.16-7.28 (5H，m)， 7.38-7.44 (3H，m)，7.53-7.60 (3H，m)，8·49 (1H，d，J=5.2 Hz) 〇 實施例592 .環丙基(本（6,7-二甲氫，套嗾-4-基氣某）茉某）脲 一 將4-(6,7-二甲氧喹啉-4-基氧）苯基胺甲酸苯酯（104 mg， ____- 642 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) &quot; 1304061 A7 B7 五、發明説明（637) 二 0.250 mmol)及環丙胺（28·5 mg，0·500 mm〇1)在二甲基亞颯 (1 ml)中’於至溫下攪;摔2小時。將反應液分溶於乙酸乙酯 及水中，有機層用1N氫氧化鈉水溶液、水及飽和食鹽水洗 淨，用無水硫酸鎂乾燥，濾除乾燥劑，以及將濾液減壓餾 去。將得到之粗生成物付諸於矽凝膠管柱層析（溶出液為乙 酸乙醋：甲醇=15 ·· 1)，再將含有目的物之溶出份濃縮，懸 浮於乙酸乙醋中，再將其以己烷稀釋，濾取結晶及用己烷 洗淨後，，藉由通風乾燥，得到為無色結晶之標題化合物（76 mg，0.200 mmol，80%) 〇 i-NMR 光譜（CDC13) 5 (ppm): 0.70-0.75 (2H，m)，0.87-0.92 (2H，m)，2.60-2.66 (1H，m)，4.04-4.07 (6H，m)，4.93 (1H，s)， 6.45 (1H, d, J=5.2 Hz), 6.99 (1H, s), 7.12-7.18 (2H, m), 1Λ2 ：：i . * ，一 ：： (1H，s)，7.50-7.56 (2H，m)，7·57 (1H，s)，8.48 (1H，d，J=5.2 一Hz), 7.52 (1H, s), 7.74 (1H, s), 7.86 (1H, s), 8.24 (1H? d, J=8.8 Hz), 8.31 (1H, s), 8.66 (lH,.s) , 8.67 (1H, d, J = 5.2 Hz) 〇. Example 589 izlir chloro-4_ cis cis-2-fluoro-cyclopropylamine carbonyl)amine benzoquinone [7-A HL p quinine # gilamine by In the same manner as in Example 11, phenyl N-(4-(6-aminocarbamido-7-methoxy-4-quinolinyl)oxy-2-chlorophenyl)aminecarboxylate (15 mg) </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; ^-NMR spectrum (DMSO-d6) 5 (ppm): 0.82 (1H, m), 1.11 (1H, πι), 2.68 (1H, m), 4.04 (3H, s), 4·78 (1H, m) ,6·54 (1H,d,J=5.2 Hz), 7.25 (1H,dd,J=2.8,8·8 Hz), 7.32 (1H,d,J=3.6 Hz), 7.50 (1H, d, J =2.8 Hz), 7.52 (1H, s), 7.74 (1H, s), 7.86 (1H, s), 8.25 (iH; s), 8.29 (1H, d, J=8.8 Hz), 8.66 (1H, s ), 8.67 (1H, d, J = 5.2 Hz). _- 640 - This paper size applies to China National Standard (CNS) A4 specification (210x 297 mm) 1304061 A7 B7 V. Description of invention (635) : Example 590 4- (3-chloro-4-(amine) Amine stupid base)-7-methyl group _ 6- 4 lea # g disk neck by the same method as in Example 11, from N-(4-(6-aminocarbazinyl-7-methoxy) -4- 4 lyophilyl phenyl oxo-2-chlorophenyl) carbamate (100 mg, 0.22 mmol), EtOAc (m.) iH-NMR spectrum (DMSO-d6) (J (ppm): 4·01 (3H, s), ό·41 (2H, s), 6.51 (1H, d, J = 5.2 Hz), 7.21 (1H, d5 J=9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.73 (1H, s), 7.84 (1H, s), 8.15 (1H, s), 8.25 (1H, d, J = 8.8 Hz), 8.65 (1H, d, J = 5.2 Hz), 8.66 (1H, s). - Example 591 ... (4-(6,7-Dimethoxyquinolin-4-yl gas)茉········································· Sesame (1 〇〇 mg, 1 00 mmol) in dimethyl hydrazine (1 ml) was stirred with heating at 85 ° C for 1 hour. The reaction solution was dissolved in ethyl acetate and water. The mixture was washed with a 1N aqueous solution of sodium hydroxide, water and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated, and the filtrate was evaporated under reduced pressure. The crude product was applied to a gel column chromatography ( The eluate was ethyl acetate:methanol = 20:1), and the fractions containing the desired product were concentrated, suspended in ethyl acetate, and then diluted with hexane, and the crystals were filtered and washed with hexane. , by ventilation and drying, get The title compound (150-m: g, 0.355 mmol, 71%). mp NMR (CDCl3) 5 (ppm): 4.02-4.05 (6H, m), 6.46 (1H, _- 641 -__ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 _B7 V. Invention description (cafe) 2d, J=5.2 Hz), 6.92 (1H, d, J=3.6 Hz ), 7.16-7.22 (2H, m), 7.40-7.44 (2H,m), 7·56 (1H,s),7·61-7·67 (2H,m),8·48 (1H, d, J = 5.2 Hz) The ruthenium intermediate system was synthesized according to the following method: Production Example 591 - 1 6,7-Dimethoxy -4-yl-monooxy) Benzene carboxylic acid phenyl ester by WO 97/17329 4-(6,7-Dimethoxyquinolin-4-yloxy)benzeneamine (2.96 g, 1 〇·〇mmol) and triethylamine 〇.21 g, 12.0 mmol) - dissolved in two Methylformamide (30 ml) was added with phenyl chloroformate (1·7 g, 11·0 mmol) under ice cooling, and then stirred at room temperature for 1 hour. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated. The obtained crude product was subjected to hydrazine gel column chromatography (eluent was ethyl acetate: hexane: 3:1), and the fractions containing the desired product were concentrated and suspended in ethyl acetate. The title compound (2.50 g, 6.00 mmol, 60%) was obtained as a colorless crystals. ) 5 (ppm): 4·05 (3H, s), 4.06 (3H, s), 6·46 (1H, d, J = 5.2 Hz), 7.12 (1H, br s), 7.16-7.28 (5H, m), 7.38-7.44 (3H, m), 7.53-7.60 (3H, m), 8.49 (1H, d, J = 5.2 Hz) 〇 Example 592. Cyclopropyl (本(6,7-II) Methyl hydrogen, 嗾-4-based gas, a certain), urea, phenyl 4-(6,7-dimethoxyquinolin-4-yloxy)phenylaminecarboxylate (104 mg, ____- 642 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) &quot; 1304061 A7 B7 V. Description of invention (637) 2 0.250 mmol) and cyclopropylamine (28·5 mg, 0·500 mm〇1 ) Stir in dimethyl hydrazine (1 ml) at room temperature; fall for 2 hours. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was evaporated. The obtained crude product was subjected to column chromatography on a gel column (the eluate was ethyl acetate: methanol = 15 ··1), and the fraction containing the target substance was concentrated, suspended in ethyl acetate, and then The title compound (76 mg, 0.200 mmol, 80%) was obtained as a colorless crystals (yield: hexanes). (ppm): 0.70-0.75 (2H, m), 0.87-0.92 (2H, m), 2.60-2.66 (1H, m), 4.04-4.07 (6H, m), 4.93 (1H, s), 6.45 (1H , d, J=5.2 Hz), 6.99 (1H, s), 7.12-7.18 (2H, m), 1Λ2 ::i . * , one:: (1H, s), 7.50-7.56 (2H, m), 7·57 (1H, s), 8.48 (1H, d, J = 5.2

Hz)。 實施例593 N- (4二L^，7-二甲虱4淋二4-基氫某）· 2-氟笨墓）-n，- 4岭-2- 基脲 將4-(6,7-二甲氧喹琳-4-基氧基）-2-氟苯基胺甲酸苯酯 (109 mg，0.250 mmol)及 2-胺基嘍唑（50·0 mg , 〇·500 mm〇1) 在二甲基亞砜（1 ml)中，於85°C下加熱攪拌2小時。將反應 液分溶於乙酸乙酯及水中，有機層用1N氫氧化鈉水溶液、 水及飽和食鹽水洗淨，用無水硫酸鎂乾燥，濾除乾燥劑， 以及將滤ΊΤ減壓館去。將得到之粗生成物付諸於矽凝膠管— 柱層析（溶出液為乙酸乙酯：甲醇= 30:丨），再將含有目的 ___ - 643 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公董）Hz). Example 593 N-(4 diL^,7-dimethylhydrazine 4 lysyl-2-ylhydrogen)·2-fluorotomb)-n,- 4 ridge-2-ylurea 4-(6,7 -Dimethoxyquinolin-4-yloxy)-2-fluorophenylaminecarboxylic acid phenyl ester (109 mg, 0.250 mmol) and 2-aminocarbazole (50·0 mg , 〇·500 mm〇1) The mixture was stirred with heating at 85 ° C for 2 hours in dimethyl sulfoxide (1 ml). The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with 1N aqueous sodium hydroxide, water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained crude product is applied to a gel column - column chromatography (eluent is ethyl acetate: methanol = 30: 丨), and then the target ___ - 643 paper size is applied to the Chinese National Standard (CNS). A4 specification (210 X 297 DON)

裝 訂Binding

線 1304061 A7 B7 五、發明説明（638) 物之溶出份濃縮，懸浮於乙酸乙酯中，再將其以己烷稀 釋，濾取結晶及用己烷洗淨後，藉由通風乾燥，得到為無 色結晶之標題化合物（95.0 mg，0.216 mmol，86%)。 iH-NMR 光譜（CDCl3)5(ppm): 4·05 (3H，s)，4·0ό (3H，s)， 6.52 (1Η, d, J=5.2 Hz), 6.92 (1H, d, J=3.6 Hz), 6.96-7.04 (2H，m)，7·36 (1H，d，J=3.6 Hz)，7.40 (1H，s)，7·53 (1H，s)， 8·30-8·36 (1H，m)，8.47 (1H，d，J=5.2 Hz) 〇 中間體係以下述方法合成。 製造例593-1 ' 二甲氧g奎-並4-基氧氟-菜甚脖甲酸苯酯 將藉由特開平1 1 - 158149之方法得到之4- (6,7-二甲氧p奎 淋-4-基氧）-2-氟本胺（3.55 g ’ 9.17 mmol)及 p 比咬（3.63 g，… 45.8 ππηόΐ)溶於二甲基甲酿胺（30 ml)中，冰冷下添加-氯甲Ά 酸苯酯（1.51 g，9.64 mmol)後，在室溫攪拌丨小時。將反應 液分溶於乙酸乙酯及水中，有機層用水及飽和食鹽水洗 淨’用無水硫酸鍰乾燥，濾除乾燥劑，以及將濾液減壓館 去。將得到之粗生成物付諸於矽凝膠管柱層析（溶出液為乙 酸乙酯··己烷=2 : 1)，再將含有目的物之溶出份濃縮，懸 浮於乙酸乙醋中，再將其以己烷稀釋，濾取結晶及用己燒 洗淨後，藉由通風乾燥，得到為無色結晶之標題化合物 (2.30 g，5.29 mmol，58%) 〇 ' iH-NMR 光譜（CDCl3)5(ppm): 4·05 (3H，s)，4.06 (3H，s)， 6·52 (1Η，〇5·2 Ηζ)，7·00-7·05 (2H，m)，7.18-7.30 (4H，m)，一 7.40-7.46 (4H，m)，7·50 (1H，S)，8.21 (1H，br s)，8·53 (1H，d/Line 1304061 A7 B7 V. Inventive Note (638) The dissolved fraction of the product is concentrated, suspended in ethyl acetate, diluted with hexane, filtered and washed with hexane, and then dried by air. The title compound (95.0 mg, 0.216 mmol, 86%). iH-NMR spectrum (CDCl3) 5 (ppm): 4·05 (3H, s), 4·0ό (3H, s), 6.52 (1Η, d, J=5.2 Hz), 6.92 (1H, d, J= 3.6 Hz), 6.96-7.04 (2H, m), 7.36 (1H, d, J = 3.6 Hz), 7.40 (1H, s), 7·53 (1H, s), 8·30-8·36 (1H, m), 8.47 (1H, d, J = 5.2 Hz) The oxime intermediate system was synthesized in the following manner. Production Example 593-1 'Dimethoxyg-quino- and 4-yloxyfluoro-calybdenum phenyl ester 4-(6,7-dimethoxyp-quine) obtained by the method of JP-A-11-158149淋-4-yloxy)-2-fluorobenzamine (3.55 g ' 9.17 mmol) and p specific bite (3.63 g,... 45.8 ππηόΐ) dissolved in dimethyl amide (30 ml), added under ice cooling - After phenyl chloroformate (1.51 g, 9.64 mmol), it was stirred at room temperature for a few hours. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine, dried with anhydrous succinate, filtered, and filtered. The obtained crude product was subjected to column chromatography on a gel column (the eluate was ethyl acetate·hexane = 2:1), and the fraction containing the desired product was concentrated and suspended in ethyl acetate. The title compound (2.30 g, 5.29 mmol, 58%) 〇' iH-NMR spectrum (CDCl3) was obtained as a colorless crystals. 5 (ppm): 4·05 (3H, s), 4.06 (3H, s), 6·52 (1Η, 〇5·2 Ηζ), 7·00-7·05 (2H, m), 7.18-7.30 (4H,m), a 7.40-7.46 (4H,m),7·50 (1H,S), 8.21 (1H,br s),8·53 (1H,d/

1304061 A7 B7 五、發明説明（咖） ^ J=5.2 Hz) 〇 實施例594 N-環二甲氫4啉-4-某氫篡V2-氣苯某、呀 將4-(6,7-二甲氧π奎淋-4-基氧）-2-氟苯基胺甲酸苯酯（1〇9 mg，0.250 mmol)及環丙胺（28.5 mg，0.500 mmol)在二甲基 亞颯（1 ml)中，於室溫下攪拌2小時。將反應液分溶於乙酸 乙酯及水中，有機層用1N氫氧化鈉水溶液、水及飽和食鹽 水洗淨.，用無水硫酸鎂乾燥，濾除乾燥劑，以及將濾液減 壓餾去。將得到之粗生成物付諸於矽凝膠管柱層析（溶出液 為乙酸乙酯：甲醇= 50: 1)，再將含有目的物之溶出份濃 縮，懸浮於乙酸乙酯中，再將其以己烷稀釋，濾取結晶及 用己烷洗淨後，藉由通風乾燥，得到為無色結晶之標題化&lt; • - 二 合物（73 mg，0.183 mmol，73%)。 二 j-NMR 光譜（CDC13) 5 (ppm): 0.71-0.76 (2H，m)，0.90-0.95 (2H, m), 2.60-2.66 (1H, m), 4.05 (3H, s), 4.06 (3H, s), 5.00 (1H, s), 6.50 (1H, d, J=5.2 Hz), 6.95-7.02 (2H, m), 7.23 (1H5 s), 7.43 (1H, s), 7.52 (1H, s), 8.25-8.32 (1H, m), 8.51 (1H, d, J=5.2 Hz) 〇 實施例595 ir(3-氣-4“環丙胺羰基）胺茉氳美7-(2-乙氣乙氫篡）-6-峻啉羧醯胺 藉由與實施例7同樣之方法，從4-(3-氯-4-(環丙胺羰基） 胺禾氧》基-7-¾基-6-峻琳幾酿胺（206 mg，0.499 mmol)， 及2-乙氧乙基溴化物，得到為淡黃色結晶之標題化合物 ___- 645 - ___ 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 —_ B7 五、發明説明（64〇) : (96.0 mg 5 0.198 mmol » 39.7%) 〇 W-NMR 光譜（DMSO-d6)5(PPm): 0.42 (2H，m)，0.65 (2H，m)， 1·16 (3H，t，J=7.2 Hz)，2.56 (1H，m)，3·53 (2H，q，J=7.2 Hz)， 3.83 (2H, m), 4.40 (2H, m), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d，J=2.8 Hz)，7.24 (1H，dd，J=2.8，9.2 Hz)，7.49 (1H，d， J=2.8 Hz), 7.56 (1H, s), 7.85 (1H, s), 7.87 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J—9.2 Hz), 8.66 (1H, d, J=5.2 Hz) 8 78 (1H s) 〇 實施例596 氳-4-(環丙胺薇胺苯氧U-7-環雨甲氧其丄癦说 幾醯胺 _ 藉由與實施例7同樣之方法，從4-(3-氯-4-(環丙胺羰基）：&lt; 胺苯氧基）-7-羥基-6-喹啉羧醯胺（206 mg，0.499 mmol) , ^ 及漠甲基環丙燒’得到為淡黃色結晶之標題化合物（61.4 mg，0.132 mmol，26.4%) 〇 iH-NMR 光譜（01\130-(16)(5(卩卩111):0.41-0.47(411，111)，0.60-0.69 (4H, m), 1.39 (1H, m), 2.56 (1H, m), 4.14 (2H, d, J=6.8 Hz), 6.52 (1H, d, J=5.2 Hz), 7.20 (1H, d5 J=2.8 Hz), 7.25 (1H, dd, J=2.8, 8.8 Hz), 7.49-7.50 (2H, m), 7.83 (1H, s), 7.85 (1H, s)，7·98 (1H，s)，8·28 (1H，d，J=8.8 Hz)，8·66 (1H，d，J=5.21304061 A7 B7 V. Description of the invention (Cal) ^ J=5.2 Hz) 〇Example 594 N-cyclodimethylhydrogen 4 -4--4-hydroquinone V2-gas benzene, yeah 4-(6,7-two Phenyl methoxy π quinolate-4-yloxy)-2-fluorophenylaminecarboxylate (1〇9 mg, 0.250 mmol) and cyclopropylamine (28.5 mg, 0.500 mmol) in dimethyl hydrazine (1 ml) The mixture was stirred at room temperature for 2 hours. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with 1N aqueous sodium hydroxide, water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained crude product was subjected to hydrazine gel column chromatography (eluent was ethyl acetate:methanol = 50:1), and the fractions containing the desired product were concentrated, suspended in ethyl acetate, and then This was diluted with hexane, and the crystals were filtered and washed with hexane, and then evaporated to dryness to give the title compound (73 mg, 0.183 mmol, 73%). Di-j-NMR spectrum (CDC13) 5 (ppm): 0.71-0.76 (2H, m), 0.90-0.95 (2H, m), 2.60-2.66 (1H, m), 4.05 (3H, s), 4.06 (3H , s), 5.00 (1H, s), 6.50 (1H, d, J=5.2 Hz), 6.95-7.02 (2H, m), 7.23 (1H5 s), 7.43 (1H, s), 7.52 (1H, s ), 8.25-8.32 (1H, m), 8.51 (1H, d, J = 5.2 Hz) 〇 Example 595 ir(3-Gas-4"cyclopropylaminecarbonyl)amine Molybdenum 7-(2-Ethylene B Hydroquinone)-6-porphyrincarboxamide was used in the same manner as in Example 7 from 4-(3-chloro-4-(cyclopropylaminecarbonyl)amineoxycarbonyl]-7-3⁄4yl-6-jun Amine (206 mg, 0.499 mmol) and 2-ethoxyethyl bromide give the title compound as light yellow crystals ___- 645 - ___ This paper size applies to the Chinese National Standard (CNS) A4 specification ( 210X 297 mm) 1304061 A7 —_ B7 V. Description of the invention (64〇) : (96.0 mg 5 0.198 mmol » 39.7%) 〇W-NMR spectrum (DMSO-d6) 5 (PPm): 0.42 (2H, m) ,0.65 (2H,m), 1·16 (3H,t,J=7.2 Hz), 2.56 (1H,m),3·53 (2H,q,J=7.2 Hz), 3.83 (2H, m), 4.40 (2H, m), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.4 9 (1H,d, J=2.8 Hz), 7.56 (1H, s), 7.85 (1H, s), 7.87 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J-9.2 Hz ), 8.66 (1H, d, J = 5.2 Hz) 8 78 (1H s) 〇 Example 596 氲-4-(cyclopropylamine phenoxy oxo U-7-cyclohexyl methoxy oxime 醯 醯 醯 _ By the same procedure as in Example 7, 4-(3-chloro-4-(cyclopropylaminecarbonyl): &lt;aminophenoxy)-7-hydroxy-6-quinolinecarboxamide (206 mg, 0.499) The title compound (61.4 mg, 0.132 mmol, 26.4%) was obtained as pale-yellow crystals (yield: </ br> </ br> </ br> : 0.41 - 0.47 (411, 111), 0.60 - 0.69 (4H, m), 1.39 (1H, m), 2.56 (1H, m), 4.14 (2H, d, J = 6.8 Hz), 6.52 (1H, d , J=5.2 Hz), 7.20 (1H, d5 J=2.8 Hz), 7.25 (1H, dd, J=2.8, 8.8 Hz), 7.49-7.50 (2H, m), 7.83 (1H, s), 7.85 ( 1H, s), 7·98 (1H, s), 8·28 (1H, d, J = 8.8 Hz), 8.66 (1H, d, J = 5.2

Hz)，8·72 (1H，s)。 — 實施你丨597 4」（3 -积,f甲胺凝基）胺笨氣基）-7 -甲氣基—6 - p套g林教gj|脖 藉由與實施例11同樣之方法，從N-( 4-(6-胺甲醯基-7-甲 ____- 646 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 _B7 五、發明説明（~~&quot; 7&quot; 氧基-4-峻淋基）氧-2-氟苯基）胺甲酸苯酯（73 mg)及甲胺 (2M四氫呋喃溶液），得到為黃色結晶之標題化合物（37 mg)。 j-NMR 光譜（DMSO-d6)5(ppm): 2·65 (3H，d，J=4.4 Hz)， 4.01 (3H, s), 6.45-6.46 (1H, m), 6.51-6.52 (1H, m), 7.04- 7·06 (1H，m)，7.28-7.31 (1H，m)，7·50 (1H，s)，7·72 (1H，s)， 7.84 (1H, s), 8.17-8.22 (1H, m), 8.40 (1H, s), 8.64-8.65 (2H, m) o 實施例598 4-(3-氟-4-(乙胺羰基）胺苯氣基）-7-甲氫某-6-崦啉教醯胺 藉由與實施例11同樣之方法，從N-(4-(6-胺甲醯基-7-甲 氧基-4-峻淋基）氧-2-鼠苯基）胺甲酸苯酯（69 mg)，及乙胺-(2M四氫呋喃溶液），得到為黃色結晶之標題化合私3 8 : ^ mg)。 iH-NMR 光譜（DMSO-d6)5(ppm): 1.05 (3H，t，J=7 Hz)，3.11 (2H, q, J=7 Hz), 4.01 (3H, s), 6.50-6.52 (1H, m), 6.57-6.58 (1H，m)，7·04-7·06 (1H，m)，7·28-7·32 (1H，m)，7.50 (1H，s)， 7.73 (1H, s), 7.84 (1H, s), 8.19-8.24 (1H, m), 8.33 (1H, s), 8.64-8.65 (2H，m) 〇 實施例599 4-((((4-(3-氣-4-(((環丙胺基）羰某）胺基）苯氣某）-7- y ' 基-6-喹啉基）羰基）胺基）甲基） 1 _六j.吡啶羧酸第三丁酯 將4-(&gt;煮:-4-(((環丙胺基）羰基）胺基）苯氧基）-7-甲氧 一 基-6-4：淋叛酸（171 mg，0.40 mmol)於氮氣蒙氣下溶解在 -647 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) ~ ' 1304061 A7 B7 五、發明説明（Hz), 8·72 (1H, s). - Implementing your 丨 4 4 4 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨From N-(4-(6-Aminomethylmercapto-7-A____-646 - This paper scale applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 _B7 V. Invention description (~~ &quot;&lt;'&gt;&gt;&lt;&gt;&gt;&gt;&lt;RTIgt;&lt;/RTI&gt;&gt;&lt;/RTI&gt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; j-NMR spectrum (DMSO-d6) 5 (ppm): 2·65 (3H, d, J = 4.4 Hz), 4.01 (3H, s), 6.45-6.46 (1H, m), 6.51-6.52 (1H, m), 7.04- 7·06 (1H, m), 7.28-7.31 (1H, m), 7·50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 8.17- 8.22 (1H, m), 8.40 (1H, s), 8.64-8.65 (2H, m) o Example 598 4-(3-Fluoro-4-(ethylaminocarbonyl)amine phenyl)-7-methylhydrogen A certain -6-porphyrin-inducing amine was obtained from N-(4-(6-aminocarbamimid-7-methoxy-4-anthranyl)oxy-2-murine by the same method as in Example 11. Phenyl) phenyl carbamate (69 mg), and ethylamine-(2M tetrahydrofuran solution) gave yellow crystals Title is private 3 8 : ^ mg). iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.05 (3H, t, J = 7 Hz), 3.11 (2H, q, J = 7 Hz), 4.01 (3H, s), 6.50-6.52 (1H , m), 6.57-6.58 (1H, m), 7·04-7·06 (1H, m), 7·28-7·32 (1H, m), 7.50 (1H, s), 7.73 (1H, s), 7.84 (1H, s), 8.19-8.24 (1H, m), 8.33 (1H, s), 8.64-8.65 (2H,m) 〇Example 599 4-((((4-(3-) -4-(((cyclopropylamino)carbonyl)amino)benzene gas))-7- y 'yl-6-quinolinyl)carbonyl)amino)methyl) 1 _hexa.pyridinecarboxylic acid Tributyl ester 4-(&gt;cook:-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-yl-6-4: retinoic acid (171 mg, 0.40 Mm) dissolved in nitrogen at -647 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) ~ ' 1304061 A7 B7 V. Description of invention (

二甲基甲醯胺（4 ml)中，於室溫依序添加4胺甲基_丨六氫 峨㈣酸第三了酿（171 mg ’ 〇.80 _。1)、三乙胺（〇2毫升） 及1H-1，2,3-苯并三嗅-l-基氧）（三（二甲胺基））鳞六氟鱗酸 鹽（265 mg，0.60 mmol)後，授拌—整夜。將反應液分溶於 乙酸乙醋及水中，將有機層用水及飽和食鹽水洗淨及用無 水硯酸鈉乾燥。餾去溶媒，懸浮於乙酸乙酯中，再將其以 己燒稀釋，/慮取結曰Θ及藉由通風乾燥，得到為白色結晶之 標題化舍物（249 mg，定量產出）。 WNMR 光譜（DMSO-d6)5(pPm): 〇.41 (2H，m)，〇 65 (2H，叫 1.05 (2H, m), 1.22 (1H, m), 1.37 (9H, s), 1.66 (2H, m), 2.56 (1H, m), 2.67 (2H, m), 3.20 (2H, m), 3.93 (2H, m), 3.99 (3ΕΓ s), 6.51 (1H, d, J=5.2 Hz), 7.17-7.24 (2H, m), 7.46 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.97 (1H, s), 8.26 (1H, dd, J=2.8, 8.8 Hz)，8·39 (1H，m)，8.46 (1H，s)，8·64 (1H，d, J=5.2 Hz)。 實施例600 甲基二}六氫咐淀甲基蓋_4·(&quot;亨^ ^ f ^ 基）胺基）笨乳基）-7-甲氣基-6-p奎，株,酿脖 在4-((((4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧基）·7_ 甲氧基-6-喹啉基）羰基）胺基）甲基六氫吡啶羧酸第三丁 酯（249 mg，0.40 mmol)中，於室溫下添加三氟醋酸（丨亳升） 並攪捽2小時。將反應液注入飽和碳酸氫納水溶液中予以中 和，以乙酸乙醋萃取3回，再將有機層用無水硫酸納乾燥。 餾去溶媒D將殘餘物溶於四氫吱喃（5 ml)-甲醇（5 ml) 中，於室溫依序添加37%甲醛水溶液（〇·5 mi)、乙酸（〇 〇5 -648 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1304061 A7In dimethylformamide (4 ml), 4 amine methyl 丨 丨 hexahydro hydrazine (tetra) acid was added to the room at room temperature (171 mg ' 〇. 80 _. 1), triethylamine (〇) 2 ml) and 1H-1,2,3-benzotrisole-l-yloxy)(tris(dimethylamino))sodium hexafluorophosphate (265 mg, 0.60 mmol), then mixed night. The reaction solution was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine and dried over sodium sulfate. The solvent was distilled off, suspended in ethyl acetate, and then diluted with hexanes, and the mixture was evaporated to dryness to afford white crystals (249 mg, quantitative yield). WNMR spectrum (DMSO-d6) 5 (pPm): 〇.41 (2H, m), 〇65 (2H, 1.05 (2H, m), 1.22 (1H, m), 1.37 (9H, s), 1.66 ( 2H, m), 2.56 (1H, m), 2.67 (2H, m), 3.20 (2H, m), 3.93 (2H, m), 3.99 (3ΕΓ s), 6.51 (1H, d, J=5.2 Hz) , 7.17-7.24 (2H, m), 7.46 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.97 (1H, s), 8.26 (1H, dd, J=2.8, 8.8 Hz), 8·39 (1H, m), 8.46 (1H, s), 8.64 (1H, d, J = 5.2 Hz). Example 600 methyl hexyl hexahydro hydrazide methyl cap _4·(&quot; Henry ^ ^ f ^ base) Amino) stupid base) - 7-methyl-based-6-p-ku, strain, brewing neck in 4-(((4-(3-chloro-4-(() Acryl)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinylcarbonyl)amino)methylhexahydropyridinecarboxylic acid tert-butyl ester (249 mg, 0.40 mmol) Trifluoroacetic acid (spike) was added at room temperature and stirred for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate to neutralize, extracted with ethyl acetate for three times, and the organic layer was dried over anhydrous sodium sulfate. Distillate solvent D. The residue was dissolved in tetrahydrofuran (5 ml)-methanol (5 ml). Square · 5 mi), acetic acid (square 〇5 -648-- this paper scale applicable Chinese National Standard (CNS) A4 size (210X297 mm) 1304061 A7

ml)及氰基硼氫鈉（50 mg , 〇·8 mm〇1)後，攪拌i小時。將反 應液分溶於乙酸乙酯及飽和碳酸氫鈉水溶液中，有機層用 碳酸氫鈉水溶液及飽和食鹽水洗淨，用無水硫酸鈉乾^。 餾t溶媒，從乙酸乙酯中使其結晶化，再將其過濾及通風 乾燥，得到為白色結晶之標題化合物（125 6 mg，〇 233 mmol，58.4%)。 H-NMR 光 if(DMSO-d6)(5(ppm): 0.42 (2H，m)，0·65 (2H，m) 1.18 (2H, m), 1.49 (1H, m), 1.64 (2H, m), 1.78 (2H, m), 2.11 (3H, s)，2.56 (1H，m)，2·73 (2H, m)，3.18 (2H，m), 3·99 (3H， s)，6·51 (1H，d，J=5.2 Hz), 7.18 (1H，d，J=2.4 Hz)，7·22 (1H， dd, J=2.8, 8.8 Hz)v7.46 (1H, d, J=2.4 Hz), 7.49 (1H, s), 7.97 (1H，s)，8.26 (1H，dd，J=2.8, 8.8 Hz)，8.35 (1H，m)，8.47 (1H，:、 s)，8·64 (1H，d，J=5.2 Hz)。 — 适 實施例601 1^1((4-(3-氣-4-((環丙胺基）羰某）胺基氧葚τ _ 麗基）-7-ρ奎淋基）氧）甲基）-1 -六氤ρ比淀複酸第三丁酯 藉由與實施例7同樣之方法，從Ν6-甲基-4-(3-氯-4-(((環 丙胺基）羰基）胺基）苯氧基）-7·羥基-6-喳淋叛醯胺（225.5 mg，0.52 8 mmol)，及4-(溴甲基）-1-六氫吡啶羧酸第三丁 酯，得到為白色結晶之標題化合物（188.4 mg，0.302 mmol，57.1%) 〇 iH-NMR光譜（DMSO-d6)5(ppm): 0.41 (2H，m)，0.65 (2H，m)， 1.13-1.2613Ή, m), 1.39 (9H, s)5 1.75 (2H, m), 2.06 (1H, m),— 2·56 (1H，m)，2.75 (1H，m)，2·81 (3H，d，J=4.8 Hz)，3.99 (2H， __- 649 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 B7 五、發明説明（似4) : m), 4.10 (2H, m), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.45 (1H, d3 J=2.8 Hz), 7.48 (1H，s)，7·96 (1H，s)，8.18 (1H，d，J=4.8 Hz)，8.25 (1H， d，J=9.2 Hz)，8·43 (1H，s)，8·64 (1H，d，J=5.8 Hz)。 實施例602 4d：_((4-(3-氣-4-((環丙脖其、端某）胺某）茉氣基 麗_基）-7- 4啉基）氧）甲某）-1 -六齡吡啶藉酸第三丁酯 藉由與實施例7同樣之方法，從Ν6-乙基-4-(3-氯-4-(((環 丙胺基）談基）胺基）苯氧基）-7-經基-6-4琳幾酿胺（170.5 mg ’ 0.3 87 mmol)，及4-(溴甲基）-1_六氫吡啶羧酸第三丁 酯’得到為淡黃色結晶之標題化合物（155.4 mg，0.244… mmol，63.0%)。 W-NMR光譜（DMSO-d6) 5(ppm): 0·41 (2H，m)，0.65 (2H: m)，：二 1.10-1.16 (4H, m), 1.27 (2H, m), 1.39 (9H, s), 1.76 (2H, m), 2.05 (1H, m), 2.56 (1H, m), 2.75 (1H, m), 3.20-3.40 (2H, m), 4.01 (2H, m), 4.11 (2H, m), 6.51 (1H, d, J=5.2 Hz), 7.17-7.23 (2H, m), 7.45 (1H, d, J=2.8 Hz), 7.48 (1H, s), 7.96 (1H, s)，8.20-8.27 (2H，m)，8·44 (1H，s)，8.64 (1H, d，J=5.2 Hz)。 實施例603 甲基-4二（3-氯-4-(((環丙胺基某、胺基）茉氣基）-7-〔丄1 -甲基-4-六氫叶[：咬基）甲氣某）-6-g套淋藉酿胺 在4-(((4-(3-氯-4-((環丙胺基）羰基）胺基）苯氧基甲 胺羰基）-^7·^奎啉基）氧）甲基）-1 -六氫吡啶羧酸第三丁酯 (179·0 mg，0·287 mmol)中，於室溫下添加三氟醋酸（1毫 ___- 650 - _ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 __ B7 五、發明説明（~~一 嫌 &quot; 升），攪拌2小時。將反應液注入飽和碳酸氫鈉水溶液中予 以中和，以乙酸乙酯-四氫呋喃（丨·· 萃取5回，再將有機 層用無水硫酸鈉乾燥。餾去溶媒後，將殘餘物溶於四氫呋 喃（5 ml) -甲醇（5 ml)中，於室溫依序添加37%甲醛水溶液 (0 · 3 ml)、乙酸（0·05 ml)及氨基刪氯制（3 6 mg ’ 0.57 mmol) 後，攪捽1小時。將反應液分溶於乙酸乙酯及飽和碳酸氫鈉 水溶液中，有機層用碳酸氫鈉水溶液及飽和食鹽水洗淨， 用無水硫酸鈉乾燥。餾去溶媒後，從乙酸乙酯中使其結晶 化，再將其過濾及通風乾燥，得到為白色結晶之標題化合 物（101.0 mg，0.188 mmol，65.4%)。 h-NMR 光譜（DMSO-d6)5(ppm): 0·41 (2H，m)，0·65 (2H，nr)， 1.34 (2H, m), 1.72-1.89 (5H, m), 2.14 (3H, s), 2.56 (1H, m),' 2.78 (2H, m), 2.82 (3H, d, J=4.4 Hz), 4.08 (2H, d, J=6.4 Hz),七 6·51 (1H，d，J=5.2 Hz)，7.19-7.23 (2H，m)，7.45 (1H，d，J=2.8 Hz)，7.48 (1H，s)，7·97 (1H，s)，8.20 (1H，d，J=4.4 Hz)，8.25 (1H，d，J=9.2 Hz)，8.45 (1H，s)，8·63 (1H，d，J=5.2 Hz)。 實施例604 16-乙基-4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氳某n (_(1 -甲基-4-六氫吡啶基）甲氣某）-6- 4:淋藉醯胺 藉由實施例603同樣之方法，從4-(((4-(3-氯-4-((環丙胺 基）羰基）胺基）苯氧基）-6-(乙胺羰基）-7-喹啉基）氧）甲基）-1-六氫吡啶羧酸第三丁酯（147·2 mg，0.231 mmol)，得到為 淡黃色結痛-之標題化合物（82.6 mg，0.1 50 mmol，64.8%)。 〜 iH-NMR 光譜（DMSO-d6)5(ppm): 0.42 (2H，m)，0.65 (2H，m)， -651 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 B7 五、發明説明（646) 1.14 (3H, t, J=7.2 Hz), 1.36 (2H, m), 1.75-1.89 (5H, m), 2.15 (3H, s), 2.56 (1H, m), 2.79 (2H, m), 3.20-3.40 (2H, m), 4.08 (2H，d，J=6.4 Hz)，6.51 (1H，d，J=5.2 Hz)，7.20-7.23 (2H，m)， 7.46 (1H, d, J=2.8 Hz), 7.48 (1H, s), 7.98 (1H, s), 8.22-8.27 (2H，m)，8·47 (1H，s)，8.64 (1H，d，J=5.2 Hz)。After ml) and sodium cyanoborohydride (50 mg, 〇·8 mm〇1), stir for 1 hour. The reaction mixture was dissolved in ethyl acetate and aq. sodium hydrogen sulfate. The solvent was evaporated, crystallized from EtOAc (EtOAc m.) H-NMR light if (DMSO-d6) (5 (ppm): 0.42 (2H, m), 0·65 (2H, m) 1.18 (2H, m), 1.49 (1H, m), 1.64 (2H, m ), 1.78 (2H, m), 2.11 (3H, s), 2.56 (1H, m), 2·73 (2H, m), 3.18 (2H, m), 3·99 (3H, s), 6· 51 (1H,d,J=5.2 Hz), 7.18 (1H,d,J=2.4 Hz), 7.22 (1H, dd, J=2.8, 8.8 Hz) v7.46 (1H, d, J=2.4 Hz), 7.49 (1H, s), 7.97 (1H, s), 8.26 (1H, dd, J=2.8, 8.8 Hz), 8.35 (1H, m), 8.47 (1H,:, s), 8.64 (1H, d, J = 5.2 Hz) - Appropriate Example 601 1^1 ((4-(3-Ga-4-((cyclopropylamino)carbonyl)) Aminooxy 葚 _ _ 丽) - ρ 淋 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) (((Cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-oxime tartamine (225.5 mg, 0.52 8 mmol), and 4-(bromomethyl)-1-hexahydro The title compound (188.4 mg, 0.302 mmol, 57.1%) was obtained as white crystals. 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.41 (2H, m), 0.65 (2H) ,m), 1.13-1.2613Ή, m), 1.39 (9H, s)5 1.75 (2H, m), 2.06 (1H, m), — 2·56 (1H, m), 2.75 (1H, m), 2·81 (3H, d, J=4.8 Hz), 3.99 (2H, __- 649 - this The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 B7 V. Invention description (4): m), 4.10 (2H, m), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.45 (1H, d3 J=2.8 Hz), 7.48 (1H, s), 7·96 (1H, s), 8.18 (1H, d, J = 4.8 Hz), 8.25 (1H, d, J = 9.2 Hz), 8.43 (1H, s), 8.64 (1H, d, J = 5.8 Hz). Example 602 4d: _((4-(3-gas-4-((cyclopropyl), end) amine) jasmine yl)-7- 4 phenyl) oxy) a) 1 - 6-instar pyridine acid tert-butyl ester by the same method as in Example 7 from Ν6-ethyl-4-(3-chloro-4-(((cyclopropylamino)) yl) benzene) Oxy)-7-ylamino-6-4 linalylamine (170.5 mg '0.387 mmol), and 4-(bromomethyl)-1_hexahydropyridinecarboxylic acid tert-butyl ester' was obtained as pale yellow The title compound (155.4 mg, 0.244... mmol, 63.0%). W-NMR spectrum (DMSO-d6) 5 (ppm): 0·41 (2H, m), 0.65 (2H: m),: 1.10.10.16 (4H, m), 1.27 (2H, m), 1.39 ( 9H, s), 1.76 (2H, m), 2.05 (1H, m), 2.56 (1H, m), 2.75 (1H, m), 3.20-3.40 (2H, m), 4.01 (2H, m), 4.11 (2H, m), 6.51 (1H, d, J=5.2 Hz), 7.17-7.23 (2H, m), 7.45 (1H, d, J=2.8 Hz), 7.48 (1H, s), 7.96 (1H, s), 8.20-8.27 (2H, m), 8.44 (1H, s), 8.64 (1H, d, J = 5.2 Hz). Example 603 Methyl-4 bis(3-chloro-4-(((cyclopropylamino), amino) oxalyl)-7-[丄1 -methyl-4-hexahydrofolate [: octyl)甲-)-6-g lysine in 4-((4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxymethylamine carbonyl)-^7· ^Quinolinyl)oxy)methyl)-1 -hexahydropyridinecarboxylic acid tert-butyl ester (179·0 mg, 0·287 mmol), added trifluoroacetic acid (1 ___- 650) at room temperature - _ This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 __ B7 V. Invention description (~~一嫌&quot; liter), stir for 2 hours. Inject the reaction solution into saturated hydrogen carbonate The mixture was neutralized with sodium sulphate, and extracted with ethyl acetate-tetrahydrofuran (5 hrs). The organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was dissolved in tetrahydrofuran (5 ml)-methanol (5) In ml), 37% aqueous formaldehyde solution (0·3 ml), acetic acid (0.55 ml) and amino-chlorinated (3 6 mg '0.57 mmol) were added sequentially at room temperature, and the mixture was stirred for 1 hour. The solution is dissolved in ethyl acetate and saturated aqueous sodium hydrogencarbonate, and the organic layer is made of hydrogen carbonate. The mixture was washed with aq. aq. EtOAc (EtOAc m. M, NMR, 65.4%) h-NMR spectrum (DMSO-d6) 5 (ppm): 0·41 (2H, m), 0·65 (2H, nr), 1.34 (2H, m), 1.72-1.89 (5H , m), 2.14 (3H, s), 2.56 (1H, m), ' 2.78 (2H, m), 2.82 (3H, d, J=4.4 Hz), 4.08 (2H, d, J=6.4 Hz),七六·51 (1H,d,J=5.2 Hz), 7.19-7.23 (2H,m), 7.45 (1H,d,J=2.8 Hz), 7.48 (1H,s),7·97 (1H,s ), 8.20 (1H, d, J = 4.4 Hz), 8.25 (1H, d, J = 9.2 Hz), 8.45 (1H, s), 8.63 (1H, d, J = 5.2 Hz). 16-Ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl))amino)phenylhydrazine) n (-(1-methyl-4-hexahydropyridyl)methyl) - 6- 4: lylamine was obtained from 4-(((4-(3-chloro-4-((cyclopropylamino)carbonyl))amino)phenoxy)-6- (Ethylamine carbonyl)-7-quinolinyl)oxy)methyl)-1-hexahydropyridinecarboxylic acid tert-butyl ester (147·2 mg, 0.231 mmol), Pain as pale yellow - The title compound (82.6 mg, 0.1 50 mmol, 64.8%). ~ iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H, m), 0.65 (2H, m), -651 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. INSTRUCTIONS (646) 1.14 (3H, t, J=7.2 Hz), 1.36 (2H, m), 1.75-1.89 (5H, m), 2.15 (3H, s), 2.56 (1H, m), 2.79 (2H, m), 3.20-3.40 (2H, m), 4.08 (2H,d,J=6.4 Hz), 6.51 (1H,d,J=5.2 Hz), 7.20-7.23 (2H,m ), 7.46 (1H, d, J=2.8 Hz), 7.48 (1H, s), 7.98 (1H, s), 8.22-8.27 (2H, m), 8·47 (1H, s), 8.64 (1H, d, J = 5.2 Hz).

實施例(SOS -~_(7_下乳基-6-见峻p林某氣-氣笨基1-3-乙基脈 藉由與製造例17同樣之操作，從4_(4_胺基-3_氯苯氧基）-氧基·«喳啉-6-甲腈（1·78 g)及氣碳酸苯酯，得到為固體 之胺甲酸酯（1.51 g)。繼而，以實施例1同樣之方式，將胺 曱酸酯（1.5 g)於二甲基亞砜中，室溫下藉由乙胺處理，得 到為固體之標題化合物（1.4 g)。 -: H-NMR 光譜（DMSO-d6)5(PPm): 1.06 (3H，t，J=7.6 Hz)，f 3.08-3.16 (2H, m), 5.45 (2H, s), 6.58 (1H, d, J=5.2 Hz), 6.99 (1H, t, J=5.2 Hz), 7.23 (1H, dd, J-2.8 Hz, J=9.2 Hz), 7.36 (1H, t, J=7.2 Hz), 7.44 (2H, t, J=7.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.54 (2H, d, J=7.2 Hz), 7.70 (lHj s)j 8.〇6 〇H, s), 8.26 (1H，d，J=8.8 Hz)，8·72 (1H，d，J=5.2 Hz)，8·76 (1H，s)。 實施例606 L·!!-氣-4-(6-氣呆二^矣氳）_茇 基）-3-乙某Μ - 以與製造例21同樣之方式，將…_(7_字氧基_6_氛士林_ 4·基氧）-2--氣苯基）.3_乙基脲（1 g)藉由三氣乙酸及硫代苯— 甲趟處理以脫保護，將得到之幾基體（〇 48㈡以與實施例EXAMPLES (SOS -~_(7_下乳基-6-见峻普林某气-气笨基1-3-Ethyl vein by the same operation as in Production Example 17, from 4_(4-amino group) -3_Chlorophenoxy)-oxy-«porphyrin-6-carbonitrile (1·78 g) and phenyl carbonate to give a solid urethane (1.51 g). In the same manner, the amine decanoate (1.5 g) was obtained from EtOAc (EtOAc) eluted -d6)5(PPm): 1.06 (3H,t,J=7.6 Hz), f 3.08-3.16 (2H, m), 5.45 (2H, s), 6.58 (1H, d, J=5.2 Hz), 6.99 (1H, t, J=5.2 Hz), 7.23 (1H, dd, J-2.8 Hz, J=9.2 Hz), 7.36 (1H, t, J=7.2 Hz), 7.44 (2H, t, J=7.2 Hz) ), 7.48 (1H, d, J=2.8 Hz), 7.54 (2H, d, J=7.2 Hz), 7.70 (lHj s)j 8.〇6 〇H, s), 8.26 (1H,d,J= 8.8 Hz), 8.72 (1H, d, J = 5.2 Hz), 8·76 (1H, s). Example 606 L·!!-气-4-(6-气呆二^矣氲)_茇基)-3-乙Μ - In the same manner as in Production Example 21, ..._(7_字氧_6_环士林_4·基氧)-2--gasphenyl).3 _ethylurea (1 g) by trigastric acid and sulfur Substituted benzene - formazan treatment for deprotection, the resulting matrix will be obtained (〇 48 (b) with the examples

----^ 1304061 A7 B7 五、發明説明（647) - 543同樣之方式處理，得到為固體之標題化合物（0.31 g)。 iH-NMR 光譜（DMSO-d6) 5 (ppm): 1·06 (3H，t，J=7.2 Hz)， 2.81 (1H, dd, J=2.8 Hz, J=5.2 Hz), 2.91 (1H5 t, J=4.8 Hz), 3.80-3.16 (2H, m), 3.44-3.48 (1H, m), 4.17 (1H, dd, J=6.4 Hz, J=11.6 Hz)，4·71 (1H，dd，J=2 Hz，J=11.6 Hz)，6.59 (1H，d， J=5.2 Ήζ), 6.99 (1H, t, J=5.2 Hz), 7.24 (1H, dd5 J=2.8 Hz, J=9.2 Hz)，7.49 (1H，d，J=2.8 Hz)，7·64 (1H，s)，8.07 (1H，s)， 8.27 (1H, d? J=9.2 Hz), 8.73 (1H, d, J=5.2 Hz), 8.76 (1H, s) ° 實施例607 1-(2-氯·4-(6-氰某羥基-3-吡咯啶-1-基丙氣基）… 4啉-4-基氣基）苯基）-3-乙某脲 以與實施例544同樣之方式，從1-(2-氯-4-(6-氰基-(2R)- $ 7-環氧乙烷甲氧喹啉-4-基氧基）-苯基）-3-乙基脲（110 mg) 及吡咯啶，得到為固體之標題化合物（38 mg)。 iH-NMR 光譜（DMSO-d6)5(ppm): 1.07 (3H，t，J=7.2 Hz)， 1.62-1.72 (4H，m)，2.44-2.56 (5H，m)，2.67-2.73 (lH，m)， 3.08-3.16 (2H, m), 3.97-4.04 (1H, m), 4.17-4.23 (1H, m), 4·25-4·32 (1H，m)，5.02 (1H，d，J=4.4 Hz)，6.57 (1H，d，J=5.2 Hz), 6.97-7.03 (1H, m), 7.23 (1H, dd, J=2.4 Hz, J=9.2 Hz), 7·49 (1H，d，J=2.4 Hz)，7.61 (1H，s)，8.07 (1H，s)，8.27 (1H， d，J=9.2 Hz)，8.72 (1H，d，J=5.2 Hz)，8.73 (1H，s)。 實施例6(TS- — 1-(2-氣-4-(6-氰基- 7-((2R)-3·二乙胺基-2-羥丙氣基）4 __- 653 -_ 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 裝 訂----^ 1304061 A7 B7 V. Inventive Note (647) - 543 The title compound (0.31 g) was obtained as a solid. iH-NMR spectrum (DMSO-d6) 5 (ppm): 1·06 (3H, t, J = 7.2 Hz), 2.81 (1H, dd, J = 2.8 Hz, J = 5.2 Hz), 2.91 (1H5 t, J=4.8 Hz), 3.80-3.16 (2H, m), 3.44-3.48 (1H, m), 4.17 (1H, dd, J=6.4 Hz, J=11.6 Hz), 4·71 (1H, dd, J =2 Hz, J=11.6 Hz), 6.59 (1H, d, J=5.2 Ήζ), 6.99 (1H, t, J=5.2 Hz), 7.24 (1H, dd5 J=2.8 Hz, J=9.2 Hz), 7.49 (1H, d, J=2.8 Hz), 7·64 (1H, s), 8.07 (1H, s), 8.27 (1H, d? J=9.2 Hz), 8.73 (1H, d, J=5.2 Hz) ), 8.76 (1H, s) ° Example 607 1-(2-Chloro-4-(6-cyanylhydroxy-3-pyrrolidin-1-ylpropenyl)... 4 phenyl-4-yl) Phenyl)-3-ethylurea in the same manner as in Example 544, from 1-(2-chloro-4-(6-cyano-(2R)-$7-oxiranylmethoxyquinoline- 4-Methoxy)-phenyl)-3-ethylurea (110 mg) mp. iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.07 (3H, t, J = 7.2 Hz), 1.62-1.72 (4H, m), 2.44-2.56 (5H, m), 2.67-2.73 (lH, m), 3.08-3.16 (2H, m), 3.97-4.04 (1H, m), 4.17-4.23 (1H, m), 4·25-4·32 (1H, m), 5.02 (1H, d, J =4.4 Hz), 6.57 (1H,d,J=5.2 Hz), 6.97-7.03 (1H, m), 7.23 (1H, dd, J=2.4 Hz, J=9.2 Hz), 7·49 (1H,d , J=2.4 Hz), 7.61 (1H, s), 8.07 (1H, s), 8.27 (1H, d, J = 9.2 Hz), 8.72 (1H, d, J = 5.2 Hz), 8.73 (1H, s ). Example 6 (TS--1-(2-Ga-4-(6-cyano-7-((2R)-3.diethylamino-2-hydroxypropyl)) 4 __- 653 -_ Paper scale applicable to China National Standard (CNS) A4 specification (210X 297 mm) Binding

1304061 A7 ___B7 五、發明説明（648) K基氧）笨基）-3-乙某月i 以與實施例544同樣之方式，從氰基“2R)-7-環氧乙烷甲氧喹啉-4-基氧基）苯基）_3_乙基脲（1〇〇 mg)及 二乙胺’得到為固體之標題化合物（丨2 mg)。 H-NMR 光 1晉（DMSO-d6)5(ppm): 〇·96 (6H，t，J=7.2 Hz)， 1.06 (3H, t, J=7.2 Hz), 2.42-2.57 (5H, m), 2.64 (1H, dd, J=7.6 Hz, J=13.2 Hz), 3.08-3.16 (2H, m), 3.91-4.00 (1H, m), 4.21 (1H, dd, J=5.2 Hz? J=i〇 Hz), 4.30 (1H, dd, J=3.6 Hz, J=10 Hz), 4.88-4.93 (1H, m), 6.57 (1H, d, J=5.2 Hz), 6.99 (1H5 t, J=4.8 Hz), 7.23 (1H, dd, J=2.8 Hz, J=9.2 Hz), 7.49 (1H，d，J=2.8 Hz)，7.61 (1H，s)，8.06 (1H，s)，8.26 (1H，d，. J=9.2 Hz), 8·72 (1H，d，J=5.2 Hz)，8·73 (1H，s)。 實施例609 — lzj2-氯-4-(0二_氣^-7-((21〇-2-軺甚-3-六氤吡啶_1-某丙氫 基)喹啉-4-某氣）笨基）-3- L其Μ 以與實施例544同樣之方式，從氯-4-(6-氰基-(2R)-7-環氧乙烷甲氧喹啉-4-基氧）苯基）·3·乙基脲（1〇〇 mg)及六 風1:1比淀’传到為固體之標題化合物（46 mg)。 1H-NMR 光譜（DMSO-d6)5(ppm): 1·〇6 (3H，t，J=7.2 Hz)， 1.32-1.39 (2H，m)，1.44-1.53 (4H，m)，2.34-2.51 (6H，m)， 3.08-3.16 (2H, m), 3.99-4.07 (1H, m), 4.19 (1H, dd, J=5.6 Hz, J=10.4 Hz), 4.30 (1H, dd, J=3.2 Hz, J=10.4 Hz), 4.93 (1H, d, J=4.4 Hz)T6.57 (1H, d, J=5.2 Hz), 6.99 (1H, t, J=5.2 Hz), 7.23 (1H, dd, J=2.8 Hz, J=9.2 Hz), 7.48 (1H, d, J=2.8 Hz), _______- 654 -_____ 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） 1304061 A7 B7 五、發明説明（649) 7·62 (1H，s)，8.06 (1H，s)，8.27 (1H，d，J=9.2 Ηζ)，8·72 (1H， d，J=5.2 Hz)，8.72 (1H，s)。 實施例610 1 - (2-氣二jb__(_6- (4-(六氫吡啶-4-基甲氣某）i某V 71^二,比哈并 「2,3-dl嘧啶_4-基氣某）茉某）-3-環丙某月尿 將4-· (4-(4-(3 -氣-4-(3 -環丙脲基）苯基）-7-(2-三甲碎燒乙 氧甲基）-7Η·吡咯并[2,3-d]嘧啶-6-基）苯氧甲基）六氫吡啶_ 1-幾酸弟二丁醋37 mg溶於三氟乙酸1 ml中，在室溫下攪拌 2小時。將反應系減壓濃縮後’添加飽和小蘇打水，調成驗 性’再用乙酸乙酯分液萃取。將有機層用硫酸鈉乾燥，且 濃縮至乾’得到標題化合物2 5 mg ^ - MS 光譜（ESI) : 533(M+1) 實施例611 — 1λ—(—2-氯-4-丨6- ( 4- ( 1 -甲六氫吡啶-4-基甲氣基）茉某I 7TT-朴k 咯并『2,3-dl嘧啶-4·基氣某}茉某）-3-環丙某脫 於1-(2-氯-4- { 6· [4-(六氫吡啶-4-基甲氧基）苯基]- 7H-吡 咯并[2,3-d]嘧啶-4-基氧卜2-苯基）-3-環丙基脲24 mg中， 添加甲醇2 ml、二氯甲烷2 m卜37%甲醛水溶液〇.〇5 ml及乙 酸4.4// 1，且在攪拌下添加三乙醯氧基硼氫化物30 mg ,於 室溫下攪捽40分鐘。加水，藉由乙酸乙酯-四氫呋喃5 ·· 1混 合溶媒萃取後，濃縮，付諸於NH矽凝膠管柱層析，得到標 題化合物12 mg。 MS光譜（&amp;ST) : 547(M+1) 實施例612 ____- 655 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）1304061 A7 ___B7 V. INSTRUCTION DESCRIPTION (648) K-based oxy) stanyl)-3-E-May i In the same manner as in Example 544, from cyano "2R)-7-oxirane methoxyquinoline -4-yloxy)phenyl)_3_ethylurea (1 mg) and diethylamine' gave the title compound (2 mg) as a solid. H-NMR light 1 (DMSO-d6)5 (ppm): 〇·96 (6H, t, J=7.2 Hz), 1.06 (3H, t, J=7.2 Hz), 2.42-2.57 (5H, m), 2.64 (1H, dd, J=7.6 Hz, J=13.2 Hz), 3.08-3.16 (2H, m), 3.91-4.00 (1H, m), 4.21 (1H, dd, J=5.2 Hz? J=i〇Hz), 4.30 (1H, dd, J= 3.6 Hz, J=10 Hz), 4.88-4.93 (1H, m), 6.57 (1H, d, J=5.2 Hz), 6.99 (1H5 t, J=4.8 Hz), 7.23 (1H, dd, J=2.8 Hz, J=9.2 Hz), 7.49 (1H, d, J=2.8 Hz), 7.61 (1H, s), 8.06 (1H, s), 8.26 (1H, d, J = 9.2 Hz), 8.72 (1H, d, J = 5.2 Hz), 8.73 (1H, s). Example 609 - lzj2-chloro-4-(0 di-gas^-7-((21〇-2-轺--3) - hexamidine pyridine-1 - a propylhydrogen) quinolin-4-one gas) phenyl)-3- L oxime in the same manner as in Example 544, from chloro-4-(6-cyano-( 2R)-7-Ethylene oxide methoxyquinolin-4-yloxy)phenyl)·3·ethyl (1 〇〇 mg) and hexafil 1:1 ratio of the title compound (46 mg) as a solid. 1H-NMR spectrum (DMSO-d6) 5 (ppm): 1·〇6 (3H, t, J=7.2 Hz), 1.32-1.39 (2H, m), 1.44-1.53 (4H, m), 2.34-2.51 (6H, m), 3.08-3.16 (2H, m), 3.99-4.07 (1H, m) , 4.19 (1H, dd, J=5.6 Hz, J=10.4 Hz), 4.30 (1H, dd, J=3.2 Hz, J=10.4 Hz), 4.93 (1H, d, J=4.4 Hz) T6.57 ( 1H, d, J=5.2 Hz), 6.99 (1H, t, J=5.2 Hz), 7.23 (1H, dd, J=2.8 Hz, J=9.2 Hz), 7.48 (1H, d, J=2.8 Hz) , _______- 654 -_____ This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1304061 A7 B7 V. Invention description (649) 7·62 (1H, s), 8.06 (1H, s ), 8.27 (1H, d, J = 9.2 Ηζ), 8.72 (1H, d, J = 5.2 Hz), 8.72 (1H, s). Example 610 1 - (2-gas two jb__(_6-(4-(hexahydropyridin-4-ylmethyl)) some V 71^2, Biha and "2,3-dl pyrimidine-4-yl Qi)) Mo) -3-cyclopropyl urinary urea 4-(4-(4-(3-cyclo-4-(3-cycloprop)ureido)phenyl)-7-(2-trimethacrylate Ethyloxymethyl)-7Η·pyrrolo[2,3-d]pyrimidin-6-yl)phenoxymethyl)hexahydropyridine _ 1-acid dibutyl vinegar 37 mg dissolved in trifluoroacetic acid 1 ml The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then the mixture was stirred and evaporated, and then the mixture was taken to ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness. 'Yield the title compound 2 5 mg ^ - MS spectrum (ESI): 533 (M+1) Example 611 - 1 λ - (- 2- chloro-4- 丨 6 - ( 4- ( 1 - hexahydropyridine - 4 - 甲甲气基) 茉一 I 7TT-朴k 咯和『2,3-dl-pyrimidine-4·基气某} 茉)-3-Cyclopropane detached from 1-(2-chloro-4- { 6. [4-(Hexahydropyridin-4-ylmethoxy)phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-yloxybu-2-phenyl)-3-cyclopropyl In 24 mg of urea, add 2 ml of methanol, 2 m of dichloromethane, 37% of formaldehyde solution, 〇5 ml and acetic acid 4.4//1, and stir Add 30 mg of triethoxyphosphonium borohydride and stir for 40 minutes at room temperature. Add water, extract with ethyl acetate-tetrahydrofuran 5 ··1 mixed solvent, concentrate, and put into NH矽 gel tube Column chromatography gave the title compound 12 mg. MS spectrum (&amp;ST): 547 (M+1) Example 612 ____- 655 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)

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線 1304061 A7 ____ B7 五、發明説明（~' 氣埽雨胧某）苯氣某卜7·(2_三甲矽烷乙 氧_〒基）-7Η-吡咯并r23_di嘧啶-6-基氧甲某}六氤吡啶-1 -羧酸第三丁酿 於1- {2-氯[6-(4-羥苯基）-7-(2-三甲矽烷乙氧甲基）-7mt嘻并[2,3-d]嘧啶-4-基氧基]-2-苯基卜3-環丙基脲60 mg中’添加4-溴甲基六氫吡啶-1 -羧酸第三丁酯3 8 mg、碳 酸鉀59 mg及二甲基甲醯胺！ m卜在70-75°c攪拌6小時。然 後’讓弟·回到室溫並加水，再用乙酸乙酿分液萃取。將齐 機層用硫酸鈉乾燥，且濃縮至乾涸，得到標題化合物63 mg 〇 MS光譜（ESI) : 766(M+23) : 實施例613 m3-二甲基_4_(甲胺羰某）胺茉氫某甲氧其沘 羧醯胺 藉由與實施例11同樣之方法，從N-(4-(6-胺甲醯基-7-甲 氧基-4-喹啉基）氧·2,3-二甲苯基）胺甲酸苯酯（^6 mg)及甲 胺（2M四氫吱喃溶液），得到為無色結晶之標題化合物（3〇 mg)。 iH-NMR光譜（DMSO-d6)5(ppm): 2·01 (3H，s)，2.14 (3H，s)， 2.64 (3H, d, J=3.2 Hz), 4.01 (3H, s), 6.24 (1H, d, J=5.2 Hz), 6.28 (1H, d, J=4.4 Hz), 6.97 (1H, d, J=8.8 Hz), 7.49 (1H, s), 7·60 (1H，d，J=8.4 Hz), 7.73-7.85 (3H，m)，8.59 (1H，d，J=4.8Line 1304061 A7 ____ B7 V. Invention Description (~' 埽 埽 ) ) 苯 苯 某 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Hexapuridine-1 -carboxylic acid tert-butyl is derived from 1-{2-chloro[6-(4-hydroxyphenyl)-7-(2-trimethyldecaneethoxymethyl)-7mt嘻[2,3 -d]pyrimidin-4-yloxy]-2-phenyl- 3-cyclopropylurea 60 mg in the addition of 4-bromomethylhexahydropyridine-1 -carboxylic acid tert-butyl ester 38 mg, carbonic acid Potassium 59 mg and dimethylformamide! The m was stirred at 70-75 ° C for 6 hours. Then, let the younger brother return to room temperature and add water, and then extract with AC acetate. The kiln layer was dried over sodium sulfate and concentrated to dryness eluting elut elut elut elut elut elut elut elut elut elut Molybdenum methoxide carboxy carbamide was obtained from N-(4-(6-aminocarbamimid-7-methoxy-4-quinolinyl)oxy-2 by the same method as in Example 11. Phenyl 3-methylphenyl)carbamate (^6 mg) and methylamine (2M in tetrahydromethane) afforded the title compound (3 mg). iH-NMR spectrum (DMSO-d6) 5 (ppm): 2·01 (3H, s), 2.14 (3H, s), 2.64 (3H, d, J = 3.2 Hz), 4.01 (3H, s), 6.24 (1H, d, J=5.2 Hz), 6.28 (1H, d, J=4.4 Hz), 6.97 (1H, d, J=8.8 Hz), 7.49 (1H, s), 7·60 (1H,d, J=8.4 Hz), 7.73-7.85 (3H,m), 8.59 (1H,d,J=4.8

Hz)，8.71 十 1Ή，s) 0 實施例614 _____- 656 - 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐） 1304061 A7 B7 五、發明説明（651) 4^12,3-二甲某-4-(乙胺羰基）胺笨氣基）-7-甲氳某-6-4毗 羧醯脖 藉由與實施例11同樣之方法，從N-(4-(6-胺甲醯基-7-甲 氧基-4-喹啉基）氧-2,3-二甲苯基）胺甲酸苯酯（55 mg)及乙 胺（2M四氫吱喃溶液），得到為無色結晶之標題化合物（33 mg) 〇 - W-NMR 光譜（DMSO-d6)5(ppm): 1·54 (3H，t，J=7 Hz), 2.01 (3H5 s), 2.14 (3H, s), 3.07-3.12 (2H, m), 4.01 (3H, s), 6.24 (1H, d, J=4.8 Hz), 6.41 (1H, m), 6.97 (1H, d, J=8.4 Hz), 7.49 (1H, s), 7.64 (1H, d, J=8.8 Hz), 7.73 (2H, br s), 7.85 (1H, s), 8·59 (1H，d，J=5.2 Hz), 8.71 (1H，s)。 ^ 實施例61 5 _一 U 3-氯-4-(((環丙胺基）羰基）胺某）茉氫某）· 7- ((2RV 2\旋S 基- 3- ( 1-p比哈淀基）丙氣基）-6·ρ奋g林籍g產脖 在4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧基）-7_羥基_ 6-喹啉羧醯胺（372.0 mg，0.90 mmol)中，添加4-甲基-1-苯 績酸（2 R)環氧乙虎-2-基甲醋（308 mg，1.35 mmol)、碳酸卸 (149 mg ’ 1.08 mmol)及二甲基甲酿胺（9 ml)，於 60 °C 攪拌 7 小時。將反應液放冷至室溫後，添加K7比洛淀（1 ml)，進一 步攪拌一整晚。將反應液分溶於乙酸乙酯及水中，將有機 層用水及飽和食鹽水洗淨，用無水硫酸鈉乾燥。將溶媒餘-去’付諸於矽凝膠管柱層析（溶出液為乙酸乙酯：甲醇 =95 : 5).…再將含有目的物之溶出份濃縮後，濾取從乙酸乙 一 酯中析出之結晶’藉由通風乾燥，得到為白色結晶之標題 -657 -Hz), 8.71 Ή1Ή, s) 0 Example 614 _____- 656 - This paper scale applies to China National Standard (CNS) A4 specification (210x 297 mm) 1304061 A7 B7 V. Description of invention (651) 4^12,3 - dimethyl-4-(ethylamine carbonyl)amine stupid base)-7-methyl hydrazine-6-4 carbaryl oxime by the same method as in Example 11, from N-(4-(6- Phenylmethylmercapto-7-methoxy-4-quinolinyloxy-2,3-xylyl)carbamate (55 mg) and ethylamine (2M tetrahydrofuran) gave colorless Crystalline title compound (33 mg) 〇-W-NMR spectrum (DMSO-d6) 5 (ppm): 1·54 (3H, t, J=7 Hz), 2.01 (3H5 s), 2.14 (3H, s) , 3.07-3.12 (2H, m), 4.01 (3H, s), 6.24 (1H, d, J=4.8 Hz), 6.41 (1H, m), 6.97 (1H, d, J=8.4 Hz), 7.49 ( 1H, s), 7.64 (1H, d, J=8.8 Hz), 7.73 (2H, s s), 7.85 (1H, s), 8·59 (1H, d, J=5.2 Hz), 8.71 (1H, s). ^ Example 61 5 _-U 3-chloro-4-(((cyclopropylamino)carbonyl)amine)))))))))淀基)丙气基)-6·ρ奋g林林g produced neck in 4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6 -Quinolinylcarboxamide (372.0 mg, 0.90 mmol), 4-methyl-1-benzoic acid (2 R) Ethylene-2-methylacetate (308 mg, 1.35 mmol), carbonic acid unloading (149 mg '1.08 mmol) and dimethyl ketoamine (9 ml), stir at 60 °C for 7 hours. After cooling the reaction solution to room temperature, add K7 piroxicam (1 ml) and stir further. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The liquid was ethyl acetate: methanol = 95: 5).... The concentrate containing the desired product was concentrated, and the crystals precipitated from the ethyl acetate were filtered off by air drying to obtain the title of white crystal - 657 -

1304061 A7 B7 五、發明説明（652) 化合物（133.3 mg，0.247 mmol ’ 27.4%)。 j-NMR光譜（DMSO-d6)5(ppm): 〇·42 (2H，m)，〇 65 (2H，瓜)， 1·67 (4H，m)，2.45-2.59 (6H，m)，2·69 (1H，m)，4 〇5 (1H，m)， 4.19 (1H，dd，&gt;6.0, 10.0 Hz)，4.32 (1H，dd，J=3 6, 1〇 〇 Hz)， 5.19 (1H, d5 J=4.8 Hz), 6.51 (1H, d, J==5.2 Hz)5 7.18 (1H, d! J-2.8 Hz)，7·24 (1H，dd，J=2.8，8·8 Hz)，7·49 (1H，d，J=2.81304061 A7 B7 V. INSTRUCTIONS (652) Compound (133.3 mg, 0.247 mmol ' 27.4%). j-NMR spectrum (DMSO-d6) 5 (ppm): 〇·42 (2H, m), 〇65 (2H, melon), 1·67 (4H, m), 2.45-2.59 (6H, m), 2 · 69 (1H,m),4 〇5 (1H,m), 4.19 (1H,dd,&gt;6.0, 10.0 Hz), 4.32 (1H,dd,J=3 6, 1〇〇Hz), 5.19 ( 1H, d5 J=4.8 Hz), 6.51 (1H, d, J==5.2 Hz)5 7.18 (1H, d! J-2.8 Hz), 7·24 (1H, dd, J=2.8, 8·8 Hz ),7·49 (1H,d,J=2.8

Hz), 7.53 (1H, s), 7.82 (1H, s), 7.97 (1H, s), 7.99 (1H, s)5 8.26 (1H，d，J=8.8 Hz)，8·66 (1H，d，j=5.2 Hz)，8.80 (1H， s)。 ’ 實施例616Hz), 7.53 (1H, s), 7.82 (1H, s), 7.97 (1H, s), 7.99 (1H, s)5 8.26 (1H,d,J=8.8 Hz),8·66 (1H,d , j = 5.2 Hz), 8.80 (1H, s).例 Example 616

Mz..{「4-(6·胺甲醯某-7: T虱基氣卜2_甲苽某 Llv氟笨某甲某版 將6-胺甲醯基_4_氣_7_甲氧基喹啉（i〇〇 ，〇·-2982 mm〇1)、N_(4.乳苯基）_Νι_(4_幾基_2甲苯基）_Ν,_甲基脉 (100 mg ’ 0.2917 _〇1)及二異丙基乙胺（〇」mi，〇 4375 賴〇1)溶於N_甲基料㈣⑶.丨ml)中在15代加熱授約 小時°冷卻至室溫後’於反應溶液中加水，用乙酸乙醋萃 取，以飽和食鹽水洗淨，用無水硫酸鎂乾燥，以及將溶媒 減壓餾去。將殘餘物藉由矽凝膠管柱層析法（己烷•乙酸乙 酯•乙醇）繼而NH矽凝膠管柱層析法（己烷•乙酸乙酯•乙 醇）精製，於得到之無定形物中添加乙醚並使之懸浮，再將 其以己烷稀釋，濾取結晶及用乙醚：己烷=1 : i洗淨，抽氣 乾燥後’得到為淡黃色結晶之標題化合物（11 mg，0.023 mmol » 7.95%) 本紙張尺度適财S國家標準.S} A4規格(210X297公梦)— 1304061 A7 B7 五、發明説明（653) : 1H-NMR 光譜（DMSO-d6)5(ppm): 2·21 (3H，s)，3.16 (3H，s)， 4.02 (3Η, s), 6.71 (1H, d, J=5.2 Hz), 7.05 (2H, t, J=8.8 Hz), 7.18 (1H, dd, J=2.8 Hz, 8.4 Hz), 7.28 (1H, d, J=2.8 Hz), 7.39-7.44 (3H, m), 7.51 (1H, s), 7.72 (1H, br s), 7.84 (1H, br s)，7·89 (1H，br s)，8·66 (1H，s)，8·70 (1H，d，J=5.2 Hz)。 起始原料係以下述之方法合成。 製造例616-1 4-芊氣基-2-甲某笨胺 將4_胺基-3-甲盼（10 g ’ 81.20mmol)溶於二甲基亞職（8〇 ml)中，再添加氫化鈉（3.25 g，81.20 mmol，60%於油中）， 在氮氣蒙氣及室溫下授拌15分鐘。於其中添加苄基溴化物 (4.83 ml，40.60 mmol)，在氮氣蒙氣及室溫下授拌一整r: 〜1 **:·二， 夜。於反應溶液中加水，用乙醚及四氫呋喃萃取，以奋和 食鹽水洗淨，用無水硫酸鎂乾燥，以及將溶媒減壓館去。 將殘餘物用碎凝膠吸附，藉由碎凝膠管柱層析（以己虎•乙 酸乙酯•乙醇溶析）繼而NH矽凝膠管柱層析（己烷•乙酸乙 酯）精製，得到為紫色油狀物之標題化合物（6.55 g , 30.72 mmol，75.64%) 〇 W-NMR 光譜（CDCl3)5(ppm): 2·16 (3H，s)，3·36 (2H，br s)， 4.99 (2Η，s)，6·61 (1Η，d，J=8.4 Ηζ)，6.69 (1Η，dd，J=2.8 Ηζ， 8.4 Hz)，6.75 (1H，d，J=2.8 Hz), 7·30 (ih，t，J=6.8 Hz)，7.37 (2H，t，J=6.8 Hz), 7.42 (2H，d，J=6.8 Hz)。 製造例61石4 一 N-甲某-4-芊氣基-2-甲某茇胺 _____- 659 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（654) : 將4-苄氧基-2-甲基苯胺（6.55 g，30.72 mmol)溶於N，N-二 甲基甲醯胺（10 ml)及甲醇（60 ml)中，再添加1H-苯并三唑-1-甲醇（4.58 g，30.72 mmol)，在室溫下攪拌〇·5小時。於其 中添加N，N-二甲基甲醯胺（20 ml)，將析出之結晶完全溶 解，在室溫下逐次添加少量氫化硼鈉（2.32 g，61.44 mmol)(内溫上升），以原樣揽拌0.5小時。於反應溶液中加 水，用乙酸乙酯萃取，以飽和食鹽水洗淨，用無水硫酸鎂 乾燥，Θ及將溶媒減壓餾去。將殘餘物用矽凝膠吸附，藉 由矽凝膠管柱層析（以己烷•乙酸乙酯溶析）精製，得到為 褐色油狀物之標題化合物（4.364 g，19.20 mmol， 62.49%)。 - 1H-NMR 光譜（CDCl3)5(ppm): 2·13 (3H，s)，2·86 (3H，s)，: :: 4.99 (2H, s), 6.24 (1H, d, J=9.6 Hz), 6.79-6.81 (2H, m), 7.30 (1H，t，J=6.8 Hz)，7·37 (2H，t，J=6.8 Hz)，7.43 (2H，d，J=6.8Mz..{"4-(6·amine-methyl 醯-7: T虱基气卜2_甲苽Llv fluoro-something a certain version of 6-amine formazan _4_gas_7_methoxy Benzyl quinoline (i〇〇, 〇·-2982 mm〇1), N_(4. lyophilyl)_Νι_(4_benzyl-2-tolyl)_Ν, _methyl vein (100 mg ' 0.2917 _〇1 And diisopropylethylamine (〇)mi, 〇4375 〇1) dissolved in N_methyl (4) (3). 丨ml) in 15 generations of heating for about hours. After cooling to room temperature, 'in the reaction solution Water was added, and the mixture was extracted with EtOAc (EtOAc). The residue was purified by hydrazine gel column chromatography (hexane, ethyl acetate, ethyl alcohol) followed by NH? gel column chromatography (hexane, ethyl acetate, ethyl alcohol). Diethyl ether was added to the residue and the residue was crystallised eluted eluted eluted eluted eluted eluted eluted eluted 0.023 mmol » 7.95%) This paper scale is suitable for S national standard. S} A4 specification (210X297 public dream) - 1304061 A7 B7 V. Description of invention (653) : 1H-NMR spectrum (DMSO-d6) 5 (ppm): 2·21 (3H, s), 3.16 (3H, s), 4.02 (3Η, s), 6.71 (1H, d, J=5.2 Hz), 7.05 (2H, t, J=8.8 Hz), 7.18 (1H , dd, J=2.8 Hz, 8.4 Hz), 7.28 (1H, d, J=2.8 Hz), 7.39-7.44 (3H, m), 7.51 (1H, s), 7.72 (1H, br s), 7.84 ( 1H, br s), 7·89 (1H, br s), 8.66 (1H, s), 8.70 (1H, d, J = 5.2 Hz). The starting materials were synthesized in the following manner. Production example 616-1 4-Indolyl-2-methyl strepamine A 4-amino-3-methyl (10 g '81.20 mmol) was dissolved in a dimethyl sub-unit (8 〇 ml), and then added Sodium hydride (3.25 g, 81.20 mmol, 60% in oil) was stirred for 15 min under nitrogen atmosphere and room temperature. Benzyl bromide (4.83 ml, 40.60 mmol) was added thereto, and the mixture was stirred at room temperature under nitrogen atmosphere and at room temperature: 〜1 **:·2, night. Water was added to the reaction solution, and the mixture was extracted with diethyl ether and tetrahydrofuran, washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was adsorbed by a pulverized gel, and purified by a gel column chromatography (eluent elution with hexane, ethyl acetate, ethanol) followed by NH(R) gel column chromatography (hexane ethyl acetate). The title compound was obtained as a purple oil (6.55 g, 30.72 mmol, 75.64%) 〇W-NMR spectrum (CDCl3) 5 (ppm): 2·16 (3H, s), 3·36 (2H, br s) , 4.99 (2Η, s), 6.61 (1Η, d, J=8.4 Ηζ), 6.69 (1Η, dd, J=2.8 Ηζ, 8.4 Hz), 6.75 (1H, d, J=2.8 Hz), 7 · 30 (ih, t, J = 6.8 Hz), 7.37 (2H, t, J = 6.8 Hz), 7.42 (2H, d, J = 6.8 Hz). Production Example 61 Stone 4 N-A -4- 芊 基 -2- 茇 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ V. INSTRUCTIONS (654): 4-Benzyloxy-2-methylaniline (6.55 g, 30.72 mmol) was dissolved in N,N-dimethylformamide (10 ml) and methanol (60 ml) Further, 1H-benzotriazole-1-methanol (4.58 g, 30.72 mmol) was added, and the mixture was stirred at room temperature for 5 hours. N,N-dimethylformamide (20 ml) was added thereto, and the precipitated crystals were completely dissolved, and a small amount of sodium borohydride (2.32 g, 61.44 mmol) was added successively at room temperature (increased internal temperature) as it was. Mix for 0.5 hours. Water was added to the reaction solution, and the mixture was extracted with EtOAc. The residue was purified by EtOAc EtOAc EtOAc elut elut elut elut elut elut elut elut . - 1H-NMR spectrum (CDCl3) 5 (ppm): 2·13 (3H, s), 2·86 (3H, s),: :: 4.99 (2H, s), 6.24 (1H, d, J=9.6 Hz), 6.79-6.81 (2H, m), 7.30 (1H, t, J=6.8 Hz), 7·37 (2H, t, J=6.8 Hz), 7.43 (2H, d, J=6.8

Hz) 〇 製造例616-3 N二(4-氟苯基羥基-2-甲茉基）-N，-甲某服 將N-甲基-4-苄氧基-2-甲基苯胺（2.64 g，11.61 mmol)溶 於N，N-二甲基甲醯胺（2〇 mi)中，再添加氫化鈉（116 g， 29.00 mm〇l ’ 6〇%於油中），以及在氮氣蒙氣及85。〇下攪拌 45分鐘。於其中添加N-(4_氟苯基）胺甲酸苯酯（3.5〇 g , 一 12.76 mmol)，進而在氮氣蒙氣及85。〇下攪拌丨小時。冷卻 至室溫後〜，-於反應溶液中加水，用乙酸乙酯萃取，以飽和 一 食鹽水洗淨，用無水硫酸鎂乾燥，以及將溶媒減壓餾去。 -------- -- DDU - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇 χ 297公釐） 1304061 A7 ___ B7 五、發明説明（咖） 二、 將殘餘物用NH矽凝膠吸附，藉由NH矽凝膠管柱層析（以己 烷•乙酸乙酯•乙醇溶析）精製，得到為黃色油狀物之 (4-芊氧基-2-甲苯基）-N-(4_氟苯基）-N’-甲基脲（2.66 g)。 將其溶於甲醇（50 ml)，添加10%鈀/碳（〇·2 g)，並在氫氣蒙 氣及室溫下攪拌2小時。濾去觸媒，用乙醇洗淨後，減壓餾 去溶媒。將析出之結晶於乙醇中懸浮，用乙醚及己烷稀釋 後，濾取結晶，用己烷洗淨，再抽氣乾燥，得到為褐色結 晶之標題化合物（0.83 g，3.0258 mmol，41.86%)。 iH-NMR光譜（DMSO-d6)5(ppm): 2·07 (3H，s)，3.04 (3H，s)， 6.63 (1Η, d, J=8.0 Hz), 6.67 (1H, s), 6.97-7.03 (3H, m), 7·34-7·39 (2H，m)，7.54 (1H，bi: s)，9·46 (1H，s)。 _ 實施例617 ·' : Ν· Π4-(7_芊氡基_ 6-氰基-4- 林某）氳1-2-甲笨基} - Nr-74- Ί 氣笨基甲基脲 將6_氰基-4-氯-7-甲氧基喹啉（90 mg，0.303 8 mmol)及N-(4-氟苯基）-N*-(4-羥基-2-甲苯基）-Nf -甲基脲（100 mg， 0.3 646 mmol)溶於二甲基甲醯胺（3 ml)中，再添加氫化鈉 (15 mg，0.3646 mmol)，在氮氣蒙氣及85°C下攪拌1小時。 冷卻至室溫後，於反應溶液中加水，用乙酸乙酯萃取，以 飽和食鹽水洗淨，用無水硫酸鎂乾燥，以及將溶媒減壓餾 去。將殘餘物藉由NH矽凝膠管柱層析（乙酸乙酯）精製，將 ' 得到之結晶懸浮於乙醚中，濾取且用乙醚洗淨，再抽氣乾· 燥後，得為粉紅色結晶之標題化合物（80 mg，0.1502 一 mmol，49.44%)。 -661 - ^紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（656) ” 1H-NMR 光譜（DMSO-d6)5(ppm): 2·21 (3H，s)，3.16 (3H，s)， 5.46 (2Η, s), 6.76 (1H, d, J=5.4 Hz), 7.05 (2H, t, J=8.8 Hz), 7.20 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.29 (1H, d, J=2.4 Hz), 7.34-7.46 (6H, m), 7.54 (2H, d, J=6.8 Hz), 7.72 (1H, s), 7.91 (1H，br s)，8·75 (1H，s)，8·77 (1H，d，J=5.4 Hz)。 實施例618 N-{「4-(6-胺甲醯某-7-甲氫基-4-4啉某）氫1-2-氣茉基}-N’-(4-氣笨基卜N-甲基脲 . 將6-胺甲醯基-4-氯-7-甲氧基喹啉（41 mg，0.1744 mmol) 及N-(2-氟-4-羥苯基）-N、（4-氟苯基）-N-甲基脲（57 mg， Ο·2048 mmol)溶於二甲基亞减（1 ·0 ml)中，再添加氫化納… (8.4 mg，0.2093 mmol)，在85°C下加熱擾拌0.5小時。將反：工〜 應溶液冷卻至室溫後，於反應溶液中加水，濾取析出之結二 晶。將該結晶進一步懸浮於丙酮：乙醚=1 : 2中，再度濾取 結晶且用乙醚洗淨，抽氣乾燥後，得到為黃色結晶之標題 化合物（46 mg，0.0961 mmol，55.13%)。 h-NMR 光譜（DMSO-d6)5(ppm): 3.44 (3H，s)，4.01 (3H，s)， 6.44 (1H, d, J=5.4 Hz), 6.99 (1H, br s), 7.10 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.34 (2H, t, J=8.8 Hz), 7.38 (1H, d, J=8.4 Hz), 7.47 (1H, s), 7.59 (2H, dd, J=5.0 Hz, 8.8 Hz), 7.69 (1H, br s)? 7.81 (1H，br s)，8.59 (1H，d，J=5.4 Hz), 8·69 (1H，s)。 起始原料係以下述方法合成。 一 製造例6HT 4-字氣基_2_氣硝基笨 ___- 662 ·______ 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） A7 B7 1304061 五、發明説明（657) 二、 將3 -氟-4-硝基紛（10 g，63.65 mmol)溶於N，N-«二甲基甲 醯胺（120 ml)中，再添加氫化鈉（2.68 g，67.00 mmo卜60% 於油中），在氮氣蒙氣及室溫下攪摔15分鐘。於其中添加爷 基溴化物（7.6 ml，63.65 mmol)，在氮氣蒙氣及室溫下攪拌 一整夜。於反應溶液中加入水，滤取析出之結晶，以水洗 淨，抽氣乾燥後，得到為淡黃色結晶之標題化合物之粗結 晶（16.06 g，定量產出）。不需更進一步精製，直接使用於 以下之反應。 A-NMR 光譜（DMSO-d6)5(ppm): 5.25 (2H，s)，7·04 (1H，dd， J=1.6 Ηζ，9·2 Hz), 7.27 (1H, dd, J=2.8 Hz, 14.0 Hz), 7.32^ 7.42 (3H, m), 7.46 (2H, d, J=6.8 Hz), 8.15 (1H, t, J=9.2 Hz) 〇 —製造例 61 8 - 2 一 'S. 4-芊氣基-2-氣笨胺 將4-卞氧基·2_氣硝基本粗結晶（16.06 g ’ 63.65 πιπιοί)溶 於乙醇（1000 ml)及水（200 ml)中，添加電解鐵粉（14.0 g， 254.60 mmol)及氯化按（27·2 g，509.20 mmol)，並加熱回流 4.5小時。將反應溶液冷卻至室溫附近，濾去不溶物，以乙 醇洗淨後，將濾液之溶媒減壓館去。殘餘物於乙酸乙酯中 溶解，以飽和食鹽水洗淨，用無水硫酸鎂乾燥，以及將溶 媒減壓餾去。將殘餘物用矽凝膠吸附，且藉由矽凝膠管柱 ' 層析法（己烷•乙酸乙酯）精製，得到為褐色油狀物之標題 化合物（1H5 g-，51.78 mmo卜 81·35%)。 一 W-NMR 光譜（CDCl3)5(ppm): 3·44 (2Η，br s)，4.98 (2Η，s)， __ 663 - 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐） 1304061 A7Hz) 〇Production Example 616-3 N-di(4-fluorophenylhydroxy-2-methylmethyl)-N,-A, N-methyl-4-benzyloxy-2-methylaniline (2.64) g, 11.61 mmol) was dissolved in N,N-dimethylformamide (2 〇mi), then sodium hydride (116 g, 29.00 mm〇l '6〇% in oil) was added, and nitrogen gas was added. And 85. Stir under the arm for 45 minutes. Phenyl N-(4-fluorophenyl)carbamate (3.5 〇 g, a 12.76 mmol) was added thereto, followed by nitrogen gas and 85. Stir under the armpit for a few hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated. -------- -- DDU - This paper scale applies to China National Standard (CNS) A4 specification (21〇χ 297 mm) 1304061 A7 ___ B7 V. Invention description (Caf) 2. Residues are NH矽 Gel adsorption, purified by NH 矽 gel column chromatography (eluent eluting with hexane, ethyl acetate, ethanol) to give (4-methoxy-2-methylphenyl) as a yellow oil. N-(4-Fluorophenyl)-N'-methylurea (2.66 g). This was dissolved in methanol (50 ml), 10% palladium/carbon (〇·2 g) was added, and stirred under hydrogen atmosphere at room temperature for 2 hours. The catalyst was filtered off, washed with ethanol, and the solvent was evaporated under reduced pressure. The precipitated crystals were suspended in EtOAc (EtOAc m.) iH-NMR spectrum (DMSO-d6) 5 (ppm): 2·07 (3H, s), 3.04 (3H, s), 6.63 (1 Η, d, J = 8.0 Hz), 6.67 (1H, s), 6.97 -7.03 (3H, m), 7·34-7·39 (2H, m), 7.54 (1H, bi: s), 9.46 (1H, s). _ Example 617 · ' : Ν· Π 4-(7_芊氡基_ 6-Cyano-4-Lin) 氲1-2-甲基基} - Nr-74- Ί 笨 基 甲基 methyl urea 6-Cyano-4-chloro-7-methoxyquinoline (90 mg, 0.303 8 mmol) and N-(4-fluorophenyl)-N*-(4-hydroxy-2-methylphenyl)-Nf -Methylurea (100 mg, 0.3 646 mmol) was dissolved in dimethylformamide (3 ml), then sodium hydride (15 mg, 0.3646 mmol) was added and stirred under nitrogen at 85 ° C for 1 hour. . After cooling to room temperature, water was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated. The residue was purified by NH.sub.2 gel column chromatography (ethyl acetate). The crystals obtained were suspended in diethyl ether, filtered, washed with diethyl ether, and then evaporated to dryness. The title compound (80 mg, 0.1502 mmol, 49.44%). -661 - ^The paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Description of invention (656) ” 1H-NMR spectrum (DMSO-d6) 5 (ppm): 2·21 ( 3H, s), 3.16 (3H, s), 5.46 (2Η, s), 6.76 (1H, d, J=5.4 Hz), 7.05 (2H, t, J=8.8 Hz), 7.20 (1H, dd, J =2.4 Hz, 8.4 Hz), 7.29 (1H, d, J=2.4 Hz), 7.34-7.46 (6H, m), 7.54 (2H, d, J=6.8 Hz), 7.72 (1H, s), 7.91 ( 1H, br s), 8·75 (1H, s), 8.77 (1H, d, J = 5.4 Hz). Example 618 N-{"4-(6-Aminomethyl hydrazine-7-methylhydrogen) -4-4 porphyrin a) hydrogen 1-2-aero-mosquito}-N'-(4-gas phenyl group N-methylurea. 6-aminoformamido-4-chloro-7-methoxy Base quinoline (41 mg, 0.1744 mmol) and N-(2-fluoro-4-hydroxyphenyl)-N, (4-fluorophenyl)-N-methylurea (57 mg, Ο·2048 mmol) In the dimethyl sub-subtraction (1 · 0 ml), add sodium hydride (8.4 mg, 0.2093 mmol), and stir at 85 ° C for 0.5 hour. React: After the solution is cooled to room temperature Adding water to the reaction solution, and filtering out the precipitated crystals. The crystal is further suspended in acetone:diethyl ether = 1:2, and the crystals are again filtered and used. The title compound (46 mg, 0.0961 mmol, 55.13%) was obtained eluted eluted eluted eluted eluted eluted 3H, s), 6.44 (1H, d, J=5.4 Hz), 6.99 (1H, br s), 7.10 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.34 (2H, t, J=8.8 Hz) ), 7.38 (1H, d, J=8.4 Hz), 7.47 (1H, s), 7.59 (2H, dd, J=5.0 Hz, 8.8 Hz), 7.69 (1H, br s)? 7.81 (1H,br s ), 8.59 (1H, d, J = 5.4 Hz), 8·69 (1H, s). The starting materials were synthesized by the following method: A manufacturing example 6HT 4-word gas base_2_qi nitro stupid ___ - 662 ·______ This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 1304061 V. Description of invention (657) II. 3-Fluoro-4-nitro (10 g, 63.65 mmol) Dissolved in N,N-«dimethylformamide (120 ml), then add sodium hydride (2.68 g, 67.00 mmo, 60% in oil), and stir for 15 minutes under nitrogen atmosphere and room temperature. The keto bromide (7.6 ml, 63.65 mmol) was added thereto, and the mixture was stirred overnight under nitrogen atmosphere and room temperature. Water was added to the reaction solution, and the precipitated crystals were filtered, washed with water, and evaporated to dryness to give crystals of the title compound (16.06 g, quantitative yield). It can be directly used in the following reactions without further purification. A-NMR spectrum (DMSO-d6) 5 (ppm): 5.25 (2H, s), 7·04 (1H, dd, J = 1.6 Ηζ, 9·2 Hz), 7.27 (1H, dd, J = 2.8 Hz , 14.0 Hz), 7.32^ 7.42 (3H, m), 7.46 (2H, d, J=6.8 Hz), 8.15 (1H, t, J=9.2 Hz) 〇—Manufacturing Example 61 8 - 2 A 'S. 4- Helium-based 2-epoxyamine 4-(oxy)- 2-nitro-nitrogen (16.06 g '63.65 πιπιοί) is dissolved in ethanol (1000 ml) and water (200 ml), and electrolytic iron powder is added ( 14.0 g, 254.60 mmol) and chlorinated (27. 2 g, 509.20 mmol) and heated to reflux for 4.5 hours. The reaction solution was cooled to near room temperature, and the insoluble matter was filtered off, washed with ethanol, and the solvent of the filtrate was decompressed. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc (EtOAc) elute elut elut elut elut elut elut 35%). A W-NMR spectrum (CDCl3) 5 (ppm): 3·44 (2Η, br s), 4.98 (2Η, s), __ 663 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x 297 mm) ) 1304061 A7

6.10 (1H, dd, J=2.8 Hz, 8.8 Hz), 6.68-6.74 (2H, m), 7 30 7·43 (5H，m)。 . 〇 製造例^^ 基-2-摄笑肽 將4-苄氧基-2-氟苯胺（11·25 g，51 78 mm〇1)溶於甲醇 ^(^^^中’再添加丨^苯并三唑基-卜甲醇^^^^叨 mmol) ’在$溫下揽拌1()小時。遽取析出之結晶將結晶 以乙醇洗淨，#由抽氣乾燥，得到為無色結晶之標題^合 物（12.01 g，34.47 mmol，66.57%)。 &quot;H-NMR光譜（DMS0.d6)5(ppm): 4 % (2H，s)，6·〇7 (2h，本 J=6.8 Hz), 6.64 (1H, dd, J=2.8 Hz, 9.2 Hz), 6.78 (1H5 dd! J=2.8 Hz, 9.2 Hz), 6.82 (1H, m), 6.99 (1H, t, J=9.2 Hz)! 7.24-7.38 (6H, m), 7.53 (1H, t, J=8.4 Hz), 7.99 (1H, d, J=8.4 Hz)，8·1〇 (ih, d, J=8.4 Hz) 〇 製造例61R-4 ii：甲基-4_;氣基-氣苯脖 將N-{1-(1H-苯并三唑基）甲基卜4_苄氧基-2·氟苯胺 (14·13 g，40·56 mmol)溶於N，N-二甲基甲醯胺（200 ml)、甲 醇（150 ml)及乙醇（50 ml)中，再添加氫硼化鈉（3.06 g , 8M2 mmol)，在室溫下攪捽2.5小時。進一步添加氫硼化鈉 (0·78 g，20.28 mmol)，並在室溫下攪捽13.5小時。於反惠 溶液中加水，用乙酸乙酯及四氫呋喃萃取，以飽和食鹽水 洗淨，用水硫酸鎂乾燥，以及將溶媒減壓餾去。將殘餘 物用矽凝膠吸附，且藉由矽凝膠管柱層析（己烷/乙酸乙酯） ____- 664 - 本紙張尺度通用中國國家標準(CNS) A4規格(210 X 297公釐） A7 B7 1304061 五、發明説明（659) ” 精製，得到為淡黃色結晶之標題化合物（5.98 g，26.31 mmol，64.87%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): 2.64 (3H，d，J=4.8 Hz)， 4.97 (2H, s), 5.02 (1H, d, J=4.8 Hz), 6.55 (1H, t, J=9.2 Hz), 6.68 (1H，d，J=9.2 Hz)，6.79 (1H，J=13.2 Hz)，7.25-7.50 (5H， m) ° g造例618-5 氧基-2-氟苽某氟苽某VN-甲基脲 將N_甲基-4-苄氧基-2-氟苯胺（250 mg，1.0805 mmol)溶 於N，N-二甲基甲醯胺（5.0 ml)中，再添加氫化鈉（65 mg， 1.6207 mmol，60%於油中），在氮氣蒙氣及95°C下攪捽45分·-鐘。於其中添加異氰酸4-氟苯酯（0.14 nU，1.1836 mmol)，：，: 並在氮氣蒙氣及85 °C下攪拌0.75小時。更進一步添加氰.:一 酸4-氟苯酯（0·14 m卜0.5094 mmol)，在氮氣蒙氣及85°C下 攪拌0.5小時。冷卻至室溫後，於反應溶液中加水，用乙酸 乙酯萃取，以飽和食鹽水洗淨，用無水硫酸鎂乾燥，且將 溶媒減壓餾去。將殘餘物用NH矽凝膠吸附，且藉由NH矽 凝膠管柱層析（以己烷•乙酸乙酯溶析）精製，得到為谈黃 色油狀物之標題化合物（〇·1〇5 g，0.2881 mmol，21.67%)。 iH-NMR 光譜（CDCl3)5(Ppni): 2·16 (3H，s)，3.44 (3H，s)， 5.01 (2Η, s), 6.90 (1H, d, J=2.0 Hz), 6.78 (1H, dd, J=2.0 Hz, 8.4 Hz), 6.91 (1H, d, J=8.4 Hz), 7.19 (2H, t, J=8.4 Hz), 7.30-7.46 (5H,-m7 〇 一 製造例618-6 -665 - 紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐Γ 1304061 A7 B7 五、發明説明（66〇) 土丄1-氟-4-轉茇某）-〜-(4-激,苯基）-1^甲基脲 將N-(4-芊氧基-2-氟苯基）-N，-(4-氟苯基）-N-甲基脲（105 mg，0.2881 mmol)溶於甲醇（10 ml)中，然後添加10%鈀/碳 (20 mg)，並在氫氣蒙氣及室溫下攪拌0.75小時。濾去觸 媒’用乙醇洗淨後，減壓餾去溶媒。將析出之結晶懸浮於 乙醚中，濾取結晶，用乙醚洗淨，再抽氣乾燥，得到為無 色結晶之標題化合物（57 mg，0.2048 mmol，71 · 10%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 2.07 (3H，s)，6·41 (1H，d， J=1.6 Hz)，6·54 (1H，dd，J=1.6 Hz，8.4 Hz)，7·00 (1H，d， J=8.4 Hz), 7.38 (2H5 t, J=8.8 Hz), 7.53 (2H, dd, J==4.8 Hz, 8·8 Hz)。 - 實施例619 環丙某-Ν’ - U4-(6-(甲氣基）胺甲醯某-7-甲氳基-4- +毗 基）氣1-2-氣苽某i服 使用N-{ [4-(6-胺甲醯基-7-甲氧基-4-喹啉基）氧]-2-氟苯 基卜Ν’ -環丙基脲（40 mg，0.0972 mmol)及0-甲基幾胺（16 mg，0.1945 mmol)進行與實施例412同樣之反應。反應終了 後，於反應溶液中加入水，用乙酸乙酯萃取，以飽和食鹽 水洗淨，用無水硫酸鎂乾燥，以及將溶媒減壓餾去。將得 到之結晶懸浮於丙酮中，用乙醚稀释後，濾取結晶，用乙 醚洗淨，再抽氣乾燥後，得到為淡黃色結晶之標題化合物 (20 mg，0.0454 mmol，46.71%)。 W-NMR光譜(DMSO-d6)5(ppm): 0.41 (2H，m)，0.66 (2H，m)， 2·56 (1H，m)，3·75 (3H，s)，3.99 (3H，s)，6·54 (1H，d，J=5.〇 ____^666 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐) &quot; &quot;6.10 (1H, dd, J=2.8 Hz, 8.8 Hz), 6.68-6.74 (2H, m), 7 30 7·43 (5H, m). 〇Manufacturing example ^^ 基-2-笑笑 Peptide 4-benzyloxy-2-fluoroaniline (11·25 g, 51 78 mm〇1) is dissolved in methanol ^(^^^中' and then added 丨^ Benzotriazolyl-bupropanol ^^^^叨mmol) 'At 1 hour, mix for 1 () hours. The precipitated crystals were taken up and washed with ethanol, and dried by suction to give the title compound (12.01 g, 34.47 mmol, 66.57%). &quot;H-NMR spectrum (DMS0.d6) 5 (ppm): 4 % (2H, s), 6 · 〇 7 (2h, this J = 6.8 Hz), 6.64 (1H, dd, J = 2.8 Hz, 9.2 Hz), 6.78 (1H5 dd! J=2.8 Hz, 9.2 Hz), 6.82 (1H, m), 6.99 (1H, t, J=9.2 Hz)! 7.24-7.38 (6H, m), 7.53 (1H, t , J=8.4 Hz), 7.99 (1H, d, J=8.4 Hz), 8·1〇 (ih, d, J=8.4 Hz) 〇Manufacturing Example 61R-4 ii: Methyl-4_; gas-based gas N-{1-(1H-benzotriazolyl)methyl b-4-benzyloxy-2·fluoroaniline (14·13 g, 40·56 mmol) was dissolved in N,N-dimethyl To a solution of formazan (200 ml), methanol (150 ml) and ethanol (50 ml), sodium borohydride (3.06 g, 8 M 2 mmol) was added and stirred at room temperature for 2.5 hours. Further sodium borohydride (0·78 g, 20.28 mmol) was added and stirred at room temperature for 13.5 hours. Water was added to the solution, extracted with ethyl acetate and tetrahydrofuran, washed with saturated brine, dried over magnesium sulfate, and evaporated. The residue was adsorbed by hydrazine gel and chromatographed by hydrazine gel column chromatography (hexane/ethyl acetate) ____-664 - General paper size (CNS) A4 size (210 X 297 mm) A7 B7 1304061 V. Inventive Note (659) "Refined to give the title compound (5.98 g, 26.31 mmol, 64.87%) as pale yellow crystals. 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 2.64 (3H, d, J = 4.8 Hz), 4.97 (2H, s), 5.02 (1H, d, J = 4.8 Hz), 6.55 (1H, t, J = 9.2 Hz), 6.68 (1H, d, J = 9.2 Hz) , 6.79 (1H, J = 13.2 Hz), 7.25-7.50 (5H, m) ° g Example 618-5 oxy-2-fluoroindole fluoroquinone a VN-methylurea N-methyl-4- Benzyloxy-2-fluoroaniline (250 mg, 1.0805 mmol) was dissolved in N,N-dimethylformamide (5.0 ml), then sodium hydride (65 mg, 1.6207 mmol, 60% in oil) , stirring in a nitrogen atmosphere at 95 ° C for 45 minutes · - clock, adding 4-fluorophenyl isocyanate (0.14 nU, 1.1836 mmol), :, : and under nitrogen gas at 85 ° C Stir for 0.75 hours. Add cyanide: 4-fluorophenyl monoester (0·14 m Bu 0.5094 mmol), stir under nitrogen atmosphere at 85 ° C for 0.5 min. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The title compound ( 〇····························································· -NMR spectrum (CDCl3) 5 (Ppni): 2·16 (3H, s), 3.44 (3H, s), 5.01 (2Η, s), 6.90 (1H, d, J=2.0 Hz), 6.78 (1H, Dd, J=2.0 Hz, 8.4 Hz), 6.91 (1H, d, J=8.4 Hz), 7.19 (2H, t, J=8.4 Hz), 7.30-7.46 (5H,-m7 制造一 manufacturing example 618-6 -665 - Paper scale applicable to China National Standard (CNS) A4 specification (210X297 mm Γ 1304061 A7 B7 V. Invention description (66〇) Bandit 1-fluoro-4-transformation) -~-(4-excited, Phenyl)-1^methylurea dissolves N-(4-decyloxy-2-fluorophenyl)-N,-(4-fluorophenyl)-N-methylurea (105 mg, 0.2881 mmol) In methanol (10 ml), 10% palladium on carbon (20 mg) was then added and stirred under a hydrogen atmosphere at room temperature for 0.75 hours. The catalyst was filtered off and washed with ethanol, and the solvent was evaporated under reduced pressure. The precipitated crystals were suspended in diethyl ether. iH-NMR spectrum (DMSO-d6) 5 (ppm): 2.07 (3H, s), 6.41 (1H, d, J = 1.6 Hz), 6·54 (1H, dd, J = 1.6 Hz, 8.4 Hz ), 7·00 (1H, d, J=8.4 Hz), 7.38 (2H5 t, J=8.8 Hz), 7.53 (2H, dd, J==4.8 Hz, 8·8 Hz). - Example 619 Cyclopropanol - Ν' - U4-(6-(methyl)aminocarbazide -7-methylindol-4-ypyl) gas 1-2-gas 苽 some use N -{[4-(6-Aminomethylhydrazino-7-methoxy-4-quinolinyl)oxy]-2-fluorophenylindolide--cyclopropylurea (40 mg, 0.0972 mmol) and 0 The same reaction as in Example 412 was carried out using methyl-methylamine (16 mg, 0.1945 mmol). After the completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The resulting crystals were suspended in EtOAc (EtOAc) elute elute elute W-NMR spectrum (DMSO-d6) 5 (ppm): 0.41 (2H, m), 0.66 (2H, m), 2·56 (1H, m), 3·75 (3H, s), 3.99 (3H, s),6·54 (1H,d,J=5.〇____^666 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) &quot;&quot;

裝 訂Binding

1304061 A7 ____ B7 五、發明説明（661) :1304061 A7 ____ B7 V. Description of invention (661):

Hz), 6.82 (1H, s), 7.08 (1H, d, J=8.4 Hz), 7.32 (1H, d, J=8.4 Hz), 7.50 (1H, s), 8.19-8.24 (2H, m), 8.43 (1H, s), 8.67 (1H5 d，J=5.0 Hz)，11.46 (1H，s)。 實施例620 乙氧乙基）胺甲醯某-7-甲氣基-4- 氟苽某1服 使用N- {[4-(6-胺甲醯基-7-甲氧基-4-喹啉基）氧卜2-氟苯 基} - Ν’：環丙基脲（4〇 mg，0.0972 mmol)及2-乙氧基乙胺（17 mg ’ 0.1945 mmol)進行與實施例412同樣之反應。反應終了 後’於反應溶液中加入水，並濾取析出之結晶。將其懸浮 於丙酮中，用乙醚稀釋，濾取結晶，用乙醚洗淨，再抽氣 乾燥後’得到為淡黃色結晶之標題化合物（33 mg，0.0684 - _ mmol，70.93%)。 — W-NMR 光譜（DMSO-d6)5(ppm): 0·39-0·44 (2Η，m)，0.63- 0.68 (2H, m), 1.14 (3H, t, J=6.6 Hz), 2.57 (1H, m), 3.46-3.55 (6H, m), 4.04 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.81 (1H, m), 7.08 (1H，m)，7·33 (1H，dd，J=2.4 Hz，11.6 Hz), 7·53 (1H，s)， 8.19-8.24 (2H, m), 8.46 (1H, t, J=5.2 Hz), 8.63 (1H, s), 8.68 (1H，d，J=5.2 Hz) 〇 實施例621 N二環丙基-Ν·-丨f 4- ( 6- (2-氟環丙基）胺甲醯基-7·甲^早1 喹啉基）氧1-2-氟茉某}服 使用N-十[本(-6_胺甲醯基-7-甲氧基_4_喹啉基）氧]_2•氣苯〜 基} - Ν’ -環丙基脲（40 mg，0.0972 mmol)及2-氟環丙胺甲苯 -667 - ^紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) ------- A7 B7 1304061 五、發明説明（啦） : r. 續酸鹽（39 mg，0.1945 mmol)進行與實施例412同樣之反 應。反應終了後，於反應溶液中加入水，用乙酸乙酯萃 取，以飽和食鹽水洗淨，用無水硫酸鎂乾燥，以及將溶媒 減壓餾去。將殘餘物用矽凝膠吸附，且藉由矽凝膠管柱層 析法（以乙酸乙酯•乙醇溶析）精製，將得到之結晶懸浮於 丙酮：-乙醚（1 : 3)中，濾取結晶，用乙醚洗淨，再抽氣乾 燥後’得到為無色結晶之標題化合物（12 mg，0.0256 mmol * 26.35%) ° iH-NMR 光譜（DMSO-d6)5(ppm): 0.42 (2H，m)，0.65 (2H，m)， 1.05-1.18 (2H，m)，2.56 (1H，m)，2·93 (lH，m)，4.01 (3H，m)， 4.54-4.93 (1H，m)，6·54 (1H，d，J=5.2 Hz)，6.80 (1H，m&gt;，… 7.08 (1H, m)5 7.32 (1H, dd, J=2.0 Hz, 11.6 Hz), 7.53 (1H, s), 8.22 (2H, m), 8.45 (1H, m), 8.52 (1H, s), 8.67 (1H, d, J=5.2 Hz) 〇 實施例622 N-丨「4-(6-(2-氰乙某）胺甲醯基-7-甲氣基-4-4啉基）氣某μ 2-氣笨某丨-N、環丙某Μ 使用N-{ [4-(6-胺甲醯基-7-甲氧基-4-喹啉基）氧]-2-氟苯 基}-N* -環丙基月尿（40 mg，0.0972 mmol)及2-氰基乙胺（14 mg，0.1945 mmol)進行與實施例412同樣之反應。反應終了 後，於反應溶液中加入水，用乙酸乙酯萃取，以飽和食鹽 水洗淨，用無水硫酸鎂乾燥，以及將溶媒減壓餾去。將得 到之結晶邊r浮於丙酮中，用乙醚稀釋，濾取結晶，用乙醚 ’ 洗淨，再抽氣乾燥後，得到為淡黃色結晶之標題化合物（1 8 ____- 668 -___ 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） A7 B7 1304061 五、發明説明（663) 二 mg，0.0684 mmol，39.96%) 〇 iH-NMR 光譜（DMSO-d6) 5 (ppm)·· 0.41 (2H，m)，0.63-0.66 (2H，m)，2.56 (1H，m)，2.82 (2H，t，J=6.4 Hz)，3·57 (2H，q， J=6.4 Hz)，4.03 (3H，s)，6·54 (1H，d，J=5.2 Hz)，6.81 (1H，m)， 7.08 (1H，m)，7.32 (1H，dd，J=2.4 Hz，11·6 Hz)，7.54 (1H，s)， 8·18-8\26 (2H，m)，8.61 (1H，s)，8·68 (1H，d，J=5.2 Hz)，8.73 (1H，m) 〇 實施例623 N-「4-(6-胺甲酿基-7 -甲氧基-4-p奎喊某、氧_2-甲菜基 甲基脲 將[4-(6-胺甲酿基-7-甲氧基-4-4琳基）氧_2-甲苯基]胺 甲酸苯酯（70 mg)加入二甲基亞砜（〇·8 ml)中。於其中加入 *- 、二·r·, 甲胺之2N四氫呋喃溶液（0·4 ml)並攪拌5分鐘。於反應裱液$ 中加入水及乙酸乙酯，濾取析出之結晶，得到標題化合物 (48 mg)。 ^-NMR (DMSO-d6) 5 (ppm): 2.20 (3H, s), 2.65 (3H, d5 J=4.8 Hz), 4.01 (3H, s), 6.38-6.47 (2H, m), 7.00-7.05 (1H, m), 7.09 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.71 (1H, br s), 7.74 (1H，s)，7.84 (1H，br s)，7.86-7.92 (1H，m)，8·63 (1H，d， J=5.2 Hz)，8·66 (1H，s)。 實施例624 N-「4-(6-胺甲醯基-7-甲氣某-4-违啉某）氫-2-甲笨基卜N1-乙基脲· 將[4-(6-胺甲醯基-7-甲氧基-4-喹啉基）氧基-2-甲苯基]- ____- 669 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7Hz), 6.82 (1H, s), 7.08 (1H, d, J=8.4 Hz), 7.32 (1H, d, J=8.4 Hz), 7.50 (1H, s), 8.19-8.24 (2H, m), 8.43 (1H, s), 8.67 (1H5 d, J=5.0 Hz), 11.46 (1H, s). Example 620 Ethoxyethyl)amine methyl hydrazine -7-methyl ketone-4-fluoroquinone 1 serving N-{[4-(6-aminocarbamimid-7-methoxy-4-quinoline) The same reaction as in Example 412 was carried out by morphyl)oxo-2-fluorophenyl}-anthracene: cyclopropylurea (4 mg, 0.0972 mmol) and 2-ethoxyethylamine (17 mg '0.1945 mmol). . After the completion of the reaction, water was added to the reaction solution, and the precipitated crystals were collected by filtration. The title compound (33 mg, 0.0684 - _ mmol, 70.93%) was obtained as a pale yellow crystals. — W-NMR spectrum (DMSO-d6) 5 (ppm): 0·39-0·44 (2Η, m), 0.63-0.68 (2H, m), 1.14 (3H, t, J=6.6 Hz), 2.57 (1H, m), 3.46-3.55 (6H, m), 4.04 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.81 (1H, m), 7.08 (1H, m), 7· 33 (1H, dd, J=2.4 Hz, 11.6 Hz), 7·53 (1H, s), 8.19-8.24 (2H, m), 8.46 (1H, t, J=5.2 Hz), 8.63 (1H, s ), 8.68 (1H, d, J = 5.2 Hz) 〇 Example 621 N-dicyclopropyl-indole--f- 4-(6-(2-fluorocyclopropyl)aminecarbamyl-7-methyl Early 1 quinolinyl)oxy1-2-fluoro-moxa} served with N-ten [this (-6-aminocarbazinyl-7-methoxy_4_quinolinyl)oxy]_2• benzene~ Base} - Ν'-cyclopropylurea (40 mg, 0.0972 mmol) and 2-fluorocyclopropylamine toluene-667 - ^ paper size applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ---- --- A7 B7 1304061 V. Inventive Note: r. The hydrochloride salt (39 mg, 0.1945 mmol) was subjected to the same reaction as in Example 412. After the completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was adsorbed by hydrazine gel and purified by hydrazine gel column chromatography (evaporation with ethyl acetate / ethanol), and the obtained crystals were suspended in acetone:-diethyl ether (1:3). The crystals were taken, washed with diethyl ether, and then evaporated to dryness to give the title compound (12 mg, 0.0256 mmol * 26.35%) as a colorless crystals. NMR NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.05-1.18 (2H, m), 2.56 (1H, m), 2.93 (lH, m), 4.01 (3H, m), 4.54-4.93 (1H, m) ,6·54 (1H,d,J=5.2 Hz), 6.80 (1H,m&gt;,... 7.08 (1H, m)5 7.32 (1H, dd, J=2.0 Hz, 11.6 Hz), 7.53 (1H, s ), 8.22 (2H, m), 8.45 (1H, m), 8.52 (1H, s), 8.67 (1H, d, J=5.2 Hz) 〇Example 622 N-丨"4-(6-(2- Cyanoethyl)Aminomethylmercapto-7-methyl-yl-4-ylolinyl)A certain μ2-gas stupid-N, cyclopropanol Μ using N-{ [4-(6-aminoformamidine) Benzyl-7-methoxy-4-quinolinyl)oxy]-2-fluorophenyl}-N*-cyclopropyl monthly urine (40 mg, 0.0972 mmol) and 2-cyanoethylamine (14 mg, The same reaction as in Example 412 was carried out at 0.1945 mmol. After the reaction was completed, water was added to the reaction solution. The extract was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Net, and then air-drying, the title compound is obtained as light yellow crystals (1 8 ____- 668 -___ This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 1304061 V. Invention description (663 ) 2 mg, 0.0684 mmol, 39.96%) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm)·· 0.41 (2H, m), 0.63-0.66 (2H, m), 2.56 (1H, m), 2.82 (2H,t,J=6.4 Hz),3·57 (2H,q, J=6.4 Hz), 4.03 (3H,s),6·54 (1H,d,J=5.2 Hz), 6.81 (1H, m), 7.08 (1H, m), 7.32 (1H, dd, J=2.4 Hz, 11.6 Hz), 7.54 (1H, s), 8·18-8\26 (2H, m), 8.61 (1H , s), 8.68 (1H, d, J = 5.2 Hz), 8.73 (1H, m) 〇 Example 623 N-"4-(6-Aminomethyl-7-methoxy-4-p Kui shouted a certain amount of [2-(6-Amino-mercapto-7-methoxy-4-4-linyl)oxy- 2-tolyl]- phenyl carbamate 70 mg) added dimethyl sulfoxide (〇·8 ml). A solution of *-, di.r., methylamine in 2N tetrahydrofuran (0.4 ml) was added thereto and stirred for 5 minutes. Water and ethyl acetate were added to the reaction mixture, and the crystals obtained were crystallized to give the title compound (48 mg). ^-NMR (DMSO-d6) 5 (ppm): 2.20 (3H, s), 2.65 (3H, d5 J=4.8 Hz), 4.01 (3H, s), 6.38-6.47 (2H, m), 7.00-7.05 (1H, m), 7.09 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.71 (1H, br s), 7.74 (1H, s), 7.84 (1H, br s), 7.86- 7.92 (1H, m), 8.63 (1H, d, J = 5.2 Hz), 8.66 (1H, s). Example 624 N-"4-(6-Aminocarboxy-7-methyl -4-pyrroline)hydro-2-methylphenylidene N1-ethylurea·[4-(6-amine) Methanyl-7-methoxy-4-quinolinyloxy-2-methylphenyl]- ____- 669 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7

五、發明説明（664) 胺甲酸苯酯（65 mg)加入二甲基亞颯（ι·〇 ml)中。於其中加 入乙胺之2N四氫呋喃溶液（0.37 ml)，並攪拌5分鐘。於 應溶液中加入水及乙酸乙酯，濾取析出之結晶，得到栏題 化合物（38 mg)。 W-NMR 光譜（DMSO-d6)5(ppm): 1·06 (3H，t，J=7 2 Hz) 2·20 (3H，s)，3.06-3.16 (2H，m)，4·01 (3H，s)，6.44 (1H d J=5.6 Hz)，6.49-6.45 (1H，m)，7.00-7.04 (1H，m)，7 〇9 (1H d J-2.8 Hz), 7.49 (1H, s), 7.68 (1H, s), 7.71 (1H, br s), 7.84 (1H5 br s), 7.88-7.95 (1H, m), 8.63 (1H, d, J==5.6 Hz) 8 66 (1H，s)。 實施例625 ϋ-『2-氣-4-(Γ 6-氰基-7-(Γ 3-( 1-六氫吡啶基）丙某[氧_ _ 琳基1氫)策某1- N〜環丙基服 — 將環丙胺（0·05 ml)加入二甲基亞ί風（〇·5 ml)中，於其中溶 解[2-氟-4-([6-氰基-7-( [3-(1-六氫吡啶基）丙基]氧基） 峻17林基]氧）苯基]胺甲酸苯醋（66 mg)，且揽摔10分鐘。於 反應溶液中加入水及乙酸乙酯，濾取析出之結晶，得到標 題化合物（33 mg)。 ^-NMR (DMSO-d6) 5 (ppm): 0.38-0.45 (2H, m), 0.61-0.69 (2H, m), 1.30-1.55 (6H, m), 1.92-2.02 (2H, m)3 2.30-2.50 (6H, m), 2.53-2.59 (1H, m), 4.33 (2H, t, J=6.0 Hz), 6.59 (1H, d, J=5.6 Hz), 6.82-6.86 (1H, m), 7.07-7.013 (1H, m), 7.31- 7.37 (lH^mJ, 7.61 (1H, s), 8.20-8.29 (2H, m), 8.72-8.77 (2H, m)。 L _- 670 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 ____B7 ______ 五、發明説明（665) 起始原料係以下述方法合成。 製造例625-1 L1-氟- 4-(「6-氰基- k六氡毗畦某）丙某·[氫）-4-喹 复]氧）苯基1胺甲醴茇酯 從2-氟-4-([6-氰基-7-([3-(1-六氫吡啶基）丙基]氧）-4-喹 琳基]氧）苯胺（66 mg)，藉由製造例141-ι記載之方法，得 到標題化合物（3 3 mg)。 !H-NMR (DMSO-d6) 5 (ppm): 1.40-1.75 (6H, m), 1.90-2.15 (4H，m)，2·50-2·67 (2H，m)，3.13-3.27 (2H，m)，4.30-4.38 (2H, m), 6.54 (1H, d, J=5.2 Hz), 6.97-7.06 (2H, m), 7.20- 7.30 (6H，m)，8.01 (1H，s)，8·27 (1H，br s)，8·66 (1H，s)，8.72 (1H，d，J=5.2 Hz)。 實施例626 一V. INSTRUCTIONS (664) Phenyl carbamate (65 mg) was added to dimethyl hydrazine (ι·〇 ml). A solution of ethylamine in 2N tetrahydrofuran (0.37 ml) was added and stirred for 5 min. Water and ethyl acetate were added to the solution, and the crystals precipitated were collected by filtration to give the title compound (38 mg). W-NMR spectrum (DMSO-d6) 5 (ppm): 1·06 (3H, t, J=7 2 Hz) 2·20 (3H, s), 3.06-3.16 (2H, m), 4·01 ( 3H, s), 6.44 (1H d J=5.6 Hz), 6.49-6.45 (1H, m), 7.00-7.04 (1H, m), 7 〇9 (1H d J-2.8 Hz), 7.49 (1H, s ), 7.68 (1H, s), 7.71 (1H, br s), 7.84 (1H5 br s), 7.88-7.95 (1H, m), 8.63 (1H, d, J==5.6 Hz) 8 66 (1H, s). Example 625 ϋ-『2-Ga-4-(Γ 6-Cyano-7-(Γ 3-( 1-hexahydropyridyl)-propanyl [oxy- _ 琳 1 hydrogen] 策一 1- N~ Cyclopropyl service - cyclopropylamine (0. 05 ml) was added to dimethyl sulphur (5 ml) to dissolve [2-fluoro-4-([6-cyano-7-([ 3-(1-hexahydropyridinyl)propyl]oxy) phenyl 17-hydroxy]phenyl]-amino phenylacetate (66 mg), and the mixture was dropped for 10 minutes. Water and acetic acid B were added to the reaction solution. The title compound (33 mg) was obtained by chromatography. (6H, m), 1.92-2.02 (2H, m)3 2.30-2.50 (6H, m), 2.53-2.59 (1H, m), 4.33 (2H, t, J=6.0 Hz), 6.59 (1H, d , J=5.6 Hz), 6.82-6.86 (1H, m), 7.07-7.013 (1H, m), 7.31- 7.37 (lH^mJ, 7.61 (1H, s), 8.20-8.29 (2H, m), 8.72 -8.77 (2H, m) L _- 670 - This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 ____B7 ______ V. Description of invention (665) Starting materials are as follows Synthesis. Production Example 625-1 L1-Fluoro- 4-("6-Cyano-k-hexa-pyrene")-M-[hydrogen]-4- Phenoxy]phenyl-1-amine methyl phthalate from 2-fluoro-4-([6-cyano-7-([3-(1-hexahydropyridyl)propyl)oxy)-4-quinolin The title compound (3 3 mg) was obtained by the method of the title compound 141-m. ???H-NMR (DMSO-d6) 5 (ppm): 1.40-1.75 (6H, m), 1.90-2.15 (4H,m),2·50-2·67 (2H,m),3.13-3.27 (2H,m),4.30-4.38 (2H, m), 6.54 (1H, d, J =5.2 Hz), 6.97-7.06 (2H, m), 7.20- 7.30 (6H,m),8.01 (1H,s),8·27 (1H,br s),8·66 (1H,s),8.72 (1H, d, J = 5.2 Hz). Example 626

EiJ4-(7-苄氧基-6-ϋ啉-心某氧）-2-氪策某1-N，-甲奚月尿 將[4-(7-苄氧基-6-氰基〃奎琳-4-基氧）-2-氯苯基]胺甲酸 苯酯（1.17 g)加入二甲基甲醯胺（6 ml)中，於其中加入甲胺 之2N四氫呋喃溶液（0.4 ml)，且攪拌10分鐘。於其中加入 水（15 ml)，濾取析出之結晶，將其以乙醚洗淨，得到標題 化合物（968 mg)。 ^-NMR (DMSO-d6) (5 (ppm): 2.66 (3H, d, J=4.0 Hz), 5.45 (2H，s)，6.59 (1H，d，J=5.2 Hz)，6.86-6.92 (1H，m)，7·24 (ih dd，J=8.8, 4.8 Hz)，7.32-7.57 (6H，m)，7.71 (1H，s)，8·12 (1H， s)，8.21-8T2S· (TH，m)，8·73 (1H，d，J=5.2 Hz)，8.76 (1H，s)。 起始原料係以下述方法合成。 -671 - 本紙張尺度適用中國國家標準(CNS) A4规格(21〇X297公爱） 1304061 A7 B7 五、發明説明（666) 一 iH 626-1 (7-卞乳基-6-亂基吟淋-4-基氣）-2 -氣笨基1-胺甲酸笨g旨 從4-(4-胺基-3-氯苯基）-7-芊氧基-6-氰基喹啉（1.68 g)， 藉由製造例141-1記載之方法，得到標題化合物（1.69 mg) ° ^H-NMR (DMSO-d6) δ (ppm): 5.28 (2H, s), 6.44 (1H, d, j=5.2 Hz), 7.09 (1H, dd, J=2.8, 9.2 Hz), 7.13-7.50 (13H, m), 8·24-8·3·0 (1H，m)，8.60-8.65 (2H，m)。 f施例627 N-『2'—氯-4-( 6-氨基-7-杏呲-4-基氣笨基卜Ν’ -甲篡胧 於三氟乙酸（10 ml)中添加Ν-[4-(7-芊氧基-6-氰基喹啉、 4-基氧）-2-氯苯基]-Ν、甲基脲（968 mg)及硫代苯甲醚（3.7 ___ 一·..-=- ml)，並在50°C攪拌一整夜。將其於減壓下濃縮後，添加乙 — 酸乙酯及碳酸氫鈉水溶液，濾取析出之結晶，且用乙酸乙 酿洗淨’得到標題化合物（849 mg)。 ^-NMR (DMSO-d6) 5 (ppm): 2.66 (3H, d, J=4.0 Hz), 5.30 (1H, d, J=5.2 Hz), 6.37 (1H, s), 6.83-6.90 (1H, m), 7.12-7.16 (1H, m), 7.33-7.35 (1H, m), 8.00 (1H, s), 8.08 (1H, br s), 8.14-8.19 (2H，m) 〇 實施例628 N^(4-{6-氰某-7-K2R)-瑗氫乙烷-2-基1甲氳4啉-4-基 一氧卜2_氣茉基）_N，-甲摹啤 將N- [ 27裘' 4- ( 6-氰基-7-羥喹啉-4-基氧）苯基]-Ν’ -甲基 脲（600 mg)加入二曱基甲醯胺（4 ml)中，於其中加入對甲 __ _- 672 -____ 一 本紙張尺度適用肀固國家標準(CNS) A4規格(21〇 X 297公釐） 1304061 A7 B7 五、發明説明（667) 苯續酸（2R)-縮水甘油酯（484 mg)及碳酸奸（450 mg)，在50 °C加熱4小時。於反應液中加入水且用乙酸乙酯萃取。將有 機層用水及飽和食鹽水依順序洗淨後，用無水硫酸鈉乾 燥，並減壓餾去溶媒。將得到之粗生成物用乙酸乙酯再結 晶’得到為淡黃色結晶之標題化合物（650 mg)。 ^-NMR (DMSO-d6) 5 (ppm): 2.68 (3H, d, J=4.8 Hz), 2.80- 2·96 (2H，m)，3.45-3.51 (1H，m)，4.18 (1H，dd，J=11.6, 6·4 Hz), 4.73 (1H, dd5 J=11.6, 2.0 Hz), 6.61 (1H, d5 J=5.2 Hz), 6.86-6.93 (1H5 m), 7.26 (1H, dd, J=9.2, 2.8 Hz), 7.51 (1H, d, J=2.8 Hz), 7.66 (1H, s)3 8.14 (1H, s), 8.27 (1H5 d, J=9.2 Hz), 8·75 (1H，d，J=5.2 Hz)，8·78 (1H，s)。 - 實施例629 :- Μτ_ί4· {6-氰基- 7-「（2R)-2- 基-3-吡咯啶-1-某丙氣某, 嗾-4-基氧卜2-氯苯某甲某脹 於Ν-(4-{6-氰基-7-[(2R)·環氧乙烷-2-基]甲氧喹啉_4_基 氧}-2-氯苯基）-Ν’ -甲基脲（110 mg)中添加四氫咬喃1 .〇 mi 及p比嘻淀（0· 10 ml) ’並在60°C加熱2小時。將此反應溶液藉 由NH矽凝膠管柱層析（乙酸乙酯/甲醇）精製，得到為淡黃色 結晶之標題化合物（65 mg)。 ^-NMR (DMSO-d6) (5 (ppm): 1.55-1.73 (4H, m), 2.45-2.58 (5H，m)，2·68-2·77 (4H，m)，4·00-4·06 (1H，m)，4.22 (1H，dd， J=10.4, 5.6 Hz), 4.32 (1H, dd, J=10.4, 3.2 Hz), 5.00-5.05 (1H，m)，6759 (1H，d，J=5.2 Hz)，6.86-6.93 (1H，m)，7,26 (1H，— dd, J=9.2 Hz, 2.8 Hz), 7.51 (1H, d, J=2.8 Hz), 7.63 (1H, s), -673 - 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) 1304061EiJ4-(7-benzyloxy-6-carboline-heart oxygen)-2-氪策一1-N,-甲奚月尿尿[4-(7-benzyloxy-6-cyanoquinone Phenyl-4-yloxy)-2-chlorophenyl]carbamic acid phenyl ester (1.17 g) was added to dimethylformamide (6 ml), and a solution of methylamine in 2N tetrahydrofuran (0.4 ml) was added. Stir for 10 minutes. Water (15 ml) was added, and the crystals crystals crystals crystals crystals ^-NMR (DMSO-d6) (5 (ppm): 2.66 (3H, d, J = 4.0 Hz), 5.45 (2H, s), 6.59 (1H, d, J = 5.2 Hz), 6.86-6.92 (1H ,m),7·24 (ih dd,J=8.8, 4.8 Hz),7.32-7.57 (6H,m),7.71 (1H,s),8·12 (1H, s),8.21-8T2S· (TH , m), 8.73 (1H, d, J = 5.2 Hz), 8.76 (1H, s) The starting materials were synthesized as follows: -671 - This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 21〇X297公爱) 1304061 A7 B7 V. Inventive Note (666) IiH 626-1 (7-卞乳基-6-乱基吟淋-4-基气)-2 - Qiqiji 1-aminecarboxylic acid The title compound was obtained by the method described in Production Example 141-1 from 4-(4-amino-3-chlorophenyl)-7-decyloxy-6-cyanoquinoline (1.68 g). (1.69 mg) ° ^H-NMR (DMSO-d6) δ (ppm): 5.28 (2H, s), 6.44 (1H, d, j = 5.2 Hz), 7.09 (1H, dd, J=2.8, 9.2 Hz ), 7.13-7.50 (13H, m), 8·24-8·3·0 (1H, m), 8.60-8.65 (2H, m) f Example 627 N-『2'-chloro-4-( 6-Amino-7-Apricot-4-yl-based gas-based hydrazine--Amidoxime added tris-[4-(7-decyloxy-6-cyanoquinoline) to trifluoroacetic acid (10 ml) , 4-yloxy)-2-chlorophenyl]-indole, Methyl urea (968 mg) and thioanisole (3.7 ___ a ·..-=- ml), and stirred at 50 ° C overnight. After concentration under reduced pressure, add B-acid B The ester and the aqueous sodium hydrogencarbonate solution were filtered, and the crystals were crystallized, and washed with ethyl acetate to give the title compound (849 mg). NMR (DMSO-d6) 5 (ppm): 2.66 (3H, d, J = 4.0 Hz), 5.30 (1H, d, J=5.2 Hz), 6.37 (1H, s), 6.83-6.90 (1H, m), 7.12-7.16 (1H, m), 7.33-7.35 (1H, m), 8.00 (1H, s), 8.08 (1H, br s), 8.14-8.19 (2H,m) 〇Example 628 N^(4-{6-Cyanyl-7-K2R)-Hydrazineethane-2- Base 1 formazan-4-yl-oxobu 2_gumyl)_N,- formazan beer will be N-[ 27裘' 4-( 6-cyano-7-hydroxyquinolin-4-yloxy Phenyl]-Ν'-methylurea (600 mg) was added to dimercaptocaramine (4 ml), and a national standard for tamping was applied to a paper size of A__ _- 672 -____ ( CNS) A4 size (21〇X 297 mm) 1304061 A7 B7 V. Description of invention (667) Benzoic acid (2R)-glycidyl ester (484 mg) and carbonated (450 mg), heated at 50 °C 4 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate and evaporated. The obtained crude product was recrystallized from ethyl acetate to give the title compound (650 mg). ^-NMR (DMSO-d6) 5 (ppm): 2.68 (3H, d, J = 4.8 Hz), 2.80- 2·96 (2H, m), 3.45-3.51 (1H, m), 4.18 (1H, dd , J=11.6, 6·4 Hz), 4.73 (1H, dd5 J=11.6, 2.0 Hz), 6.61 (1H, d5 J=5.2 Hz), 6.86-6.93 (1H5 m), 7.26 (1H, dd, J =9.2, 2.8 Hz), 7.51 (1H, d, J=2.8 Hz), 7.66 (1H, s)3 8.14 (1H, s), 8.27 (1H5 d, J=9.2 Hz), 8·75 (1H, d, J = 5.2 Hz), 8.78 (1H, s). - Example 629 :- Μτ_ί4· {6-Cyano- 7-"(2R)-2-yl-3-pyrrolidine-1-one propane gas, 嗾-4-yloxybu-2-chlorobenzene a swelling in Ν-(4-{6-cyano-7-[(2R)·oxiran-2-yl]methoxyquinolin-4-yloxy}-2-chlorophenyl)-Ν -Methylurea (110 mg) was added with tetrahydrocyanate 1. 〇mi and p were compared with yttrium (0·10 ml)' and heated at 60 ° C for 2 hours. The reaction solution was passed through an NH矽 gel tube. Column chromatography (ethyl acetate / MeOH) eluted eluted elut elut elut elut elut elut elut elut 2.58 (5H,m),2·68-2·77 (4H,m),4·00-4·06 (1H,m), 4.22 (1H,dd, J=10.4, 5.6 Hz), 4.32 (1H , dd, J = 10.4, 3.2 Hz), 5.00-5.05 (1H, m), 6759 (1H, d, J = 5.2 Hz), 6.86-6.93 (1H, m), 7, 26 (1H, - dd, J=9.2 Hz, 2.8 Hz), 7.51 (1H, d, J=2.8 Hz), 7.63 (1H, s), -673 - This paper size applies to Chinese National Standard (CNS) A4 size (210x 297 mm) 1304061

8.14 (1H, br s), 8.27 (1H, dd, J=9.2, 2.8 HZ), 8.72-8.76 (2H, m)。 實施例630 腿二…氰皋-?-「(2R)-2-掷幕某丙氳某】 喳啉-4-基氧}-2-H基）-N、甲其研 於N-(4-{6-氰基-7-U2R)-環氧乙烷·2_基]甲氧 4基 氧}-2-氣苯基）-N，-甲基脲（110 mg)中添加四氫呋喃2〇… 及=氫咻啶（0·20 ml)，然後在60t；加熱3小時，將此反應麥 液藉由NH矽凝膠管柱層析（乙酸乙酯/曱醇）精製，得到為淡 κ色結晶之標題化合物（80nig)。 ^-NMR (DMSO-d6) 5 (ppm): 1.30-1.42 (2H, m), 1.45-1.57 (4H, m), 2.35-2.50 (6H, m), 2.68 (3H, d, J=4.4 Hz), 4.00-4·08 (1H，m)，4.22 (m，dd，J=10.4, 6.0 Hz)，4 32 (1’H，，dd， J=10.4, 3.2 Hz), 4.93-4.97 (1H, m), 6.59 (lH, d, J=5.6 Hz), 6.86-6.93 (1H, m), 7.26 (1H, dd, J=9.2, 2.8 Hz)5 7.51 (1H, d, J=2.8 Hz), 7.64 (1H, s), 8.14 (1H, br s), 8.27 (1H, dd, J=9.2, 2·8 Hz), 8.72-8.76 (2H, m)。 實施例631 K_4-{6-氰棊-7-「3_二乙胺基]2R)-2i丙氳某卜杏嗾-心 基氧卜2-氣苯基甲某胧 於N-(4- { 6-氰基-7- [ (2R)-環氧乙垸-2-基]甲氧峻淋-4-基 氧卜2-氯苯基）-Ν· -甲基脲（1〇〇 mg)中添加四氫呋喃3 〇 ml 及二乙胺tl.50 ml) ’並在60°C加熱5小時。將此反應溶液藉 由NH矽凝膠管柱層析（乙酸乙酯/甲醇）精製，得到為淡黃色 -674 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 A7 B7 五、發明説明（669) 結晶之標題化合物（75 mgp ^-NMR (DMSO-d6) 5(ppm): 0.98 (6H, t, J=7.2 Hz), 2.40- 2.70 (9H，m)，3·93-4·00 (1H，m)，4.23 (1H, d〇10.4, 5·68.14 (1H, br s), 8.27 (1H, dd, J=9.2, 2.8 HZ), 8.72-8.76 (2H, m). Example 630 Leg 2...Cyanide-?-"(2R)-2-throwing a certain 氲) porphyrin-4-yloxy}-2-H-))-N, a research on N-(4 -{6-Cyano-7-U2R)-Ethylene oxide·2_yl]methoxy-4-yloxy}-2-phenylphenyl)-N,-methylurea (110 mg) with tetrahydrofuran 2〇 ... and = hydrogen acridine (0·20 ml), then at 60t; heating for 3 hours, the reaction wheat liquid was purified by NH矽 gel column chromatography (ethyl acetate / methanol) to obtain a light κ The title compound (80nig) of the crystals. NMR (DMSO-d6) 5 (ppm): 1.30-1.42 (2H, m), 1.45-1.57 (4H, m), 2.35-2.50 (6H, m), 2.68 (3H, d, J=4.4 Hz), 4.00-4·08 (1H, m), 4.22 (m, dd, J = 10.4, 6.0 Hz), 4 32 (1'H,, dd, J = 10.4, 3.2 Hz), 4.93-4.97 (1H, m), 6.59 (lH, d, J=5.6 Hz), 6.86-6.93 (1H, m), 7.26 (1H, dd, J=9.2, 2.8 Hz)5 7.51 ( 1H, d, J = 2.8 Hz), 7.64 (1H, s), 8.14 (1H, br s), 8.27 (1H, dd, J=9.2, 2·8 Hz), 8.72-8.76 (2H, m). Example 631 K_4-{6-cyanoindole-7-"3-diethylamino]2R)-2i-propionium 卜 嗾 嗾 心 心 心 心 心 心 心 心 心 心 心 2- 2- 2- 2- 2- 2- 2- { 6-Cyano-7-[ (2R)-epoxyacetamidin-2-yl]methoxyxanthene-4- Add tetrahydrofuran 3 〇ml and diethylamine tl.50 ml)' to the oxime 2-chlorophenyl)-indole-methylurea (1 〇〇 mg) and heat at 60 ° C for 5 hours. The solution was purified by NH(R) gel column chromatography (ethyl acetate/methanol) to give a pale yellow color - 674 - the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. BRIEF DESCRIPTION OF THE INVENTION (669) Crystalline title compound (75 mg p ^-NMR (DMSO-d6) 5 (ppm): 0.98 (6H, t, J = 7.2 Hz), 2.40- 2.70 (9H, m), 3.93- 4·00 (1H, m), 4.23 (1H, d〇10.4, 5·6

Hz), 4.32 (1H, dd, 1=10.4, 3.6 Hz), 4.93 (1H, br s), 6.59 (1H5 d，J=5.6 Hz)，6.86-6.93 (1H，m)，7·26 (1H，dd，J=9.2, 2 8 Hz)， 7.51 (1H，d，J=2.8 Hz)，7·63 (1H，s)，8.14 (1H，br s)，8.27 (1H，dd，J=9.2, 2.8 Hz)，8.72-8.76 (2H，m)。 實施例632Hz), 4.32 (1H, dd, 1=10.4, 3.6 Hz), 4.93 (1H, br s), 6.59 (1H5 d, J=5.6 Hz), 6.86-6.93 (1H, m), 7·26 (1H ,dd,J=9.2, 2 8 Hz), 7.51 (1H,d,J=2.8 Hz),7·63 (1H,s),8.14 (1H,br s),8.27 (1H,dd,J=9.2 , 2.8 Hz), 8.72-8.76 (2H, m). Example 632

Izi丄氯-4-(((甲胺某 &gt;&gt; 羰基）胺基）笨氣某6 4 琳羧酸甲酯 將Ν-(2-：^-4-(7-甲氧基）-6-甲氧談基·4 -峻琳基）氧苯基） 胺甲酸苯酯（1.92 g ’ 4.00 mmol)及40%甲胺（甲醇溶液）（2 __ ml)於二甲基甲醯胺（8 ml)中，於室溫攪拌3〇分鐘。將一應S 液分溶於乙酸乙酯及水中，有機層用水及飽和食鹽水洗 淨，用無水硫酸鎂乾燥，再濾去乾燥劑，將濾液減壓餾 去。將得到之粗生成物懸浮於乙酸乙酯中，再將其以己燒 稀釋’濾取結晶及用己烷洗淨後，藉由通風乾燥，得到為 白色結晶之標題化合物（1·41 g，3.39 mmol，85%)。 ifi-NMR 光譜（DMSO-d6)5(ppm): 2·68 (3H，d，J=4.4 Hz) 3.87 (3H, s), 3.99 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.89 (1H, q, J=4.4 Hz), 7.25 (1H, dd, J=2.8, 9.0 Hz), 7.50 (1H d 一 J-2·8 Hz)，7.54 (1H，s)，8.13 (1H，s)，8·26 (1H，d，J=9.〇 Hz) 8.58 (lHrs^T 8·69 (1H，d，J=5.2 Hz)。 ’ 一 實施例633 -675 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 _ ._B7_._ 五、發明説明（67〇) 二 Γ. K3-氯-4-(((甲胺基）羰某）胺某）茉氩某17-甲氣基-6-4 啉羧酸 於4-(3-氯-4-(((甲胺基）羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸曱酯（ΐ·31 g，3· 15 mmol)中添加甲醇（14 ml)及2 當量濃度氫氧化鈉水溶液（7 ml)，然後於60。(：攪拌30分 鐘。將反應液放冷至室溫，添加2當量濃度鹽酸中和後，餾 去甲醇，濾取析出之白色結晶，充分水洗後，於6(TC乾 燥’仔到標題化合物（1.26 g，3 · 15 mmol，100%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 2·68 (3H，d，J=4.4 Hz)， 3.98 (3H, s), 6.54 (1H, d, J=5.0 Hz), 6.89 (1H, q, J=4.4 Hz), 7.25 (1H, dd, J=2.85 9.0 Hz), 7.48-7.53 (2H, m), 8.13 (1H, s);-- 8.25 (1H, d, J=9.0 Hz), 8.54 (1H, s), 8.69 (1H, d, J=5.0 Hz), 13.12 (1H，br s)。 一 實施例634 啦二^基..:4-(3-氯-4-(((甲胺某）羰基）胺某）茉氫某）-7-甲氛 基-6-喹啉#醯胺 將4-(3-氯-4-(((甲胺基）羰基）胺基）苯氧基）-7_甲氧基-6-4啉羧酸（1〇〇 mg，0.250 mmol)溶於二甲基甲醯胺（3 ml) 中，於室溫依序添加40%甲胺-甲醇溶液（〇·ι〇〇 mi)、三乙 胺（0.250毫升）及1H-1，2,3-苯并三唑-1-基氧）（三（二曱胺基）） 鳞六氟鱗酸鹽（221 mg，0.500 mmol)後，撥拌15小時。將 反應液分溶於乙酸乙酯及水中，將有機層用水及飽和食鹽 水洗淨，H水硫酸鈉乾燥。餾去溶媒後，懸浮於乙酸乙 酯中，再將其以己烷稀釋，濾取結晶及藉由通風乾燥，得 ___- 676 -___ 本紙張尺度適用ta ®家標準(CNS) A4規格(21GX 297公釐) 一 1304061 A7 B7 五、發明説明（671) 二 到為白色結晶之標題化合物（85.0 mg，0.204 mmol， 82%” W-NMR 光譜（DMSO-d6)(5(ppm): 2.68 (3H，d，J=4.2 Hz)， 2.84 (3H5 d, J=4.2 Hz), 4.02 (3H, s), 6.53 (1H, d, J-5.2 Hz), 6·88 (1H，q，J=4.2 Hz)，7·22 (1H，dd，J=2.8，9·2 Hz), 7.45 (1H，d，J=2.8 Hz)，7·52 (1H，s)，8·12 (1H，s)，8.24 (1H，d， J=9.2 Hz), 8.36 (1H, q, J=4.2 Hz), 8.59 (1H, s), 8.67 (1H, d, J=5.2 Hz) 〇 實施例635 基-4-(3-氯-4-j ((甲胺基）蕤某）胺基）笨氫基甲氣 基-6-邊淋截酿胺 - 從4-(3-氯-4-(((甲胺基）羰基）胺基）苯氧基）-7-甲氧基 6-喹啉羧酸（100 mg，0.250 mmol)及2.0M乙胺（四氫呋4溶 ’ 液），藉由實施例634同樣之方法，得到為白色結晶之標題 化合物（93.0 mg，0.217 mmol，87%)。 h-NMR 光譜（DMSO-d6) 5(ppm): 1.15 (3H，t，J=7.2 Hz)， 2.68 (3H, d, J=4.4 Hz), 3.28-3.38 (2H, m), 4.02 (3H, s), 6.53 (1H, d, J=5.2 Hz), 6.87 (1H, q, J=4.4 Hz), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.51 (1H, s), 8.11 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.38 (1H, m), 8.54 (1H, s), 8.66 (1H，d, J=5.2 Hz)。 實施例636 N6-環丙条-U3-氪-4-(((甲胺某）羰基）胺基）笨氣基）-7-氣基-6-4啉藉醯胺 _ ._ 677 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210Χ 297公釐） 1304061 A7 _B7五、發明説明（672) 二 從4-(3-氯-4-(((甲胺基）羰基）胺基）苯氧基）-7-甲氧基-6-p奎琳瘦酸（100 mg，0.250 mmol)及環丙胺，藉由實施例 634同樣之方法，得到為白色結晶之標題化合物（66.0 mg， 0.150 mmol，60%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): 0.59 (2H，m)，0.69 (2H，m)， 2·68 (3H，d，J=4.8 Hz)，2·87 (1H，m)，3·99 (3H，s)，6·53 (1H， d, J=5.2 Hz), 6.88 (1H, q, J=4.8 Hz), Ί.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.49 (1H? s), 8.12 (1H, s)5 _ 8.25 (1H, d, J=9.2 Hz), 8.34 (1H, d, J=4.0 Hz), 8.41 (1H, s), 8_66 (1H，d，J=5,2 Hz) 〇 實施例637 ' · N6-甲氧基-4-(3-氯-4-q(甲胺基）羰基）胺某）苯氫基）-7-甲 氣基-6-4啉羧醯胺 一 ’ 從4-(3-氯-4-(((甲胺基）羰基）胺基）苯氧基）-7-甲氧基-6-峻淋瘦酸（100 mg，0.250 mmol)及甲氧基胺鹽酸鹽，藉由 與實施例634同樣之方法，得到為白色結晶之標題化合物 (51.0 mg，0.118 mmol，47%)。 W-NMR 光譜（DMSO-d6)5(ppm): 2.56 (3H，d，J=4.4 Hz)， 3.74 (3H, s), 3.99 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.88 (1H, q, J=4.4 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 8.12 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.43 (1H，s)，8.67 (1H，d，J=5,2 Hz)，11.46 (1H，s)。 實施例631〜 N6-(2-甲氣乙基）-4-(3-氯- 4-L((甲胺基）羱其、胺某）笨氣 -678 - 本紙張尺度適用令國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（673) - * 基）-7-甲氡基-6〃杳啉羧醯胺 從4-(3 -氯-4-(((甲胺基）羰基）胺基）苯氧基）-7-甲氧基- 6- 峻淋致酸（100 mg，0.250 mmol)及2-甲氧乙胺，藉由實施 例634同樣之方法，得到為白色結晶之標題化合物（71 .〇 mg，0.154 mmol，62%) 〇 W-NMR 光譜（DMSO-d6)(5(ppm): 2·68 (3H，d，J=4.4 Hz)， 3.30 (3H, s), 3.46-3.52 (4H, m), 4.03 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.88 (1H, q, J=4.4 Hz), 7.23 (1H, dd, J=2.8, 9.2 .Izi丄chloro-4-(((methylamine)&gt;&gt; carbonyl)amine) stupid certain 6 4 Lincarboxylic acid methyl ester will be Ν-(2-:^-4-(7-methoxy)- 6-methoxy-based 4-aryl-phenyl oxyphenyl) phenyl carbamate (1.92 g ' 4.00 mmol) and 40% methylamine (methanol solution) (2 __ ml) in dimethylformamide In 8 ml), stir at room temperature for 3 minutes. The solution was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The obtained crude product was suspended in ethyl acetate, and the residue was crystallised from hexanes. 3.39 mmol, 85%). Ifi-NMR spectrum (DMSO-d6) 5 (ppm): 2·68 (3H, d, J = 4.4 Hz) 3.87 (3H, s), 3.99 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.89 (1H, q, J=4.4 Hz), 7.25 (1H, dd, J=2.8, 9.0 Hz), 7.50 (1H d a J-2·8 Hz), 7.54 (1H, s), 8.13 (1H, s), 8.26 (1H, d, J = 9. Hz) 8.58 (lHrs^T 8·69 (1H, d, J = 5.2 Hz). 'One embodiment 633 - 675 - This paper The scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 _ ._B7_._ V. Description of invention (67〇) II. K3-chloro-4-(((methylamino)carbonyl) Amine argon a 17-methyl-hydroxy-6-4 carboxylic acid in 4-(3-chloro-4-(((methylamino)carbonyl))amino)phenoxy)-7-methoxy Methyl 6-quinolinecarboxylate (ΐ·31 g, 3·15 mmol) was added with methanol (14 ml) and a 2 N aqueous solution of sodium hydroxide (7 ml), then at 60. (: 30 min. The reaction solution was allowed to cool to room temperature, neutralized by adding 2 equivalents of hydrochloric acid, and then methanol was distilled off, and the precipitated white crystals were filtered, washed with water, and then dried at 6 (TC) to the title compound (1.26 g, 3 · 15 mmol, 100%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 2·68 ( 3H,d,J=4.4 Hz), 3.98 (3H, s), 6.54 (1H, d, J=5.0 Hz), 6.89 (1H, q, J=4.4 Hz), 7.25 (1H, dd, J=2.85 9.0 Hz), 7.48-7.53 (2H, m), 8.13 (1H, s); -- 8.25 (1H, d, J=9.0 Hz), 8.54 (1H, s), 8.69 (1H, d, J=5.0 Hz), 13.12 (1H, br s). An example 634 hexanes..: 4-(3-chloro-4-((methylamine)carbonyl)amine)))) Methylamino-6-quinoline# decylamine 4-(3-chloro-4-(((methylamino)carbonyl))amino)phenoxy)-7-methoxy-6-4 carboxylic acid (1 〇〇 mg, 0.250 mmol) was dissolved in dimethylformamide (3 ml), and 40% methylamine-methanol solution (〇·ι〇〇mi) and triethylamine (0.250) were added sequentially at room temperature. ML) and 1H-1,2,3-benzotriazol-1-yloxy) (tris(diamine)) squarrlux (221 mg, 0.500 mmol) were mixed for 15 hours. The reaction mixture was dissolved in ethyl acetate and water. After distilling off the solvent, it was suspended in ethyl acetate, and then diluted with hexane. The crystals were collected by filtration and dried by air drying to obtain ___- 676 -___ This paper scale was applied to the ta ® standard (CNS) A4 specification ( 21GX 297 mm) A 1304061 A7 B7 V. Inventive Note (671) The title compound (85.0 mg, 0.204 mmol, 82%) as white crystals. W-NMR spectrum (DMSO-d6) (5 (ppm): 2.68 (3H,d,J=4.2 Hz), 2.84 (3H5 d, J=4.2 Hz), 4.02 (3H, s), 6.53 (1H, d, J-5.2 Hz), 6·88 (1H,q,J =4.2 Hz), 7·22 (1H, dd, J=2.8, 9·2 Hz), 7.45 (1H, d, J=2.8 Hz), 7·52 (1H, s), 8·12 (1H, s), 8.24 (1H, d, J = 9.2 Hz), 8.36 (1H, q, J = 4.2 Hz), 8.59 (1H, s), 8.67 (1H, d, J = 5.2 Hz) 〇 Example 635 4-(3-chloro-4-j ((methylamino) oxime) amine) phenylhydrocarbyl-6-side leaching amine - from 4-(3-chloro-4-(( (Methylamino)carbonyl)amino)phenoxy)-7-methoxy 6-quinolinecarboxylic acid (100 mg, 0.250 mmol) and 2.0 M ethylamine (tetrahydrofuran 4 solution) by The title compound (93.0 mg, 0.217 mm) OL, 87%) h-NMR spectrum (DMSO-d6) 5 (ppm): 1.15 (3H, t, J = 7.2 Hz), 2.68 (3H, d, J = 4.4 Hz), 3.28-3.38 (2H, m), 4.02 (3H, s), 6.53 (1H, d, J=5.2 Hz), 6.87 (1H, q, J=4.4 Hz), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.47 ( 1H, d, J=2.8 Hz), 7.51 (1H, s), 8.11 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.38 (1H, m), 8.54 (1H, s), 8.66 (1H, d, J = 5.2 Hz). Example 636 N6-cyclopropane-U3-indole-4-((methylamine)carbonyl)amino)phenyl)-7-yl-6 -4 porphyrin oxime _ ._ 677 - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210Χ 297 mm) 1304061 A7 _B7 V. Invention description (672) II from 4-(3-chloro-4- (((Methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-p-quineline acid (100 mg, 0.250 mmol) and cyclopropylamine, in the same manner as in Example 634, The title compound was obtained as white crystals (66.0 mg, 0.150 mmol, 60%) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.59 (2H, m), 0.69 (2H, m), 2·68 ( 3H,d,J=4.8 Hz),2·87 (1H,m),3·99 (3H,s),6·53 (1H, d, J=5.2 Hz), 6.88 (1H, q, J= 4.8 Hz), Ί.22 (1H, Dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.49 (1H? s), 8.12 (1H, s)5 _ 8.25 (1H, d, J=9.2 Hz), 8.34 (1H, d, J = 4.0 Hz), 8.41 (1H, s), 8_66 (1H, d, J = 5, 2 Hz) 〇 Example 637 ' · N6-methoxy-4-(3-chloro- 4-q(methylamino)carbonyl)amine a)phenylhydro)-7-methyl-6-7-carboxycarboxamide-'from 4-(3-chloro-4-(((methylamino))) A carbonyl)amino)phenoxy)-7-methoxy-6-anthracene acid (100 mg, 0.250 mmol) and methoxyamine hydrochloride were obtained by the same method as in Example 634. The title compound (51.0 mg, 0.118 mmol, 47%) W-NMR spectrum (DMSO-d6) 5 (ppm): 2.56 (3H, d, J = 4.4 Hz), 3.74 (3H, s), 3.99 (3H, s), 6.54 (1H, d, J = 5.2 Hz ), 6.88 (1H, q, J=4.4 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 8.12 (1H , s), 8.25 (1H, d, J = 9.2 Hz), 8.43 (1H, s), 8.67 (1H, d, J = 5, 2 Hz), 11.46 (1H, s). Example 631~ N6-(2-Methylethyl)-4-(3-chloro-4-L((methylamino) oxime, amine) stupid -678 - This paper scale applies to national standards (CNS) A4 size (210X 297 mm) 1304061 A7 B7 V. Inventive Note (673) - * Base)-7-Mercapto-6-porphyrin Carboxamide from 4-(3-chloro-4-( ((Methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-phosphonic acid (100 mg, 0.250 mmol) and 2-methoxyethylamine, the same as in Example 634 The title compound (71. 〇mg, 0.154 mmol, 62%) was obtained as white crystals. 〇W-NMR spectrum (DMSO-d6) (5 (ppm): 2·68 (3H, d, J = 4.4 Hz) , 3.30 (3H, s), 3.46-3.52 (4H, m), 4.03 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.88 (1H, q, J=4.4 Hz), 7.23 ( 1H, dd, J=2.8, 9.2 .

Hz), 7.48 (1H, d, J=2.8 Hz), 7.53 (1H, s), 8.12 (1H, s), 8.25 (1H，d，J=9.2 Hz), 8·46 (1H，m)，8.61 (1H，s)，8.67 (1H，d， J=5.2 Hz)。 -… 會施例639 · N6-(2-氟乙基1-4-(3-氯-4-(((甲胺基）赛基）胺基）笨氣基:: 7- 甲氣基-6〃奎淋藉醯胺 從4-(3-氯-4-(((甲胺基）羰基）胺基）苯氧基甲氧基-6-喹淋羧酸（100 mg，0.250 mmol)及2-氟乙胺鹽酸鹽，藉由 與實施例634同樣之方法，得到為白色結晶之標題化合物 (86.0 mg ^ 0.192 mmol » 77%) 〇 h-NMR 光譜（DMSO-d6)5(ppm): 2.68 (3H，d，J=4.4 Hz)， 3·59 (1H，m)，3.67 (1H，m)，4.03 (3H，s)，4·50 (1H，m)，4.62 (1H, m), 6.54 (1H, d, J=5.2 Hz), 6.88 (1H, q, J=4.4 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.53 (1H, s), 8.12 (1Η3), 8.24 (1H, d, J=9.2 Hz), 8.58-8.62 (2H, m), 8.67 (1H，d，J=5.2 Hz)。 __- 679 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（674) 二 二 實施例640 N6-( (2R)四fi.-2-呋喃甲基）-4-(3-氪-4-(7(甲胺基）羰某）胺 基）笨氣基）-7-甲氣基-6-崦啉#醯胺 從4-(3-氯-4-(((甲胺基）羰基)胺基）苯氧基）-7-甲氧基-6- 口奎淋複酸（100 mg，0.250 mmol)及R-四氫祿胺，藉由與 實施例634同樣之方法，得到為白色粉末之標題化合物 (81.0 mg，0.167 mmol，67%) 〇 iH-NMR 光譜（DMSO-d6) 5 (ppm): 1·62 (1H，m)，1.80-2.00 (3H, m), 2.68 (3H, d, J=4.4 Hz), 3.40 (2H, m), 3.66 (1H, dd, J=3.6, 14.0 Hz), 3.81 (1H, dd, J=4.0, 14.0 Hz), 3.99 (1H, m), 4.02 (3H, s)5 6.54 (1H, d, J=5.2 Hz), 6.88 (1H, q, J=4.4 Hz), _ · 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.54 &gt; (1H, s), 8.12 (1H, s), 8.24 (1H, d, J=8.8 Hz), 8.43 (1H, m), 8·61 (1H，s), 8.67 (1H，d，J=：5.2 Hz)。 實施例641 M6-((2S)四氫-2-吱喃甲基）-4-(3-氯-4-(^(甲胺某）凝基）胺 基）笨乳基）-7-甲氧基-6-0奎?林藉酿胺 從4-(3-氯-4-(((甲胺基）羰基）胺基）苯氧基甲氧基-6-喹淋幾酸（1〇〇 mg，0·2 50 mmol)及S-四氫糠胺，藉由實施 例634同樣之方法，得到為白色粉末之標題化合物（85 〇 mg，0.175 mmol，70%) 0 實施例642Hz), 7.48 (1H, d, J=2.8 Hz), 7.53 (1H, s), 8.12 (1H, s), 8.25 (1H,d,J=9.2 Hz), 8·46 (1H,m), 8.61 (1H, s), 8.67 (1H, d, J = 5.2 Hz). -... will be applied 639 · N6-(2-fluoroethyl 1-4-(3-chloro-4-(((methylamino)) yl)amino) stupid base:: 7-methyl-based - 6〃奎淋 by amidoxime from 4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxymethoxy-6-quinolinic acid (100 mg, 0.250 mmol) and The title compound (86.0 mg ^ 0.192 mmol) &lt;RTI ID=0.0&gt;&gt;&gt; : 2.68 (3H,d,J=4.4 Hz), 3·59 (1H,m), 3.67 (1H,m),4.03 (3H,s),4·50 (1H,m),4.62 (1H, m ), 6.54 (1H, d, J=5.2 Hz), 6.88 (1H, q, J=4.4 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz) ), 7.53 (1H, s), 8.12 (1Η3), 8.24 (1H, d, J=9.2 Hz), 8.58-8.62 (2H, m), 8.67 (1H, d, J=5.2 Hz). __- 679 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Description of invention (674) Twenty-two embodiment 640 N6-((2R)tetrafi.-2-furanylmethyl) 4-(3-indole-4-(7(methylamino)carbonyl)amino) stupid)-7-methyl-6-carboline#p-amine from 4-(3-chloro-4) -(((methylamino) Carbonyl)amino)phenoxy)-7-methoxy-6-mesaquinic acid (100 mg, 0.250 mmol) and R-tetrahydroramine were obtained in the same manner as in Example 634. The title compound of the white powder (81.0 mg, 0.167 mmol, 67%) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 1·62 (1H, m), 1.80-2.00 (3H, m), 2.68 ( 3H, d, J=4.4 Hz), 3.40 (2H, m), 3.66 (1H, dd, J=3.6, 14.0 Hz), 3.81 (1H, dd, J=4.0, 14.0 Hz), 3.99 (1H, m ), 4.02 (3H, s)5 6.54 (1H, d, J=5.2 Hz), 6.88 (1H, q, J=4.4 Hz), _ · 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.54 &gt; (1H, s), 8.12 (1H, s), 8.24 (1H, d, J=8.8 Hz), 8.43 (1H, m), 8·61 ( 1H, s), 8.67 (1H, d, J =: 5.2 Hz). Example 641 M6-((2S)tetrahydro-2-indolylmethyl)-4-(3-chloro-4-(^(methylamine))-amino)amino)phenyl--7-A Oxy-6-0 quinone by amine from 4-(3-chloro-4-(((methylamino)carbonyl))amino)phenoxymethoxy-6-quinolinic acid (1〇 The title compound (85 mg, 0.175 mmol, 70%) was obtained as a white powder. </ br> </ br> </ br> </ br> </ br>

Mr_(2-乙m)-4-_(3—-氣-4-(((甲脖基）赛甚、眩莘、苇$ 一 基）-7-甲氩基-6〃奎啉羧醯胺 __- 680 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明(~^— 從4-(3-氯-4-(((甲胺基）羰基）胺基）苯氧基）-7-甲氧基_ 6-喹啉羧酸（100 mg，0.250 mmol)及2-乙氧乙胺，藉由與實 施例634同樣之方法，得到為白色粉末之標題化合物（94,〇 mg，0.199 mmol，80%)。 iH-NMR 光譜（DMSO-d6)(5(ppm): 1·15 (3H，t，J=6.8 Hz)， 2.68 (3H, d, J=4.4 Hz), 3.45-3.56 (6H, m), 4.04 (3H, s)3 6.54 (1H, d, J=5.2 Hz), 6.89 (1H, q, J=4.4 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.54 (1H, s), 8 13 (1H, s), 8.25 (1H, dd, J=2.8, 9.2 Hz), 8.46 (1H, m), 8.64 (1H s)，8·67 (1H，d，J=5.2 Hz)。 實施例643 N6-異丁氧基-4·-(3-氣-4_(((甲胺基）裁基）脖華）装孝華 甲氣基-6〃杳啉藉酿胺 .一 從4-(3-氯-4-(((甲胺基）羰基）胺基）苯氧基）_7_甲氧羞^ 6-喹啉羧酸（100 mg，0.250 mmol)及異丁氧胺鹽酸鹽，藉由 與實施例634同樣之方法’得到為白色粉末之標題化^物 (72.0 mg，0.152 mmol，61%) 〇 j-NMR 光譜（DMSO-d6)5(ppm): 〇·95 (6H，d，J=6.8 1.97 (1H，m)，2·68 (3H，d，J=4.4 Hz)，3·71 (2H，d，J=6.8 ΗΖ/ 3·99 (3H，s)，6·54 (1H，d，J=5.2 Hz)，6·89 (1H，q，j=4.4 Hz)’ 7·23 (1H，dd，J=2.8, 9.2 Hz), 7·48 (1H，d，J=2.8 Hz) η 5〇Mr_(2-Bm)-4-_(3—-Gas-4-(((甲甲基)赛,, 莘, 苇$一基)-7-A-aryl-6〃 quinoliniumcarboxylate Amine __- 680 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Description of invention (~^- From 4-(3-chloro-4-(((methylamine)) The carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (100 mg, 0.250 mmol) and 2-ethoxyethylamine were obtained in the same manner as in Example 634. The title compound (94, 〇mg, 0.199 mmol, 80%) as white powder. iH-NMR spectrum (DMSO-d6) (5 (ppm): 1·15 (3H, t, J = 6.8 Hz), 2.68 ( 3H, d, J=4.4 Hz), 3.45-3.56 (6H, m), 4.04 (3H, s)3 6.54 (1H, d, J=5.2 Hz), 6.89 (1H, q, J=4.4 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.54 (1H, s), 8 13 (1H, s), 8.25 (1H, dd, J=2.8 , 9.2 Hz), 8.46 (1H, m), 8.64 (1H s), 8.67 (1H, d, J = 5.2 Hz). Example 643 N6-isobutoxy-4·-(3-gas- 4_(((Methylamino)))))))))) Phenoxy)_7_methoxy &lt;6&gt;-Quinolinecarboxylic acid (100 mg, 0.250 mmol) eluted eluted eluted elute %) 〇j-NMR spectrum (DMSO-d6) 5 (ppm): 〇·95 (6H,d,J=6.8 1.97 (1H,m),2·68 (3H,d,J=4.4 Hz),3 ·71 (2H,d,J=6.8 ΗΖ/ 3·99 (3H,s),6·54 (1H,d,J=5.2 Hz),6·89 (1H,q,j=4.4 Hz)' 7 · 23 (1H, dd, J = 2.8, 9.2 Hz), 7·48 (1H, d, J = 2.8 Hz) η 5〇

(1H, s), 8.13 (1H, s), 8.25 (1H, dd, J=2.8, 9.2 Hz), 8.36 (lH s)，8.67 (tir; d，J=5.2 Hz), 11.35 (1H，br s)。 ’ 實施例644(1H, s), 8.13 (1H, s), 8.25 (1H, dd, J=2.8, 9.2 Hz), 8.36 (lH s), 8.67 (tir; d, J=5.2 Hz), 11.35 (1H, br s).例 Example 644

裝 訂Binding

k -681 -k -681 -

1304061 A7 B7 五、發明説明（676) 二 二 ir—C3-氣-4-(((環丙胺某）羱某）胺基）茉氣基）-7-a2R)-3-二 乙胺基-2-巍丙氧某）-6- p奎淋藏酿胺 於4-(3-氣-4-(((環丙胺基）羰基）胺基）苯氧基）-7-羥基-6 -峻淋複酿胺（372.0 mg，0.90 mmol)中添加4-甲基-1-苯橫 酸（2R)環氧乙規-2-基甲酯（308 mg，1.35 mmol)、碳酸4甲 (149 mg，1.08 mmol)及二甲基甲醯胺（9 ml)，並在60°C攪 拌6小時。繼而添加二乙胺（2 ml)且更進而在50°C攪拌一整 晚。將尽應液分溶於乙酸乙酯及水，有機層用水及飽和食 鹽水洗淨，用無水硫酸鈉乾燥。餾去溶媒，且付諸於矽凝 膠管柱層析（溶出液為乙酸乙酯：甲醇= 95: 5)，將含有目 的物之溶出份濃縮後，濾取從乙醚中析出之結晶，藉由通.. 風乾燥，得到為白色結晶之標題化合物（177.5 mg，0.327 ::上: mmol，36.3%)。 4 - NMR 光譜（DMSO-d6)5(ppm): 0.42 (2H，m)，0·65 (2H，m)， 〇·94 (6H，t，J=7.2 Hz)，2.44-2.60 (7H，m)，3.98 (1H，m)，4.21 (1H, dd, J=5.6, 10.0 Hz), 4.31 (1H, dd, J=3.2, 10.0 Hz), 5.09 (1H, d, J=4.4 Hz), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d5 J=2.8 Hz), 7.24 (1H, dd, J=2.8, 8.8 Hz), 7.49 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.84 (1H, s), 7.97 (1H, s), 8.00 (1H, s), 8.26 (1H，d，J=8.8 Hz), 8·65 (1H，d, J=5.2 Hz)，8·81《1H，s)。 實施例645 甲基-7-〔草董.基）-4-(3-氣-(4-((甲胺某）淼篡）胺基）笨 1基）-6-跨毋#醯胺 ’ 藉由與實施例11同樣之方法，從N-(4-(7-(芊氧基）-6-(甲 ___ - 682 -__ 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）1304061 A7 B7 V. INSTRUCTIONS (676) Di-di-C3-gas-4-(((cyclopropylamine)))))))))))) 2-巍propoxyl)-6-p-quinone-branched amine in 4-(3-carb-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-jun Add 4-methyl-1-phenylphosphonic acid (2R) epoxyethyl-2-methyl ester (308 mg, 1.35 mmol), carbonic acid 4 (149 mg) to the amine (372.0 mg, 0.90 mmol) , 1.08 mmol) and dimethylformamide (9 ml), and stirred at 60 ° C for 6 hours. Then diethylamine (2 ml) was added and further stirred at 50 ° C overnight. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and subjected to column chromatography on a gel column (ethyl acetate: methanol = 95:5), and the fractions containing the desired material were concentrated, and then crystals which were precipitated from diethyl ether were collected by filtration. The title compound was obtained as white crystals (177.5 mg, 0.327::: 4 - NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H, m), 0·65 (2H, m), 〇·94 (6H, t, J = 7.2 Hz), 2.44-2.60 (7H, m), 3.98 (1H, m), 4.21 (1H, dd, J=5.6, 10.0 Hz), 4.31 (1H, dd, J=3.2, 10.0 Hz), 5.09 (1H, d, J=4.4 Hz), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d5 J=2.8 Hz), 7.24 (1H, dd, J=2.8, 8.8 Hz), 7.49 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.84 (1H, s), 7.97 (1H, s), 8.00 (1H, s), 8.26 (1H, d, J = 8.8 Hz), 8·65 (1H, d, J=5.2 Hz), 8.81 "1H, s". Example 645 Methyl-7-[oxalyl.yl)-4-(3-gas-(4-((methylamine)))))))) By the same method as in Example 11, from the N-(4-(7-(decyloxy)-6-(methyl___-682-__) paper scale applicable to the Chinese National Standard (CNS) A4 specification (210X297 public) PCT)

裝 訂Binding

線 1304061 A7 B7 五、發明説明（677) 二， 二 胺基）羰基-4-喹啉基）氧-2-氣苯基）胺甲酸苯酯（645 mg , 1·16 mmol)及2M甲胺-四氫呋喃溶液，得到為淡褐色結晶之 標題化合物（466 mg，0.950 mmol，81.6%)。 !H-NMR 光譜（DMSO-d6)5(ppm)·· 2·66 (3H，d，J=4.4 Hz) 2.81 (3H, d, J=4.4 Hz), 5.42 (2H, s), 6.51 (1H, d, J=5.2 Hz) 6.86 (-1H，q，J=4.4 Hz)，7.21 (1H，dd，J=2.8, 9.2 Hz)，7,3〇. 7·45 (4H，m)，7.52-7.55 (3H，m), 8.10 (1H，s)，8·22 (1H，d， J=9.2 Hz), 8.38 (1H, q, J=4.4 Hz), 8.49 (1H, s), 8.62 (1H, d5 J=5.2 Hz)。 ' 起始原料係以下述方法合成。 製造例645-1 4-(((2,2-二甲基-4,6-二嗣基-1，3-亞二氣六圜-5-華）ψ其） 胺基）-2-輕基辛酸笨酯 — - 在4_胺基水楊酸苯酯（42.2 g，184 mmol)中添加麥爾多拉 姆酸（29.2 g，202 mmol)、原甲酸三乙酯（200 ml)及異丙醇 (200 ml)，於100°C加熱攪拌1小時、將反應液放冷至室溫 後’進一步攪拌一整晚。濾取析出之結晶，用異丙醇及乙 醚洗淨後，藉由通風乾燥，得到為白色結晶之標題化合物 (69.5 mg，181 mmol，99%) 〇 W-NMR光譜（DMSO-d6) 5 (ppm): 1.69 (6H，s)，7.21-7.28 (2H， m)，7·29-7·36 (3H，m)，7·44-7·52 (2H，m)，8·04 (1H，d，J=8.4 —Line 1304061 A7 B7 V. Description of the Invention (677) Diphenylamine diamino)carbonyl-4-quinolinyloxy-2-phenylphenylamine amide (645 mg, 1.16 mmol) and 2M methylamine The title compound (466 mg, 0.950 mmol, 81.6%). !H-NMR spectrum (DMSO-d6) 5 (ppm)·· 2·66 (3H, d, J=4.4 Hz) 2.81 (3H, d, J=4.4 Hz), 5.42 (2H, s), 6.51 ( 1H, d, J=5.2 Hz) 6.86 (-1H, q, J=4.4 Hz), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7,3〇. 7·45 (4H,m), 7.52-7.55 (3H,m), 8.10 (1H,s),8·22 (1H,d, J=9.2 Hz), 8.38 (1H, q, J=4.4 Hz), 8.49 (1H, s), 8.62 (1H, d5 J=5.2 Hz). 'The starting materials were synthesized in the following manner. Production Example 645-1 4-(((2,2-Dimethyl-4,6-dimercapto-1,3-ylidenequinone-5-hua) ψ)) Amino)-2-Light Butyl octanoate - Add merdoram acid (29.2 g, 202 mmol), triethyl orthoformate (200 ml) and different phenyl 4-aminosalicylate (42.2 g, 184 mmol) Propanol (200 ml) was stirred with heating at 100 ° C for 1 hour, and the reaction solution was allowed to cool to room temperature and then further stirred overnight. The precipitated crystals were filtered, washed with EtOAc EtOAc (EtOAc) Ppm): 1.69 (6H, s), 7.21-7.28 (2H, m), 7·29-7·36 (3H, m), 7·44-7·52 (2H, m), 8·04 (1H ,d,J=8.4 —

Hz), 8.64 (1H, s), 10.52 (1H, br s), 11.24 (1H, br s) 〇 羞造例64H .… 一 基）-4·酮基-1，4·二氣-6-啐啉淼酸茉酯Hz), 8.64 (1H, s), 10.52 (1H, br s), 11.24 (1H, br s) 〇 造 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 64 Porphyrin citrate

1304061 A7 B7 五、發明説明（678) 將4-(((2，2 -二甲基-4,6-二酮基-1，3 -亞二氧六圜-5-基）甲 基）胺基）-2-羥基芊酸苯酯（ιι·5 g，0.030 mm〇i)、芊基溴化 物（5·64 g，0·033 mmol)及碳酸鉀（4·56 g，0.033 mmol)添加 於一甲基甲酿胺（45 ml)中，並在80 °C攪拌3小時。將反應 液分溶於乙酸乙酯-四氫呋喃混合溶媒及水中，有機層用水 及飽和食鹽水洗淨，用無水硫酸鎂乾燥，濾除乾燥劑，以 及將濾液減壓餾去。將得到之粗生成物懸浮於乙醇，再將 其以己烷稀釋，濾取結晶及用己烷洗淨後，藉由通風舞 燥’知到白色結晶。將得到之粗結晶在Dowtherm A( 50 ml) 中，於200°C加熱攪拌1小時。將反應液放冷至室溫後，添 加乙酸（2 5 ml)，進一步撥拌一整晚。滤取析出之結晶，用 乙醚洗淨後，藉由通風乾燥，得到為白色結晶之標題化合 物（1.20 g，3.23 mmol，11%) 〇 一 ΐ WNMR光譜（DMSO-d6)5(ppm): 5·33 (2Η，s)，6.03 (1Η，d， J=7.4 Hz), 7.19 (1H, s), 7.21-7.27 (2H, m), 7.28-7.36 (2H, m), 7.36-7.43 (2H, m), 7.43-7.50 (2H, m), 7.52-7.58 (2H, m), 7.90 (1H，d, J=7.4 Hz)，8.71 (1H, s), 11·79 (1H，br s)。 製造例645-3 甲基主氧基）-4-氟-6-p杏说淼Bfe蔣： 於7-(爷氧基）-4-酮基-1，4-二氫-6-喹啉羧酸苯酯（1.20 g ’ 3.23 mmol)中添加亞硫酿氯（12 ml)及觸媒量之二甲基甲 硫胺’並於攪拌下加熱回流2小時。將反應液減壓濃縮，與 甲苯共彿〜2次後，將殘餘物懸浮於二甲基甲醯胺（2〇 ml)， 中’在冰水浴冷卻下，慢慢地添加40〇/〇甲胺-甲醇溶液（5 684 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公董） 13040611304061 A7 B7 V. INSTRUCTIONS (678) 4-(((2,2-Dimethyl-4,6-dione-1,3-dioxapyridin-5-yl)methyl)amine Phenyl-2-hydroxydecanoate (ιι·5 g, 0.030 mm〇i), decyl bromide (5·64 g, 0·033 mmol) and potassium carbonate (4·56 g, 0.033 mmol) It was stirred in monomethylamine (45 ml) at 80 ° C for 3 hours. The reaction mixture was dissolved in ethyl acetate-tetrahydrofuran-mixed solvent and water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated. The obtained crude product was suspended in ethanol, and then diluted with hexane, and crystals were collected by filtration and washed with hexane, and then white crystals were obtained by ventilating. The obtained crude crystals were stirred in Dowtherm A (50 ml) at 200 ° C for 1 hour. After the reaction solution was allowed to cool to room temperature, acetic acid (25 ml) was added and the mixture was further stirred overnight. The precipitated crystals were filtered, washed with diethyl ether and evaporated to dryness crystals crystals crystalsssssssssssssssssssss · 33 (2Η, s), 6.03 (1Η, d, J=7.4 Hz), 7.19 (1H, s), 7.21-7.27 (2H, m), 7.28-7.36 (2H, m), 7.36-7.43 (2H , m), 7.43-7.50 (2H, m), 7.52-7.58 (2H, m), 7.90 (1H,d, J=7.4 Hz),8.71 (1H, s), 11·79 (1H,br s) . Production Example 645-3 Methyl-based oxy)-4-fluoro-6-p Apricot 淼Bfe Chiang: 7-(yloxy)-4-keto-1,4-dihydro-6-quinoline To the phenyl carboxylate (1.20 g '3.23 mmol), sulfite-brewed chlorine (12 ml) and a catalytic amount of dimethylmethylthioamine were added and heated under reflux for 2 hours with stirring. The reaction solution was concentrated under reduced pressure, and the mixture was stirred with toluene~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Amine-methanol solution (5 684 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 DON) 1304061

ml),且攪拌丨小時。將反應液分溶於乙酸乙酯·四氣呋喃混 合溶媒（1 : 1)及水中，有機層用飽和氯化銨水溶液、水及 飽和食鹽水洗淨，用無水硫酸鈉乾燥。餾去溶媒，添加乙 醚繼而添加己烷，以使之結晶化，濾取結晶且通風乾燥， 得到為淡黃色結晶之標題化合物（947 mg，2 9〇 mmQl , 89.7%) 〇 H-NMR光譖（CDCl3)6(ppm): 2.97 (3H，d，J=4.8 Ηζ)，5·35 (2H，s)，.7.40-7.52 (6H，m)，7·64 (1H，s)，7.91 (1H，m)，8 j5 (1H，q，J=4.8 Hz)，9.16 (1H，s)。 製造例645-4Ml), and stir for 丨 hours. The reaction mixture was dissolved in ethyl acetate-tetrahydrofuran (1:1) and water, and the organic layer was washed with saturated aqueous ammonium chloride, water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and diethyl ether was added, followed by the addition of hexane to crystallize, crystals were crystallized, and dried to give the title compound (947 mg, 2 9 〇mmQl, 89.7%) as a pale yellow crystal. (CDCl3)6 (ppm): 2.97 (3H,d,J=4.8 Ηζ),5·35 (2H,s),.7.40-7.52 (6H,m),7·64 (1H,s),7.91 ( 1H, m), 8 j5 (1H, q, J = 4.8 Hz), 9.16 (1H, s). Manufacturing Example 645-4

Mr甲基-4- ( 4_胺幕-3-氯苯氧基）-7_ ( :¾:氫基）-6· +林讀酿 將4-胺基-3-鼠紛（624 mg，4·35 mmol)溶於二甲基亞石風 (15 ml)中’在至溫.反十笑地添加氫化鉤（174 mg，4.35 mmol) 且攪拌30分鐘。添加N6-甲基-7-(芊氧基）-4-氯·6-喹啉羧 醯胺（947 mg，2.90 mmol)，然後在100。(：攪拌下加熱2小 時。放冷至室溫，將反應液分溶於乙酸乙酯及水中，有機 層用1N氫氧化鈉水溶液、水及飽和食鹽水洗淨，用無水硫 酸誤乾燥。館去i谷媒’懸浮於乙酸乙g旨中，再將其以己燒 稀釋’濾取結晶，藉由通風乾燥，得到為淡褐色結晶之標 題化合物（ 1.098 g，2.53 mmol，87.3%)。 iH-NMR 光譜（CDCl3)5(ppm): 2·96 (3H，d，J=4.8 Hz)，4.10 (2H, m), 3：35 (2H, s), 6.46 (1H, d, J=5.2 Hz), 6.84 (1H, d, J=8.8 Hz), 6.93 (1H, dd5 J=2.8, 8.8 Hz), 7.14 (1H, d, J=2.8 • 685 - ^紙張尺度適用中國國家標準(°NS) A4規格(210x297公釐） 1304061 A7 —__B7 五、發明説明（68〇) 二 二Mr methyl-4-(4_amine curtain-3-chlorophenoxy)-7_ (:3⁄4:hydrogen)-6· +Linning will be 4-amino-3-rat (624 mg, 4 · 35 mmol) was dissolved in dimethyl sulphur (15 ml). Add hydrogenated hooks (174 mg, 4.35 mmol) to the temperature and stir for 30 minutes. N6-Methyl-7-(decyloxy)-4-chloro-6-quinolinecarboxamide (947 mg, 2.90 mmol) was added followed by 100. (The mixture was heated under stirring for 2 hours. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with 1N aqueous sodium hydroxide, water and brine, and dried over anhydrous The title compound ( 1.098 g, 2.53 mmol, 87.3%) was obtained as a light brown crystal. mp. -NMR spectrum (CDCl3) 5 (ppm): 2·96 (3H, d, J = 4.8 Hz), 4.10 (2H, m), 3:35 (2H, s), 6.46 (1H, d, J=5.2 Hz), 6.84 (1H, d, J=8.8 Hz), 6.93 (1H, dd5 J=2.8, 8.8 Hz), 7.14 (1H, d, J=2.8 • 685 - ^The paper scale applies to the Chinese national standard (°NS A4 size (210x297 mm) 1304061 A7 —__B7 V. Description of invention (68〇) 22

Hz), 7.39-7.54 (5H, m)5 7.58 ( 1 H, s), 7.95 (1H, br), 8.62 (1H, d，J=5.2 Hz), 9·28 (1H，s” 製造例645-5 芊氧基）-6-(甲胺墓）羰基-4-4啉某）氣-2-氪苽基） 歷甲酸苯酯 藉由與製造例17同樣之方法，從N6-甲基-4-(4-胺基-3-氯苯氧基）-7-(芊氧基）-6-喹啉羧醯胺（1.098 g，2.53 mmol) ’·得到為淡褐色結晶之標題化合物（1 &quot;I g , 2 ?3 , mmo卜 92.1%” 1H-NMR 光譜（CDCl3)5(ppm): 2·96 (3H，d，JN4.8 Ηζ)，5·35 (2Η, s), 6.50 (1Η, d, J=5.2 Hz), 7.15 (1H, dd, J=2.8, 8.8 HzJ,.. 7.19-7.30 (6H, m), 7.40-7.52 (6H, m), 7.61 (1H, s), 7.95 (1H, v.% m), 8.30 (1H, q, J=4.8 Hz), 8.67 (1H, d, J=5.2 Hz), 9.27 (1H, s) ° f施例646 1甲基-7-(芊1基）_4-(3-氣“4-q乙胺基）蕤某）胺某）装 1基）-6- p奎，林卷酿胺 藉由與實施例11同樣之方法，從N-(4-(7-(苄氧基）-6-(甲 胺基）羰基-4-喹啉基）氧-2-氯苯基）胺甲酸苯酯（645 mg， 1.16 mmol)及2M乙胺-四氫呋喃溶液，得到為淡褐色結晶之 標題化合物（579 mg，1·15 mmol，98.4%)。 iH-NMR 光譜（DMSO-d6)(5(ppm): 1·06 (3H，t，J=7.2 Hz)， 2·81 (3H，〜d; J=4:8 Hz)，3·11 (2H，m)，5·42 (2H，s)，6·51 (1H， d, J=5.2 Hz), 6.99 (1H, m), 7.19 (1H, dd, J=2.8, 9.2 Hz), ___- 686 -_ 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) &quot;&quot; 1304061 A7 B7 五、發明説明（681 ) 二 7.30-7.45 (4H，m)，7.52-7.55 (3H，m)，8·06 (1H，s)，8.24 (1H， d，J=9.2 Hz)，8.37 (1H，q，J=4.8 Hz)，8.49 (1H，s)，8.62 (1H， d，J=5.2 Hz) 0 實施例647 N6-甲基- 4-(3-氯- 4-(((甲胺基）談基）胺基）笨氣基）-7-與 基-6-g奎g林複酿胺 從N6-甲基-7-(苄氧基）-4-(3-氯-4-(((甲胺基）羰基）胺基） 苯氧基）-6 -p奎淋幾酿胺（466.3 mg，0.95 mmol)，藉由與實 施例83同樣之方法，得到為黃色結晶之標題化合物（365.7 mg，0.91 mmol，96.1%) 〇 W-NMR光譜（DMSO-d6)6(ppm): 2·66 (3H，br s)，2·85 (3H， br s)，6.37 (1H，m)，6.86 (1H，m)，7.10-7.30 (2H，m)，7·45、 (1H, m), 8.09 (1H, br s), 8.22 (1H, m), 8.56 (1H, m), 8.84 (lH，brs)〇 實施例648 基-4-(3 -氯-4-(((乙胺某）数基）胺基）笨氣某與 基-6-口奎淋藉酿胺 藉由與實施例83同樣之方法，從N6-甲基-7-(苄氧基）-4-(3-氯-4-(((乙胺基）羰基）胺基）苯氧基）-6〃奎淋幾酸胺 (578.5 mg，1.15 mmol)，得到為淡黃色結晶之標題化合物 (431.4 mg，1.04 mmol，90.8%)。 1H-NMR 光譜（DMSO-d6)5(ppm)·· 1·06 (3H，t，J=7.2 Hz), 2.85 (3Hy^bf-s),-3.12 (2H, m), 6.36 (1H, m), 6.98 (1H, m), 7.20-7.24 (2H, m), 7.45 (1H, d, J=2.8 Hz), 8.05 (1H, s), 8.25 -687 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 _ B7 五、發明説明（~~) ~_ 7 二 (1H，d，J=9.2 Ηζ)，8·55 (1H，m)，8·84 (1H，s) 〇 實施例649 企二(（（4-(3-氣-4-((甲胺基）羰某）胺基）笨氳甚V 6-Γ甲脖羱 基）-7 - 4啉基）氣）甲基）-1-六氤吡啶羧酸第三丁酯 藉由與實施例7同樣之方法，從N6-甲基-4-(3-氯-4-(((甲 胺基）羰基）胺基）苯氧基）-7-羥基-6-喹啉羧醯胺（120 mg， 0.299 mmol)及4-(溴甲基）-1-六氫吡啶羧酸第三丁酯，得到 為淡褐，色結晶之標題化合物（98.4 mg，〇. 165 mmol _， 55.0%) 〇 iH-NMR 光譜（DMSO-d6) 5 (ppm): 1.17-1.33 (3Η，m)，1·39 (9H，s)，1.75 (2H，m)，2.06 (1H，m)，2.66 (3H，d, J=4.4 HzJ，._ 2.77 (1H, m), 2.81 (3H, d, J=4.8 Hz), 3.97 (2H, m), 4.10 (2H,；v ：* . ---- 一 .-r-— d，J=6.0 Hz)，6·51 (1H，d，J=5.2 Hz)，6.85 (1H，q，J=4.4 Hz)， 一 7.20 (1H, dd, J=2.8, 8.8 Hz), 7.44 (1H, d, J=2.8 Hz), 7.48 (1H, s), 8.10 (1H, s), 8.18 (1H, q, J=4.8 Hz), 8.22 (1H, d, J=8.8 Hz)，8·43 (1H，s)，8·63 (1H，d，J=5.2 Hz)。 實施例650 1/((4-(3- #.-4-((乙胺基）羰基）胺基）茉氳篡6-(甲胺羰 H 7- 4啉某）氣）甲基）-1 -六氫吡啶#酸第三丁酯 藉由與實施例7同樣之方法，從N6-甲基-4-(3-氯-4-(((乙 胺基）羰基）胺基）苯氧基）-7-輕基- 6-0奎淋羧酸胺（143 mg， 0.345 mmol)及4-(溴甲基）-1-六氫吡啶羧酸第三丁酯，得到 為淡褐色、錄晶之標題化合物（119.5 mg，0· 195 mmol， 56.6%)。 ____- 688 ____ 本紙張尺度適用中國國家標準(CNS) Α4規格(21〇X 297公釐） 1304061 683 五、發明説明（ ^H-NMR 光譜（DMSO-d6)5(ppm): 1〇6 (3H，t，J=7 2 Hz)， LiW.26 (3H，m)，i.39 (9H，s)，h76 (2H，m)，2 % (ih ⑷ 2.77 (1H5 m)3 2.81 (3H, d5 J=4.8 Hz), 3.12 (2H, m), 3.98^(2^ m), 4.10 (2H, d, J=6.0 Hz), 6.51 (lH, d, J=5.2 Hz), 6.97 (1h/ m)，7.19 (1H，dd，J=2.8，8·8 Hz), 7.44 (1H，d，J=2 8 Hz) 7.48 (1H, s), 8.04 (1H, s), 8.18 〇H, q, J=4.8 Hz), 8.24 (1h! d，J=8.8 Hz)，8·43 (1H，s)，8·63 (1H，d，J=5.2 Hz)。 實施例651Hz), 7.39-7.54 (5H, m)5 7.58 ( 1 H, s), 7.95 (1H, br), 8.62 (1H, d, J=5.2 Hz), 9·28 (1H, s) Manufacturing Example 645 -5 decyloxy)-6-(methylamine tomb) carbonyl-4-4 oxo) gas-2-mercapto) phenyl benzoate by the same method as in Production Example 17, from N6-methyl- 4-(4-Amino-3-chlorophenoxy)-7-(decyloxy)-6-quinolinecarboxamide (1.098 g, 2.53 mmol). &quot;I g , 2 ?3 , mmo 卜 92.1%" 1H-NMR spectrum (CDCl3) 5 (ppm): 2·96 (3H, d, JN4.8 Ηζ), 5·35 (2Η, s), 6.50 (1Η, d, J=5.2 Hz), 7.15 (1H, dd, J=2.8, 8.8 HzJ,.. 7.19-7.30 (6H, m), 7.40-7.52 (6H, m), 7.61 (1H, s) , 7.95 (1H, v.% m), 8.30 (1H, q, J=4.8 Hz), 8.67 (1H, d, J=5.2 Hz), 9.27 (1H, s) ° f Example 646 1 methyl- 7-(芊1基)_4-(3-gas "4-qethylamino) oxime) amine) 1 base)-6-p-quine, linolenic amine by the same method as in Example 11. From phenyl N-(4-(7-(benzyloxy)-6-(methylamino)carbonyl-4-quinolinyl)oxy-2-chlorophenyl)aminecarboxylate (645 mg, 1.16 mmol) And 2M ethylamine-tetrahydrofuran solution, which is light The title compound (579 mg, 1·15 mmol, 98.4%), iH-NMR spectrum (DMSO-d6) (5 (ppm): 1·06 (3H, t, J = 7.2 Hz), 2·81 (3H,~d; J=4:8 Hz), 3·11 (2H,m), 5·42 (2H,s),6·51 (1H, d, J=5.2 Hz), 6.99 (1H, m), 7.19 (1H, dd, J=2.8, 9.2 Hz), ___- 686 -_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210x 297 mm) &quot;&quot; 1304061 A7 B7 V. Invention Description (681) II 7.30-7.45 (4H, m), 7.52-7.55 (3H, m), 8·06 (1H, s), 8.24 (1H, d, J = 9.2 Hz), 8.37 (1H, q, J = 4.8 Hz), 8.49 (1H, s), 8.62 (1H, d, J = 5.2 Hz) 0 Example 647 N6-methyl- 4-(3-chloro-4-(((methylamino)) Base)amino) stupid base)-7- and base-6-g-quine-g-compound amine from N6-methyl-7-(benzyloxy)-4-(3-chloro-4-((( Methylamino)carbonyl)amino)phenoxy)-6-p-quine-amine (466.3 mg, 0.95 mmol), m. , 0.91 mmol, 96.1%) 〇W-NMR spectrum (DMSO-d6) 6 (ppm): 2·66 (3H, br s), 2·85 (3H, br s), 6.37 (1H m), 6.86 (1H, m), 7.10-7.30 (2H, m), 7.45, (1H, m), 8.09 (1H, br s), 8.22 (1H, m), 8.56 (1H, m) , 8.84 (lH, brs) 〇 Example 648 -4-(3-chloro-4-(((ethylamine))))))) From the same procedure as in Example 83, from N6-methyl-7-(benzyloxy)-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-6 The title compound (431.4 mg, 1.04 mmol, 90.8%) was obtained as pale yellow crystals. 1H-NMR spectrum (DMSO-d6) 5 (ppm)··1·06 (3H, t, J=7.2 Hz), 2.85 (3Hy^bf-s), -3.12 (2H, m), 6.36 (1H, m), 6.98 (1H, m), 7.20-7.24 (2H, m), 7.45 (1H, d, J=2.8 Hz), 8.05 (1H, s), 8.25 -687 - This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1304061 A7 _ B7 V. Description of invention (~~) ~_ 7 II (1H, d, J=9.2 Ηζ), 8·55 (1H, m), 8.84 (1H, s) 〇 Example 649 企二(((4-(3-Ga-4-((methylamino)carbonyl)))))))))))) 3 benzyl 4-(3-chloro-4-(((()) Amino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide (120 mg, 0.299 mmol) and 4-(bromomethyl)-1-hexahydropyridinecarboxylic acid tributyl The title compound (98.4 mg, 〇. 165 mmol _, 55.0%) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.17-1.33 (3 Η, m), 1 · 39 (9H, s), 1.75 (2H, m), 2.06 (1H, m), 2.66 (3H, d, J = 4.4 HzJ, ._ 2.77 (1H, m), 2.81 (3H, d, J =4.8 Hz), 3.97 (2H, m), 4.10 (2H,;v :* . ---- one.-r-- d, J=6.0 Hz),6·51 (1H,d,J=5.2 Hz), 6.85 (1H, q, J=4.4 Hz), a 7.20 (1H, dd, J=2.8, 8.8 Hz), 7.44 (1H, d, J=2.8 Hz), 7.48 (1H, s), 8.10 (1H, s), 8.18 (1H, q, J=4.8 Hz), 8.22 (1H, d, J=8.8 Hz), 8·43 (1H, s), 8.63 (1H, d, J=5.2 Hz). Example 650 1/((4-(3- #.-4-((ethylamino)carbonyl)amino)) jasmine 6-(methylamine carbonyl H 7- 4 porphyrin) gas) -1 -hexahydropyridine #acid butyl ester by the same method as in Example 7, from N6-methyl-4-(3-chloro-4-((ethylamino)carbonyl)amino group Phenoxy)-7-light- 6-0 quinonecarboxylic acid amine (143 mg, 0.345 mmol) and tert-butyl 4-(bromomethyl)-1-hexahydropyridinecarboxylate The title compound (119.5 mg, 0·195 mmol, 56.6%) was obtained. ____- 688 ____ This paper scale applies to Chinese National Standard (CNS) Α4 specification (21〇X 297 mm) 1304061 683 V. Inventive Note ( ^H-NMR spectrum (DMSO-d6) 5 (ppm): 1〇6 ( 3H,t,J=7 2 Hz), LiW.26 (3H,m),i.39 (9H,s),h76 (2H,m),2 % (ih (4) 2.77 (1H5 m)3 2.81 (3H , d5 J=4.8 Hz), 3.12 (2H, m), 3.98^(2^ m), 4.10 (2H, d, J=6.0 Hz), 6.51 (lH, d, J=5.2 Hz), 6.97 (1h / m), 7.19 (1H, dd, J = 2.8, 8 · 8 Hz), 7.44 (1H, d, J = 2 8 Hz) 7.48 (1H, s), 8.04 (1H, s), 8.18 〇H, q, J = 4.8 Hz), 8.24 (1h! d, J = 8.8 Hz), 8.43 (1H, s), 8.63 (1H, d, J = 5.2 Hz).

N6-甲基-4-(3-氣-4- 甲..基-4_六氫吡，噱基）甲氧羞上藏酿胺 在4-(((4-(3-氯-4-((甲胺基）羰基）胺基）苯氧基卜心胺 羰基）-7-喹啉基）氧基）甲基^六氫吡啶羧酸第三丁酯 (98.4 mg，〇· 165 mmol)中於室溫添加三氟乙酸（ι ^ 拌2小時。將反應液減壓濃縮後，將殘餘物溶於甲醇中，將 三乙胺滴入以中和。餾去溶媒，將殘餘物溶於四氫呋喃 ml)-甲醇（2 ml)中’於室溫下依序添加37%甲醛水溶^ ml)、乙酸（〇.〇5 ml)及氰基硼氫納（21 mg , 〇 33 _ 攪拌30分鐘。將反應液分溶於乙酸乙酯-四氫呋喃（1 : 飽和碳酸氫鈉水溶液中，將有機層用飽和碳酸氫納水产及 及飽和食鹽水洗淨，及用無水硫酸鈉乾燥。餾去溶=硬 付諸於矽凝膠管柱層析，將目的物溶出份減壓濃縮，1 , 酸乙酯-己烷（1 : 5)中結晶化，濾取結晶且通風乾燥^ ^ 為白色結各之標題化合物（64.2 mg , 0.125 mmQi , % 2&lt;)于】 H-NMR 光譜（DMSO-d6)占（ppm): 1.34 m、 ) 、，m)，172·1·89N6-Methyl-4-(3-Gas-4-methyl-.-yl-4-hexahydropyridyl, fluorenyl)methoxine on the 4-((4-(3-chloro-4-) ((Methylamino)carbonyl)amino)phenoxybutylamine carbonyl)-7-quinolinyl)oxy)methyl^hexahydropyridinecarboxylic acid tert-butyl ester (98.4 mg, 〇·165 mmol) Trifluoroacetic acid was added at room temperature (mixed for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol, triethylamine was added dropwise to neutralize. The solvent was distilled off and the residue was dissolved. Tetrahydrofuran in ml)-methanol (2 ml), adding 37% formaldehyde in water at room temperature, ml, acetic acid (〇.〇5 ml) and cyanoborohydride (21 mg, 〇33 _ stirring for 30 minutes) The reaction solution was dissolved in ethyl acetate-tetrahydrofuran (1: aqueous saturated sodium hydrogen carbonate). The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine and dried over anhydrous sodium sulfate. Hardly applied to the gel column chromatography, the target extract was concentrated under reduced pressure, 1 , acid ethyl ester-hexane (1: 5) crystallized, filtered and crystallized and dried ^ ^ as white knot The title compound (64.2 mg, 0.125 mmQi, % 2 &lt;) in H-NM R spectrum (DMSO-d6) accounted for (ppm): 1.34 m, ), m), 172·1·89

1304061 A7 B7 (5H, m), 2.15 (3H, s), 2.66 (3H, d, J=4.4 Hz), 2.77-2.83 (5H, m), 4.08 (2H, d, J=6.4 Hz), 6.51 (1H, d, J=5.2 Hz), 6.85 (1H, q, J=4.8 Hz), 7.20 (1H, dd, J=2.8, 8.8 Hz), 7.44 (1H, d, J=2.8 Hz), 7.48 (1H, s), 8.10 (1H, s), 8.20 (1H, q, J=4.4 Hz), 8.22 (1H, d, J=8.8 Hz), 8.45 (1H, s), 8.63 (1H, d, J=5.2 Hz) 實施例652 则-甲基-4-( 3-氯-4-(((乙胺基）羰基）胺某、笑氮基 平基-4-六氫叶1：淀基）甲氣基）-6- 4:淋籍醯脖 在4-(((4-(3 -氯- 4-((乙胺基）談基）胺基）苯氧基）-6-(甲胺 羰基）-7- 4:淋基）氧）甲基）-1-六氫π比啶幾酸第三丁酯（119.5 mg，0.195 mmol)中，於室溫添加三氟乙酸（1 ml)，並攪拌 2小時。將反應液減壓濃縮後，將殘餘物溶於甲醇中，蔣三 乙胺滴入以中和。餾去溶媒，將殘餘物溶於四氫呋喃（2 ml)-甲醇（2 ml)中，然後於室溫下依序添加37%甲醛水溶液 (〇_3 ml)、乙酸（〇·〇5 ml)及氰基硼氫鈉（25 mg，0.39 mmol)，並攪捽30分鐘。將反應液分溶於乙酸乙酯_四氫咬 喃（1 ·· 1)及飽和碳酸氫鈉水溶液中，將有機層用飽和碳酸 氫鈉水溶液及飽和食鹽水洗淨，用無水硫酸納乾燥。餘去 溶媒後，付諸於矽凝膠管柱層析，將目的物溶出份減壓濃 縮，從乙酸乙酷-己燒（1 · 5)中結晶化，滤取結晶且通風乾 燥，得到為白色結晶之標題化合物（78.3 mg，〇 149 mmQl , 76.2%) 〇 iH-NMR 光譜（DMSO-d6)(5(ppm): 1·〇6 (3H，t，J=7.2 Hz) 690 - 1304061 A7 B7 五、發明説明（咖） 二 二 1·34 (2H，m)，1.72-1.89 (5H，m)，2.15 (3H，s)，2·76-2·82 (5H， m), 3.12 (2H, m), 4.08 (2H, d, J=6.4 Hz), 6.51 (1H, d, J=5.2 Hz), 6.97 (1H5 m), 7.19 (1H, dd, J=2.8, 8.8 Hz), 7.44 (1H, d? J=2.8 Hz), 7.48 (1H, s), 8.04 (1H, s), 8.19 (1H, q, J=4.4 Hz), 8.24 (1H, d, J=8.8 Hz), 8.45 (1H, s), 8.63 (1H, d, J=5.2 Hz) 〇 - 實施例653 ^^二¥基-4-(3-氯-4-((7甲胺某）#某）胺某）茉氣基）_7-以210 -3·二乙胺基羥基丙氧某）啉羧醯胺 在N6-甲基-4-(3-氯-4-(((甲胺基）羰基）胺基）苯氧基）-7-羥基-6-喳啉羧醯胺（12〇 mg，0.299 mmol)中，添加4-甲基--1-苯磺酸（2R)環氧乙烷-2_基甲酯（103 mg，0.499 mmol)、：:: 碳酸鉀（50 mg，0.359 mmol)及二甲基甲醯胺（3 ^1)，$60 C授捽7小時。繼而添加二乙胺（1 ·5 ml)，進一步於6〇°C攪 捽一整晚。將反應液分溶於乙酸乙酯-四氫嗅喃（1: 1)及水 中’有機層用水及飽和食鹽水洗淨，用無水硫酸納乾燥。 將溶媒餾去，付諸於矽凝膠管柱層析（溶出液為乙酸乙酯： 甲醇=95 ·· 5)，再將含有目的物之溶出份濃縮後，濾取從乙 酸乙酯-己烷（1 : 1)中析出之結晶，藉由通風乾燥，得到為 白色結晶之標題化合物（718 mg，0.135 mmol，45.2%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 〇·95 (6H，t，j=7.2 Hz)， 2.40-2.60 (6H，m)，2·66 (3H，d，J=4.8 Hz)，2·85 (3H，d，J=4.8 Hz)，4.00飞ltt，m)，4.18 (1H，dd，J=6.0，10.0 hz)，4 32 (iH 〜 dd，J=3.2，10.0 Hz)，5·12 (1H，d，J=4.0 Hz)，6·52 (m，d， -!--- - 691 - 本紙張尺度適用中國國家標準(CNS) 公釐厂 &quot;一&quot; --- 1304061 A7 B7 五、發明説明（686 ) J=5.2 Hz), 6.86 (1H, q, J=4.8 Hz), 7.22 (1H, d, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.53 (1H, s), 8.10 (1H, s), 8.23 (1H, d, J=9.2 Hz), 8.50 (1H, q, J=4.8 Hz), 8.65 (1H, d, J=5.2 Hz)，8.71 (1H，s) 〇 實施例654 基-4-(3-氯-4-(((乙胺某u笼某）胺某）茉氣某）-7-((2R) -3 -二乙胺基-2-經基丙氧基奎淋藏酿胺 藉由與實施例653同樣之方法，從N6-甲基-4-(3-氯-4-(((乙胺基）羰基）胺基）苯氧基）-7-羥基-6-喹啉羧醯胺（143 mg ’ 0.345 mmol)，得到為白色結晶之標題化合物（92.4 mg，0.170 mmo卜 49.3%) 〇 _ iH-NMR 光譜（DMSO-d6)5(ppm): 〇·95 (6H，t, J=7.2 Hz)， 1.06 (3H, t, J=7.2 Hz), 2.40-2.60 (6H, m), 2.85 (3H, d, J=4.8 Hz), 3.12 (2H, m), 4.00 (1H, m), 4.18 (1H, dd, J=6.0, 9.6 Hz), 4.32 (1H, dd, J=3.2, 9.6 Hz), 5.12 (1H, d, J=4.4 Hz), 6.51 (1H, d, J=5.2 Hz), 6.98 (1H, m), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.53 (1H, s), 8.05 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.50 (1H, q, J=4.8 Hz), 8.65 (1H, d5 J=5.2 Hz)，8·72 (1H，s)。 實施例655 N6-甲基-4-(3-氯-4-(((甲胺基）羰基）胺某）茉氳某 -2-羥基-3- (1 -吡咯啶基）丙氧基）-6- 4啉讀醯胺 在N6-甲〜基-4，（3-氯-4-(((甲胺基）羰基）胺基）苯氧基）_7一 罗至基-6-4淋叛酿胺（120 mg，0.299 mmol)中，添加4_甲基- __- 692 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（挪） : 二 1-苯磺酸（2R)環氧乙烷-2-基甲酯（103 mg，0.499 mmol)、 碳酸钾（50mg ’ 0·359 mmol)及二甲基甲酿胺（3 mi),於60 °C攪拌7小時。將反應液放冷至室溫後，添加吡咯啶（〇 5 ml)，並進一步攪拌一整晚。將反應液分溶於乙酸乙酯-四 氫呋喃（1 : 1)及水中，將有機層用水及飽和食鹽水洗淨， 然後用典水硫酸納乾燥。將溶媒館去，付諸於碎凝膠管柱 層析（溶出液為乙酸乙酿：甲醇= 95: 5)，再將含有目的物 之溶出份濃縮後，濾取從乙酸乙酯-己烷（丨：丨）中析出之結 晶，藉由通風乾燥，得到為白色結晶之標題化合物（79.3 mg，0.150 mmol，50.2%) 〇 1 H-NMR 光謂（DMSO-d6) 5 (ppm): 1 ·67 (4H，m)，2.40-2.60 .. (5Η, m), 2.64-2.69 (4H, m), 2.85 (3H, d, J=4.8 Hz), 4.06 (1H,； m), 4.17 (1H, m), 4.33 (1H, dd, J=3.6, 10.4 Hz), 5.23 (1H, d, J=4.8 Hz), 6.52 (1H, d, J=5.2 Hz), 6.86 (1H, q；7=4.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.54 (1H, s), 8.10 (1H, s)3 8.23 (1H5 d5 J=9.2 Hz), 8.50 (1H, q, J=4.8 Hz), 8.65 (1H, d，J=5.2 Hz), 8.71 (1H, s)。 實施例656 m基-4-(3-氣-4-(((乙胺基）羰基）胺基）芙氪基 二2 -經基-3 - (1 - ρ比啥淀基）丙氧基）-6 -峰淋致醯胺 藉由與實施例655同樣之方法，從N6-甲基-4-(3-氯-4-(((乙胺基）羰基）胺基）苯氧基）-7-經基-6-p奎琳幾酿胺（143 mg ’ 0.34¾ mmol) ’仔到為白色結晶之標題化合物（94.8 mg，0.175 mmol，50.7%) 0 ___- 693 - ___ 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 __B7______ 五、發明説明（688 ) 二 j-NMR 光譜（DMSO-d6)5(Ppm): 1·〇6 (3H，t，J=7.2 Hz)， 1.67 (4H, m), 2.40-2.60 (5H, m), 2.66 (1H, dd, J=6.4, 12.4 Hz)； 2.85 (3H, d, J=4.8 Hz), 3.12 (2H, m), 4.06 (1H, m), 4.16 (1H, dd, J=6.0, 10.0 Hz), 4.33 (1H, dd, J=3.2, 10.0 Hz), 5.23 (1H，d, J=5.2 Hz)，6.51 (1H，d，J二5.2 Hz)，6.98 (1H，m)， 7·21 (1H，dd，J=2.8, 8.8 Hz)，7·47 (1H，d，J=2.8 Hz)，7.53 (1H, s), 8.05 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.50 (1H, q, J=4.8 Hz)，8·65 (1H，d，J=5.2 Hz)，8.71 (1H，s)。 實施例657 &amp;環丙基-Ν·-(4-(6-(4-(2-二Λ脉乙氳基芡篡）-7H-吡咯 鼓|2,3-dl嘧啶-4-基氣某）-2_氮茇篡）脲 - 將N-環丙基-N，-(4-(6-(4-(2-二乙胺乙氧基）-苯基）-7- 二 (2_三曱矽烷乙氧甲基）·7Η-吡咯并[2,3_d]嘧啶·‘基氧疒2-氟苯基）脲65 mg溶於四氫呋喃2 ml中，滴入四丁基銨氟化 物（四氫呋喃1M溶液）〇·5 m卜然後回流3小時。讓其回至室 溫且加水攪拌，濾取析出之結晶，並用乙醚-己烷=1 ·· i清 洗及減壓乾煤’得到標題化合物2 5 mg。 W-NMR光譜：（DMSO-d6) 0.38-0.43 (2H，m)，0·62-0·68 (2H， 0.99 (6H, t, J=7.3 Hz), 2.53-2.61 (5H, m)5 2.80 (2H, t, J=6.9 Hz), 4.08 (2H, t, J=6.9 Hz), 6.79-6.84 (1H, m), 6.91 (1H, s), 7.01-7.07 (3H, m), 7.26 (1H, dd, J=2.9, 11.2 Hz), 7.28 (2H, d, J=9.0 Hz), 8.05-8.16 (1H, m), 8.18 (1H, br s), 8.28 (1H，寸，12.68 (1H，br s)。 一 中間體係以下述方法合成。 ------- 694 - 本紙張尺度適用中國國家標準(CNS) Α4規格(21〇χ297公釐） 1304061 A7 ______ Β7 五、發明説明（689 ) &quot; 製造例657-1 4-芊氣茉某）-4-(3-氣-4-硝苯氫某）-7-(2-三甲矽烷乙氣 ΐ基）-7H-吡咯并f 2,3-dl嘧啶 於6-(4-苄氧苯基）-4-氯-7-( 2-三甲矽烷乙氧甲基）-7H-吡 嘻并[2,3-d] 口密淀490 mg中，添加3-氟-4-硝基驗248 mg、 2,6-二甲基吡啶〇·208 ml及N-甲基吡咯啶1 ml，在130°C攪 拌24小時。然後，讓其回至室溫，加水並用乙酸乙酯-四氫 呋喃混合溶媒分液萃取，有機層用飽和食鹽水洗淨，用無 水硫酸鈉乾燥，濃縮且付諸於NH矽凝膠管柱層析（乙酸乙 S&amp; )，得到標題化合物472 mg。 W-NMR光譜：（DMSO-d6) -0.08 (9H，s)，0·87 (2H，t，J=7.41304061 A7 B7 (5H, m), 2.15 (3H, s), 2.66 (3H, d, J=4.4 Hz), 2.77-2.83 (5H, m), 4.08 (2H, d, J=6.4 Hz), 6.51 (1H, d, J=5.2 Hz), 6.85 (1H, q, J=4.8 Hz), 7.20 (1H, dd, J=2.8, 8.8 Hz), 7.44 (1H, d, J=2.8 Hz), 7.48 (1H, s), 8.10 (1H, s), 8.20 (1H, q, J=4.4 Hz), 8.22 (1H, d, J=8.8 Hz), 8.45 (1H, s), 8.63 (1H, d, J = 5.2 Hz) Example 652 - Methyl-4-(3-chloro-4-((ethylamino)carbonyl)amine, nitroazyl-4-pyrene-4-phosphate: decidyl) A gas base)-6- 4: 醯 醯 在 in 4-(((4-(3-chloro-4-((ethylamino))) yl) phenoxy)-6-(methylamine) Carbonyl)-7- 4: lysyl)oxy)methyl)-1-hexahydropipipiric acid tert-butyl ester (119.5 mg, 0.195 mmol), trifluoroacetic acid (1 ml) was added at room temperature. Stir for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol, and triethylamine was dropped to neutralize. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran (2 ml)-methanol (2 ml), and then 37% aqueous formaldehyde (?3 ml), acetic acid (〇·〇5 ml) and Sodium cyanoborohydride (25 mg, 0.39 mmol) was stirred for 30 minutes. The reaction mixture was dissolved in ethyl acetate-tetrahydrocarbazide (1··1) and saturated aqueous sodium hydrogen carbonate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine and dried over anhydrous sodium sulfate. After the solvent was removed, it was applied to a gel column chromatography, and the target dissolved fraction was concentrated under reduced pressure, crystallized from ethyl acetate-hexane (1.5), crystallized by filtration, and ventilated and dried to obtain The title compound of white crystals (78.3 mg, 〇149 mmQl, 76.2%) 〇iH-NMR spectrum (DMSO-d6) (5 (ppm): 1·〇6 (3H, t, J=7.2 Hz) 690 - 1304061 A7 B7 V. Description of invention (cafe) 22:1.34 (2H,m), 1.72-1.89 (5H,m), 2.15 (3H,s),2·76-2·82 (5H, m), 3.12 ( 2H, m), 4.08 (2H, d, J=6.4 Hz), 6.51 (1H, d, J=5.2 Hz), 6.97 (1H5 m), 7.19 (1H, dd, J=2.8, 8.8 Hz), 7.44 (1H, d? J=2.8 Hz), 7.48 (1H, s), 8.04 (1H, s), 8.19 (1H, q, J=4.4 Hz), 8.24 (1H, d, J=8.8 Hz), 8.45 (1H, s), 8.63 (1H, d, J = 5.2 Hz) 〇- Example 653 ^^2¥--4-(3-chloro-4-((7-methylamine)#)) Mosquito-based _7- to 210-3·diethylamino hydroxypropoxy) carboxylic acid carboxamide in N6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)) Benzyl)-7-hydroxy-6-carboline carboxamide (12 mg, 0.299 mmol), 4-methyl--1-benzenesulfonic acid (2R) ethylene oxide-2_ Methyl ester (103 mg, 0.499 mmol), ::: potassium carbonate (50 mg, 0.359 mmol) and dimethylformamide (3 ^ 1), $ 60 C seize granted for 7 hours. Then diethylamine (1. 5 ml) was added and further stirred overnight at 6 °C. The reaction mixture was dissolved in ethyl acetate-tetrahydro succinol (1:1) and water. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and subjected to column chromatography on a gel column (ethyl acetate: methanol = 95 ··5), and the fractions containing the desired product were concentrated, and then filtered from ethyl acetate-hexane. The crystals which crystallized from hexanes (1:1) were obtained from the title compound (yield: 718 mg, 0.135 mmol, 45.2%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 〇·95 (6H, t, j = 7.2 Hz), 2.40-2.60 (6H, m), 2·66 (3H, d, J = 4.8 Hz) , 2·85 (3H, d, J = 4.8 Hz), 4.00 fly ltt, m), 4.18 (1H, dd, J = 6.0, 10.0 hz), 4 32 (iH ~ dd, J = 3.2, 10.0 Hz) ,5·12 (1H,d,J=4.0 Hz),6·52 (m,d, -!--- - 691 - This paper scale applies to China National Standard (CNS) Gongchang&quot;One&quot; - -- 1304061 A7 B7 V. INSTRUCTIONS (686) J=5.2 Hz), 6.86 (1H, q, J=4.8 Hz), 7.22 (1H, d, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.53 (1H, s), 8.10 (1H, s), 8.23 (1H, d, J=9.2 Hz), 8.50 (1H, q, J=4.8 Hz), 8.65 (1H, d, J = 5.2 Hz), 8.71 (1H, s) 〇 Example 654 -4-(3-chloro-4-(((ethylamine) a cage) amine) 茉 某)-7-((2R -3 -Diethylamino-2-pyridyloxyquinidine-branched amine from N6-methyl-4-(3-chloro-4-(((B) Amino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide (143 mg '0.345 mmol) gave the title compound as white crystals (92.4 mg, 0.170 mmo, 49.3%) 〇 _ iH-NMR spectrum (DM SO-d6)5 (ppm): 〇·95 (6H, t, J=7.2 Hz), 1.06 (3H, t, J=7.2 Hz), 2.40-2.60 (6H, m), 2.85 (3H, d, J=4.8 Hz), 3.12 (2H, m), 4.00 (1H, m), 4.18 (1H, dd, J=6.0, 9.6 Hz), 4.32 (1H, dd, J=3.2, 9.6 Hz), 5.12 ( 1H, d, J=4.4 Hz), 6.51 (1H, d, J=5.2 Hz), 6.98 (1H, m), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J =2.8 Hz), 7.53 (1H, s), 8.05 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.50 (1H, q, J=4.8 Hz), 8.65 (1H, d5 J= 5.2 Hz), 8·72 (1H, s). Example 655 N6-Methyl-4-(3-chloro-4-(((methylamino)carbonyl)amine))) -6- 4 morphine read guanamine in N6-methyl-yl-4, (3-chloro-4-(((methylamino)carbonyl))amino)phenoxy)_7-iro-yl-6-4 Add 4-methyl- __- 692 to the Amine (120 mg, 0.299 mmol) - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention Description ) : Diphenyl-benzenesulfonate (2R) oxiran-2-ylmethyl ester (103 mg, 0.499 mmol), potassium carbonate (50 mg '0·359 mmol) and dimethyl ketoamine (3 mi) Stir at 60 ° C for 7 hours. After the reaction solution was allowed to cool to room temperature, pyrrolidine (〇 5 ml) was added, and the mixture was further stirred overnight. The reaction mixture was dissolved in ethyl acetate-tetrahydrofuran (1:1) and water, and the organic layer was washed with water and brine, and then dried over sodium sulfate. The solvent was removed and subjected to crushing gel column chromatography (the eluate was acetic acid: methanol = 95: 5), and the fractions containing the desired product were concentrated, and then filtered from ethyl acetate-hexane. The crystals precipitated from (yield: 丨) were obtained from white crystals (79.3 mg, 0.150 mmol, 50.2%) 〇1H-NMR photo (DMSO-d6) 5 (ppm): 1 · 67 (4H, m), 2.40-2.60 .. (5Η, m), 2.64-2.69 (4H, m), 2.85 (3H, d, J=4.8 Hz), 4.06 (1H,; m), 4.17 ( 1H, m), 4.33 (1H, dd, J=3.6, 10.4 Hz), 5.23 (1H, d, J=4.8 Hz), 6.52 (1H, d, J=5.2 Hz), 6.86 (1H, q;7 =4.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.54 (1H, s), 8.10 (1H, s)3 8.23 (1H5 d5 J =9.2 Hz), 8.50 (1H, q, J=4.8 Hz), 8.65 (1H, d, J=5.2 Hz), 8.71 (1H, s). Example 656 m-based 4-(3-carb-4-((ethylamino)carbonyl)amino) fluorenyl 2 -alkyl-3 -(1 - ρ than decyl)propoxy - 6 - peak-induced guanamine from N6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl))amino)phenoxy) by the same procedure as Example 655 -7-Phosyl-6-p-quinelined amine (143 mg '0.343⁄4 mmol) 'The title compound (94.8 mg, 0.175 mmol, 50.7%) as white crystals 0 ___- 693 - ___ Applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 __B7______ V. Description of invention (688) Di-j-NMR spectrum (DMSO-d6) 5 (Ppm): 1·〇6 (3H, t, J=7.2 Hz), 1.67 (4H, m), 2.40-2.60 (5H, m), 2.66 (1H, dd, J=6.4, 12.4 Hz); 2.85 (3H, d, J=4.8 Hz), 3.12 ( 2H, m), 4.06 (1H, m), 4.16 (1H, dd, J=6.0, 10.0 Hz), 4.33 (1H, dd, J=3.2, 10.0 Hz), 5.23 (1H,d, J=5.2 Hz ), 6.51 (1H, d, J two 5.2 Hz), 6.98 (1H, m), 7·21 (1H, dd, J=2.8, 8.8 Hz), 7·47 (1H, d, J=2.8 Hz) , 7.53 (1H, s), 8.05 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.50 (1H, q, J=4.8 Hz), 8.65 (1H, d, J=5.2 Hz) , 8.71 (1H, s). Example 657 &amp; cyclopropyl-indole-(4-(6-(4-(2-dioxanthionyl)-7H-pyrrole drum|2,3-dl-pyrimidin-4-yl gas a certain -2_azepine)urea-N-cyclopropyl-N,-(4-(6-(4-(2-diethylamine ethoxy)-phenyl)-7-di(2) _Trioxane ethoxymethyl)·7Η-pyrrolo[2,3_d]pyrimidinyl-yloxy-2-fluorophenyl)urea 65 mg is dissolved in 2 ml of tetrahydrofuran, and tetrabutylammonium fluoride is added dropwise ( Tetrahydrofuran 1M solution) 〇·5 m b and then refluxed for 3 hours. Let it return to room temperature and stir with water, filter the crystals, and wash with diethyl ether-hexane = 1 ·· 2 5 mg. W-NMR spectrum: (DMSO-d6) 0.38-0.43 (2H, m), 0·62-0·68 (2H, 0.99 (6H, t, J=7.3 Hz), 2.53-2.61 (5H , m)5 2.80 (2H, t, J=6.9 Hz), 4.08 (2H, t, J=6.9 Hz), 6.79-6.84 (1H, m), 6.91 (1H, s), 7.01-7.07 (3H, m), 7.26 (1H, dd, J=2.9, 11.2 Hz), 7.28 (2H, d, J=9.0 Hz), 8.05-8.16 (1H, m), 8.18 (1H, br s), 8.28 (1H, Inch, 12.68 (1H, br s). An intermediate system is synthesized as follows. ------- 694 - This paper scale applies to the Chinese National Standard (CNS) Α 4 Specification (21〇χ297 mm) 1304061 A7 ______ Β7 V. Invention description (689) &quot; Manufacturing example 657-1 4-芊气茉)-4-(3-Ga-4-nitrobenzene hydrogen)-7 -(2-trimethyldecaneethane fluorenyl)-7H-pyrrolof 2,3-dl pyrimidine in 6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethyldecaneethoxymethyl - 7H-pyridoxo[2,3-d] 490 mg in the mouth, adding 3-fluoro-4-nitro 248 mg, 2,6-dimethylpyridinium 208 ml and N-A 1 ml of pyrrolidine was stirred at 130 ° C for 24 hours. Then, it was allowed to return to room temperature, and water was added and extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Concentrated and applied to NH(R) gel column chromatography (ethyl acetate) to give the title compound 472 mg. W-NMR spectrum: (DMSO-d6) -0.08 (9H, s), 0·87 (2H ,t,J=7.4

Hz), 3.63 (2H, t, J=7.4 Hz), 5.20 (2H, s), 5.61 (2H, s), 6.83 (1H, s), 7.00-7.80 (1 1H, m), 8.30 (1H, t, J=8.6 Hz), 8.40 (1H, s) 〇 製造例657-2 生-(6-(4-芊氣苯基卜7-(三甲矽烷乙氣甲基）-7H-吡咯并 ]^，3-(11嘧啶-4-某氳某）-2-顧.茇脖 於6-(4-苄氧苯基）-4-(3-氟-4-硝苯氧基）-7-(三甲碎烷乙 氧甲基）-711-0比洛并[2,3-d]p密淀470 mg中，添加鐵粉400 mg、氯化铵1 g、乙醇20 ml、四氫吱喃10 ml及水10 ml，然 後在85°C攪拌3小時。讓其回至室溫後，用矽藻土過濾，於 濾液中加乙酸乙酯及水並分液萃取。將有機層用飽和食鹽 水洗淨，、永硫酸鈉乾燥，以棉栓過濾，濃縮且付諸於 NH矽凝膠管柱層析（己烷-乙酸乙酯），得到標題化合物263 _- 695 - ___ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（690) mg 0 MS 光譜（ESI): 557(M+1)。 iH-NMR 光譜：（DMSO-d6) -0.09 (9H，s)，0.85 (2H，t，J=8.9 Hz), 3.61 (2H, t, J=8.9 Hz), 5.09-5.13 (2H, m), 5.19 (2H, s), 5·59 (2H，s)，6.60 (1H，s)，6.79-6.73 (2H，m)，7.03 (1H，d， J=11.5 Hz), 7.16 (2H, d, J=9.6 Hz), 7.32-7.50 (5H, m), 7.70 (2H，d，J=9.6 Hz)，8·40 (1H，s)。 製造例657-3Hz), 3.63 (2H, t, J=7.4 Hz), 5.20 (2H, s), 5.61 (2H, s), 6.83 (1H, s), 7.00-7.80 (1 1H, m), 8.30 (1H, t, J=8.6 Hz), 8.40 (1H, s) 〇Production Example 657-2 Raw-(6-(4-helium phenyl b-7-(trimethyl decane ethanemethyl)-7H-pyrrole]^ , 3-(11-pyrimidin-4-one 氲)-2-Gu.茇 neck in 6-(4-benzyloxyphenyl)-4-(3-fluoro-4-nitrophenoxy)-7-( Trimethyl acetal ethoxymethyl)-711-0 piroxime [2,3-d]p 470 mg, iron powder 400 mg, ammonium chloride 1 g, ethanol 20 ml, tetrahydrofuran 10 10 ml of water and 10 ml of water, then stirred at 85 ° C for 3 hours. After returning to room temperature, it was filtered through celite, ethyl acetate and water were added to the filtrate, and the mixture was separated and extracted. Washed, dried over anhydrous sodium sulfate, filtered with a cotton plug, concentrated, and applied to NH(H) gel column chromatography (hexane-ethyl acetate) to give the title compound 263 _- 695 - ___ National Standard (CNS) A4 Specification (210 X 297 mm) 1304061 A7 B7 V. Description of Invention (690) mg 0 MS Spectrum (ESI): 557 (M+1). iH-NMR Spectrum: (DMSO-d6) - 0.09 (9H, s), 0.85 (2H, t, J = 8.9 Hz ), 3.61 (2H, t, J=8.9 Hz), 5.09-5.13 (2H, m), 5.19 (2H, s), 5·59 (2H, s), 6.60 (1H, s), 6.79-6.73 ( 2H,m),7.03 (1H,d,J=11.5 Hz), 7.16 (2H, d, J=9.6 Hz), 7.32-7.50 (5H, m), 7.70 (2H,d,J=9.6 Hz), 8·40 (1H, s). Manufacturing Example 657-3

N- (4-(卜(.,4二车氧苯基）-7- (2-三甲矽烷λ氣甲某）_ 7H-吡咯 并f 2,3-dl p密淀-4_基乳）-2-氣苯基環丙基服 將4-[6-(4-芊氧苯基）-7-(三甲矽烷乙氧甲基）-7H-吡咯并 [2,3-d]嘧啶-4-基氧]-2-氟苯胺261 mg溶於二甲基甲醯胺K • * - — - ·、:ϋ ml中，添加吡啶0.053 ml及氯碳酸苯酯0.082 ml，在室溫攪P 拌2小時後，添加環丙胺0.081 ml且攪捽一整夜。加水並用 乙酸乙酯分液萃取，有機層用飽和食鹽水洗淨，用硫酸鈉 乾燥，濃縮且付諸於矽凝膠管柱層析（己烷-乙酸乙酯），得 到標題化合物2 65 mg。 h-NMR光譜：（DMSO-d6) -0·09 (9H，s)，0.38-0.43 (2H，m)， 0.60-0.70 (2H，m)，0.87 (2H，t，J=7.5 Ηζ)，2·50-2·60 (1H，m)， 3.61 (2H, t, J=7.5 Hz), 5.20 (2H, s), 5.60 (2H, s), 6.61 (1H, s), 6.68-6.72 (1H, m), 7.04 (1H, d, J=8.3 Hz), 7.18 (2H, d5 J=9.0 Hz), 7.28 (1H, dd, J=3.4, 11.7 Hz), 7.32-7.53 (5H, m), 7.72 (2ΗΓ^； J=9.0 Hz), 8.10 (1H, t, J=8.2 Hz), 8.18 (1H, br s), 8.40 (1H，s) 〇 _____- 696 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 691 1304061 五、發明説明（ 製造例657^N-(4-(Bu(.,4-Carbo-oxyphenyl)-7-(2-trimethylnonane λ) _ 7H-pyrrolof 2,3-dl p-precipitate-4_based milk) 2-[6-(4-indolylphenyl)-7-(trimethyldecaneethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4 - oxy]-2-fluoroaniline 261 mg dissolved in dimethylformamide K • * - — - ·,: ϋ ml, add pyridine 0.053 ml and phenyl chlorocarbonate 0.082 ml, stir at room temperature After 2 hours, the mixture was stirred and stirred overnight. The title compound (65 mg) was obtained. 2H,m),0.87 (2H,t,J=7.5 Ηζ), 2·50-2·60 (1H,m), 3.61 (2H, t, J=7.5 Hz), 5.20 (2H, s), 5.60 (2H, s), 6.61 (1H, s), 6.68-6.72 (1H, m), 7.04 (1H, d, J=8.3 Hz), 7.18 (2H, d5 J=9.0 Hz), 7.28 (1H, dd , J=3.4, 11.7 Hz), 7.32-7.53 (5H, m), 7.72 (2ΗΓ^; J=9.0 Hz), 8.10 (1H, t, J=8.2 Hz), 8.1 8 (1H, br s), 8.40 (1H, s) 〇 _____- 696 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 691 1304061 V. Description of invention (manufacturing example 657^

~并「2T3-dl 崎 將ΗΜδ，爷氧苯基卜7♦三甲㈣乙氧甲基）眞 比洛并[2,3-d]喃呢.心基氧基卜2_氟苯基卜％環丙基膽⑽ ^容，乙醇7 ml及四氫呋喃3 mi中，添加氧化銘30 mg，在 至壓下及風氧象氣下攪拌一整夜後，用碎漠土過遽， 且減壓濃縮◊將殘餘物付諸於矽凝膠管柱層析（己烷-乙酸 乙酯）’得到標題化合物1 6〇 mg。 H-NMR光：|f:(DMSO-d6) -0.08 (9H，s)，0.39-0.43 (2H，m)， 0.61-0.68 (2H，m)，〇·86 (2H，t，J=7.5 Ηζ)，2·50-2·60 (1H，m)-， 3.61 (2H，t，J=7.5 Hz)，5·58 (2H，s)，6·63 (1H，s)，6.78-6.82 (1H，m)，6.90 (2H，d，J=8.6 Hz)，7.01-7.07 (1H，m)，7·28 (1H， dd, J=3.3, 11.9 Hz), 7.60 (2H, d, J=8.6 Hz), 8.06-8.13 (1H, m)，8.19 (1H, br s)，8.40 (1H，s) 〇 製造例657-5 N:··.環丙基-N’-(4-(6-(4-(2-二 胺乙氣某）-茇某）-7-(2Ί 1梦烷乙氧甲基）-7!^吡咯并「2.3-(11嘧啶-4-基氩某）-2-1 笨基）脲 將Ν-環丙基-Ν·-(2-氟-4-(6-(4-羥苯基）-7-(2-三甲矽烷 乙氧甲基）-7H-吡咯并[2,3-d]嘧啶-4-基氧）-2-苯基）脲100 mg溶於二甲基甲醯胺1 ml中，添加2-氯乙基二乙胺鹽酸鹽 110 mg及破-酸钾.126 mg，並在80°C攪拌15小時。然後，讓 其回至室溫，加水並用乙酸乙酯-四氫吱喃混合溶媒分液萃 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 B7 五、發明説明（692 ) 取。將有機層用飽和食鹽水洗淨，用硫酸納乾燥，濃縮且 付諸於NH矽凝膠管柱層析（己烷-乙酸乙酯）’得到標題化 合物67 mg。 MS 光譜（ESI) : 649(M+1)。 實施例658 N-環¾某-N，-(2-氟-4-(6-(4-(Ύ2R)-2-羥基-3-吡咯啶l-莘 丙氣某）茇某）-7H-吡咯并「2.3- dl嘧啶-4-基氧」苯基）脲 藉由與實施例657同樣之方法，從N-環丙基-&gt;1’-(2-氟_4-(6-(4-((2R)-2-羥基-3-吡咯啶丙氧基）-苯基）-7-(2·三甲矽 烷乙氧甲基）-7H-吡咯并[2,3-d]嘧啶-4-基氧）-苯基）脲63 mg，得到標題化合物30 mg。 - MS 光譜（ESI): 547(M+1)， W-NMR光譜：（DMSO-d6) 0.38-0.43 (2H，m)，0.60-0.69 (2H， m), 1.65-1.72 (4H, m), 2.45-2.70 (7H, m, covered by DMSO peak), 3.90-4.10 (3H, m), 4.96 (1H, br s), 6.91 (1H, s), 6.76-6.80 (1H, m), 7.01-7.07 (3H, m), 7.26 (1H, dd5 J=10.9, 2.4 Hz), 7.88 (2H, d, J=9.1 Hz), 8.06-8.14 (1H, m)5 8.15 (1H, br s)，8·28 (1H, s), 12.60 (1H, br s) 〇 中間體係以下述方法合成。 製造例65 8-1 Ν··:環丙暮- Ν’ - ( 2-氟-4-(6-(4-((21〇-2-趟某-2-叶卜哈症丙氣^ 基）笨I ) - 7- (2-三甲碎歧乙氣甲基）-7Η-叶卜哈并f 2,3- dl 口密_ 爽-4-基fT装某）脲 將N-環丙基-Ν’-(2-氟-4-(6-(4-經苯基）-7-(2-三甲碎燒 ___ - 698 - 本紙張尺度適用中@ S家標準(CNS) A4規格(21G X 297公董) &quot;----&quot; 裝 訂~ and "2T3-dl 崎 ΗΜ δ, ethoxy phenyl brom 7 ♦ trimethyl (tetra) ethoxymethyl) 眞 洛 并 [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ Cyclopropyl choline (10) ^, 7 ml of ethanol and 3 mi of tetrahydrofuran were added with 30 mg of oxidized infusion. After stirring overnight under atmospheric pressure and atmospheric oxygen, the mixture was smashed with crushed desert soil and concentrated under reduced pressure. The residue was subjected to hydrazine gel column chromatography (hexane-ethyl acetate) to afford the title compound (1 hexanes). H-NMR light: |f: (DMSO-d6) -0.08 (9H, s ), 0.39-0.43 (2H, m), 0.61-0.68 (2H, m), 〇·86 (2H, t, J=7.5 Ηζ), 2·50-2·60 (1H, m)-, 3.61 ( 2H,t,J=7.5 Hz),5·58 (2H,s),6·63 (1H,s),6.78-6.82 (1H,m),6.90 (2H,d,J=8.6 Hz),7.01 -7.07 (1H,m),7·28 (1H, dd, J=3.3, 11.9 Hz), 7.60 (2H, d, J=8.6 Hz), 8.06-8.13 (1H, m), 8.19 (1H, br s), 8.40 (1H, s) 〇Production Example 657-5 N:··.Cyclopropyl-N'-(4-(6-(4-(2-diamineethane)-茇))- 7-(2Ί 1 dream ethoxymethyl)-7!^pyrrole and "2.3-(11 pyrimidin-4-yl argon)-2-1 stupyl) urea Ν-cyclopropyl-Ν·-( 2-fluoro-4-(6-(4) -hydroxyphenyl)-7-(2-trimethyldecaneethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-phenyl)urea 100 mg dissolved in dimethyl To 1 ml of carbamide, add 2-chloroethyldiethylamine hydrochloride 110 mg and potassium bromate.126 mg, and stir at 80 ° C for 15 hours. Then, let it return to room temperature and add water. And use ethyl acetate-tetrahydrofuran mixed solvent to separate the paper. The standard is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 B7 5. Inventive Note (692) Take the organic layer with saturated brine After washing, it was dried over sodium sulfate, EtOAc (EtOAc)EtOAc. Example 658 N-cyclo 3⁄4-N,-(2-fluoro-4-(6-(4-(Ύ2R)-2-hydroxy-3-pyrrolidine l-莘-propanyl) 茇))-7H-pyrrole Further, "2.3- dl pyrimidin-4-yloxy"phenyl)urea was obtained from N-cyclopropyl-&gt;1'-(2-fluoro-4-(6-(4) in the same manner as in Example 657. -((2R)-2-hydroxy-3-pyrrolidinyloxy)-phenyl)-7-(2·trimethyldecaneethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -yloxy)-phenyl)urea 63 Mg, the title compound 30 mg was obtained. - MS spectroscopy (ESI): 547 (M+1), W-NMR spectrum: (DMSO-d6) 0.38-0.43 (2H, m), 0.60-0.69 (2H, m), 1.65-1.72 (4H, m) , 2.45-2.70 (7H, m, covered by DMSO peak), 3.90-4.10 (3H, m), 4.96 (1H, br s), 6.91 (1H, s), 6.76-6.80 (1H, m), 7.01- 7.07 (3H, m), 7.26 (1H, dd5 J=10.9, 2.4 Hz), 7.88 (2H, d, J=9.1 Hz), 8.06-8.14 (1H, m)5 8.15 (1H, br s),8 · 28 (1H, s), 12.60 (1H, br s) The intermediate system was synthesized in the following manner. Production Example 65 8-1 Ν··: Cyclopropanol- Ν' - (2-Fluoro-4-(6-(4-((21〇-2-趟)-2-叶卜哈症丙气) base ) Stupid I) - 7- (2-Trimethythine Ethylmethyl)-7Η-Yebuha and f 2,3- dl Mouth _ Shuang-4-Base fT Pack a) Urea will be N-cyclopropyl -Ν'-(2-Fluoro-4-(6-(4-Phenylphenyl)-7-(2-Trimethyst ___ - 698 - This paper size applies to @S家标准(CNS) A4 specification ( 21G X 297 Gongdong) &quot;----&quot; Binding

線 1304061 A7 B7 693 五、發明説明（ 乙氧甲基）-7H-吡咯并[2,3_d]嘧啶_4_基氧）苯基）脲89 mg溶 於二甲基甲酿胺2 ml中，添加對甲苯磺酸縮水甘 /甴酉Hi 111 mg( 3當里）及碳酸却η〗mg( 5當量），在65°C揽拌 一整夜。然後，靜置讓其回至室溫，並傾出上清液（二甲基 甲酿胺1.8 ml)。於其中添加加吡咯啶〇 1 ml，在65。〇攪拌3 小時、然後加水並用乙酸乙酯-四氫呋喃分液萃取。將有機 層濃縮且付諸於NH碎凝膠管柱層析（己垸-乙酸乙酿），得 到標題化合物63 mg。 MS 光譜（ESI) : 677(M+1)。 ' 實施例659 ϋ:_.環丙基- N’-(4-(6-(4-(3•二乙胺基-(2IO-2-蕤丙氣某苯 基」-7Η-吡咯并「2,3- dl嘧啶-4-基氣）-2-氟笨某）月尿 藉由與實施例657同樣之方法，從N-環丙基-N，-(4:{6-(4-(3·二乙胺基- (2R)-2-羥丙氧基）-苯基）-7-( 2-三甲矽烷 乙氧甲基）-7H-吡咯并[2,3-d]嘧啶-4_基氧）-2-氟苯基）脈5 mg，得到標題化合物1 mg。 MS光譜（ESI) : 549(M+1)。 中間體係以下述方法合成。 製造例659-1 K-環丙某-N1-(4-(6-(4-Π-二乙胺基羥丙氣某）ί 基）-7-(2-三甲矽烷乙氣甲基）-7^吹咯并「213-(11嘧啶-4-^ 氣）-2-氮茉某）脲 將N-環.肩-基'Ν’ - (2-氣- 4-(6-(4-¾本基）·7-(2-三甲碎燒 乙氧甲基）-7Η-吡咯并[2,3-d]嘧啶-4-基氧）-2-苯基）脲89 -699 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 _____Β7 五、發明説明（694 ) &quot; ' mg溶於二甲基甲醯胺2 ml中，添加對甲苯磺酸（2R)-(-)-縮 水甘油酯111 mg(3當量）及碳酸鉀112 mg(5當量），並在65 艺攪拌一整夜。然後，靜置讓其回至室溫，並傾出上清液 (二甲基甲醯胺0.2 ml)。於其中添加加四氫呋喃} mi及二乙 胺0.4 ml ’並在65 °C攪摔30分鐘。然後加水並用乙酸乙酿-四氫吱·喃分液萃取。將有機層濃縮且付諸於NH矽凝膠管柱 層析（己燒-乙酸乙醋）’仔到標題化合物5 mg。 MS 光譜(ESI) ·· 679(M+1)。 實施例660 'Line 1304061 A7 B7 693 V. Description of the invention (Ethoxymethyl)-7H-pyrrolo[2,3_d]pyrimidin-4-yloxy)phenyl)urea 89 mg is dissolved in 2 ml of dimethylamine Add p-toluenesulfonic acid glycidin / 甴酉 Hi 111 mg (3 oz) and carbonic acid η mg (5 equivalents), and mix at 65 ° C overnight. Then, it was allowed to stand at room temperature, and the supernatant (1.8 ml of dimethylamine) was decanted. Add 1 μml of pyrrolizidine to the solution at 65. The mixture was stirred for 3 hours, then water was added and extracted with ethyl acetate-tetrahydrofurane. The organic layer was concentrated and applied to EtOAc EtOAc (EtOAc) MS spectrum (ESI): 677 (M+1). Example 659 ϋ:_.Cyclopropyl-N'-(4-(6-(4-(3•diethylamino)-(2IO-2-蕤-propene phenyl)-7Η-pyrrole" 2,3- dl pyridin-4-yl gas)-2-fluorophenidyl) monthly urine by the same method as Example 657, from N-cyclopropyl-N,-(4:{6-(4- (3. Diethylamino-(2R)-2-hydroxypropoxy)-phenyl)-7-(2-trimethyldecaneethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine- 4 mg of oxy)-2-fluorophenyl) 5 mg gave the title compound 1 mg. MS spectrum (ESI): 549 (M+1). Intermediate system was synthesized by the following method.乙-N1-(4-(6-(4-Π-diethylamino hydroxypropane) yl)-7-(2-trimethyl decane ethane methyl)-7^ 吹 吹 ” ” (11 pyrimidine-4-^ gas)-2-nitrogen) urea will be N-ring. shoulder-based 'Ν' - (2-gas- 4-(6-(4-3⁄4))·7-( 2-Trimethyst-burning ethoxymethyl)-7Η-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-phenyl)urea 89 -699 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304061 A7 _____Β7 V. Invention description (694 ) &quot; ' mg dissolved in 2 ml of dimethylformamide, added p-toluenesulfonic acid (2R)-(-)-glycidol 111 mg (3 equivalents) and potassium carbonate 112 mg (5 equivalents), and stirred overnight at 65 °. Then, let it stand back to room temperature and pour out the supernatant (dimethylformamide 0.2 Ml), add tetrahydrofuran} mi and diethylamine 0.4 ml ' and stir at 65 ° C for 30 minutes. Then add water and extract with acetic acid - tetrahydroanthracene errone. Concentrate the organic layer and put it into Chromatography on NH(R) gel column chromatography (hexanes-ethyl acetate) to the title compound 5 mg. MS spectrum (ESI) · · 679 (M + 1). Example 660 '

Zzl.苄氧基）-4-(3-氯-(4-((環丙胺基）瀠某）胺某1草巧奚 6-π奎琳鮝酸 於7-(芊氧基）-4-(3-氯-(4-((環丙胺基）談基）胺基）苯氧 基）_6-口奎琳幾酸甲酉旨（2.218 g ’ 4.28mmol)中添加甲轉} 30 ml)及2當里;辰度風氧化鋼水落液（1〇 ml)，然後於6〇 擾摔 1小時。將反應液放冷至室溫，添加1當量濃度鹽酸中和 後，餾去甲醇，濾取析出之淡褐色結晶，充分水洗後，於 70 °C乾燥，得到標題化合物（2.121 g，4.21 mmai， 98.3%) 〇 iH-NMR 光譜（〇]^〇-(16)5(??111):0.43(211，111)，0.67(211，111)· 2·57 (1H，m)，5·40 (2H，s)，6·56 (1H，d，J=5.2 Hz)，7·21 (iH， d，J=2.8 Hz)，7·26 (1H，dd，J=2.8, 8.8 Hz)，7·32-7·44 (3H，m)3 7.51 (1H，d，J=2.8 Hz)，7·56 (2H，d，J=6.8 Hz)，7·60 (1H，s)， 8.00 (1H,^-)7 8.28 (1H, dd, J=2.8, 8.8 Hz), 8.57 (1H, s), 8.69 (1H，d，J=5.2 Hz)。 ' -700 - 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) 1304061 A7 B7 五、發明説明（695 ) 實施例661 N6-甲基-7-(芊氩某）-4-(3-氣-4-(((環丙胺基）羰基）胺基） 笨氣基）-6- 4啉勒醯胺 將7-(芊氧基）-4-(3-氯-(4-((環丙胺基）羰基）胺基）苯氧 基）-6 -p奎琳羧酸（1.056 g，2.10 mmol)於氮氣蒙氣下溶解在 二甲基甲醯胺（10 ml)中，於室溫依序添加40%甲胺-甲醇溶 液（2 ml)、三乙胺（1 ml)及（1H-1，2,3-苯并三唑-1-基氧）（三 (二甲胺基））鱗六氟磷酸鹽（1.11 g，2.52 mmol)後，攪拌6小 時。將反應液加水使析出結晶，過濾且充分水洗後，藉由 於70°C乾燥，得到為白色結晶之標題化合物（988 mg，1.91 mmol，91.2%) 〇 _ iH-NMR 光譜（DMSO-dJcHpP111): 0·42 (2H，m)，0·65 (2H，m)，_ 2.56 (1H, m), 2.82 (3H, d, J=4.4 Hz), 5.42 (2H, s), 6.5Γ'〇Η, ：；^ d, J=5.2 Hz), 7.18 (1H, d3 J=2.8 Hz), 7.21 (1H, dd, J=2.8, 8.8 Hz)，7.30-7.55 (7H，m)，7·96 (1H，s), 8.25 (1H，d，J=8.8Zzl.benzyloxy)-4-(3-chloro-(4-((cyclopropylamino)))) 1 1 草 奚 6-π 奎 鮝 鮝 于 7 7-(芊 ))-4- (3-Chloro-(4-cyclo(cyclopropylamino)-yl)amino)phenoxy)-6-hydroxy-pyrene acid-methyl hydrazine (2.218 g ' 4.28 mmol) added with formazan} 30 ml) 2In the inside; Chendu wind oxidation steel falling water (1〇ml), then disturbed for 1 hour at 6 。. The reaction solution was allowed to cool to room temperature, neutralized with 1 equivalent of hydrochloric acid, distilled off, and filtered. The pale brown crystals which precipitated were washed with water and dried at 70 ° C to give the title compound (2.121 g, 4.21 mmai, 98.3%) 〇iH-NMR spectrum (〇)^〇-(16)5(??111): 0.43(211,111),0.67(211,111)· 2·57 (1H,m),5·40 (2H,s),6·56 (1H,d,J=5.2 Hz),7·21 ( iH, d, J=2.8 Hz), 7·26 (1H, dd, J=2.8, 8.8 Hz), 7·32-7·44 (3H, m)3 7.51 (1H, d, J=2.8 Hz) ,7·56 (2H,d,J=6.8 Hz),7·60 (1H,s), 8.00 (1H,^-)7 8.28 (1H, dd, J=2.8, 8.8 Hz), 8.57 (1H, s), 8.69 (1H,d,J=5.2 Hz). ' -700 - This paper size applies to Chinese National Standard (CNS) A4 size (210x 297 mm) 13040 61 A7 B7 V. INSTRUCTIONS (695) EXAMPLE 661 N6-Methyl-7-(芊 某)-4-(3-Gas-4-(((cyclopropylamino)carbonyl)))) -6- 4 oxazolamide 7-(decyloxy)-4-(3-chloro-(4-((cyclopropylamino)carbonyl)amino)phenoxy)-6-p-quine carboxy The acid (1.056 g, 2.10 mmol) was dissolved in dimethylformamide (10 ml) under nitrogen atmosphere, and 40% methylamine-methanol solution (2 ml) and triethylamine (1) were added sequentially at room temperature. Ml) and (1H-1,2,3-benzotriazol-1-yloxy)(tris(dimethylamino))sodium hexafluorophosphate (1.11 g, 2.52 mmol), stirred for 6 hours. The reaction mixture was added with water to give crystals, which was crystallized, filtered, and washed with water, and the title compound was obtained as white crystals (988 mg, 1.91 mmol, 91.2%) 干燥 _ iH-NMR spectrum (DMSO-dJcHpP111): 0 · 42 (2H, m), 0·65 (2H, m), _ 2.56 (1H, m), 2.82 (3H, d, J=4.4 Hz), 5.42 (2H, s), 6.5Γ'〇Η, :;^ d, J=5.2 Hz), 7.18 (1H, d3 J=2.8 Hz), 7.21 (1H, dd, J=2.8, 8.8 Hz), 7.30-7.55 (7H,m),7·96 (1H ,s), 8.25 (1H,d,J=8.8

Hz), 8.38 (1H, q, 1=4.4 Hz), 8.49 (1H, s), 8.62 (1H, d, J=5.2 Hz) 〇 / 實施例662 N6-乙基-7-(芊氫某）-4-(3-氯-4-(((環丙胺某）蕤某）胺甚、 苯氧基）-6-崦啉#醯胺 從7-(苄氧基）-4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧 ' 基）-6-峻淋叛酸（1.056 g，2· 10 mmol)及2M乙胺-四氫咬喃 溶液，藉成實施例661同樣之方法，得到為白色結晶之標題 -化合物（ 1.022 g，1.92 mmol，91.8%)。 -701 -本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1304061 A7 _____B7 五、發明説明（696 ) 二 j-NMR 光譜（DMSO-d6)5(ppm): 0.42 (2H，m)，0.65 (2H，m)， 1.04 (3H，t，J=7.2 Ηζ)，2·56 (1H，m)，3.25-3.31 (2H，m)，5·39 (2H, s), 6.52 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.32-7.44 (3H, m), 7.47 (1H, d, J=2.8 Hz), 7.56 (2H, d, J=7.2 Hz), 7.59 (1H, s), 7.97 (1H, s)5 8.26 (1H, d, J=8.8 Hz), 8.34 (1H, t, J=7.2 Hz), 8.49 (1H, s), 8·64 (1H，d，J=5.2 Hz)。 實施例663 甲基-4-(3-氣-4-(((環丙胺某、羱某）胺某）茉氳基）_7·羥 基-6-喹淋藉醯胺 藉由與實施例83同樣之方法，從Ν6-甲基-7-(芊氧基）-4-_ (3-氯- 4-(((環丙胺基）羧基）胺基）苯氧基&gt;6- 4淋叛醯胺 (983 mg ’ 1·90 mmol)，得到為淡黃色結晶之標題化i物 (811 mg，1.90 mmol，定量產出）。 iH-NMR光譜（DMSO-d6)(5(ppm): 0.42 (2H, m)，0·65 (2H，m)， 2.56 (1H, m), 2.85 (3H, s), 6.32 (1H, br), 7.18-7.24 (4H, m), 7.45 (1H, s), 7.96 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.51 (1H, m)，8.81 (1H，s) 〇 實施例664 Μ·乙基-4-(3-氪-4-(((環丙胺某）羰基）胺基）茉氣基 基-6-Ρ杳淋藉gj胺 藉由與實施例83同樣之方法，從N6-乙基-7-(芊氧基）-4- _ (3 -氯-4 - (X (策丙胺基）羰基）胺基）苯氧基）_ 6 -喹啉羧醯胺 (1·〇16 g，1.91 mmol)，得到為淡黃色結晶之標題化合物 ____- 702 - 本妖張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（697 ) 二 .•5 (845 mg，1.91 mmol，定量產出）。 iH-NMR 光譜（DMSO-d6)5(ppm)·· 0·42 (2H，m)，0·65 (2H，m)， 1.16 (3H, t, J=7.2 Hz), 2.56 (1H, m), 3.36 (2H, m), 6.41 (1H, d, J=5.2 Hz), 7.15-7.35 (4H, m), 7.49 (1H, d, J=2.4 Hz), 7.97 (1H, s), 8.27 (1H, dd, J=4.0, 9.2 Hz), 8.60 (1H, d, J=5.2 Hz), 8,88 (LH，s)，12.68 (1H，br)。 實施例665 N6-甲基-4-(3-氯-4-(((環丙胺某）羰基）胺基）茉氳基）-7-(3-Π -叶匕嘻淀基）丙氧基）-6-口杳淋藉酿胺 從N6-甲基-4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧基）-7-經基-6-π奎琳幾酿胺（213.4 mg，0.50 mmol)及1-(3-氯丙― 基）吡咯啶鹽酸鹽，藉由實施例7同樣之方法，得到為淡黃、 ' - Ύ. 色結晶之標題化合物（78·4 mg，0· 146 mmol，29.1%)。— iH-NMR光譜（DMSO-d6)5(ppm): 0.42 (2H，m)，0·65 (2H，m)， 1.68 (4H, m), 1.99 (2H, m), 2.44 (4H, m), 2.54-2.59 (3H, m), 2.83 (3H, d, J=4.8 Hz), 4.28 (2H, m), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.47 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.96 (1H, s)5 8.24-8.27 (2H, m)，8.53 (1H，s)，8.64 (1H，d，J=5.2 Hz)。 實施例666 N6-乙基-4-(3-氯- 4-(((環丙胺某）羰基）胺基）茉氫某）-7-(3-( 1-口比哈淀基）丙氧基）-6 -口奎饮林破釀胺 藉由與實同樣之方法，從N6-乙基-4-(3-氯-4-(((環 ~ 丙胺基）羰基）胺基）苯氧基）-7-羥基-6-喹啉羧醯胺（213.4 __- 703 -__ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（ 698 ) mg ’ 0.50 mmol)及1-(3-氯丙基）吡咯啶鹽酸鹽，得到為淡 育色結晶之標題化合物（85·0 mg，0· 1 54 mmol，30.8%)。 iH-NMR光譜（DMSO-d6)5(ppm): 0.42 (2H，m)，0.65 (2H，m)， 1·16 (3H，t，J=7.2 Hz)，1.68 (4H，m)，2·00 (2H，m)，2.44 (4H， m), 2.53-2.60 (3H, m), 3.32-3.36 (2H, m), 4.27 (2H, m), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.48 (1H, s), 7.96 (1H, s), ,8.24-8.27 (2H, m), 8.51 (1H, s)5 8.64 (1H, d, J=5.2 Hz)。 實施例667 Ιϋν甲基- 4.-(3-氯-4-(((環丙胺基）羰某）胺基）笨氣某）·ία 2R)環 氣乙烷·2-某） 甲氣基杏 4淼醯脸 藉由與實施例7同樣之方法，從N6-甲基-4-(3-氯-4-( (環 丙胺基）羰基）胺基）苯氧基）-7-經基-6-峻，林幾醯胺（426.9 mg，1.00 mmol)及4-甲基-1-苯磺酸（2R)環氧乙烷-2-基甲 酯，得到為淡黃色結晶之標題化合物（230.0 mg，0.476 mmol，47.6%) 〇 W-NMR光譜（DMSO-d6)(5(ppm): 0·42 (2H，m)，0.65 (2H，m)， 2.56 (1H，m), 2·79-2·90 (2H，m)，2·84 (3H，d，J=4.4 Hz)， 3.47 (1H, m), 4.16 (1H, dd, J=6.0, 11.6 Hz), 4.63 (1H, dd, J=2.4, 11.6 Hz), 6.52 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.47 (1H, d, J=2.8 Hz), 7.54 (ΙΗΓδ), 7；97 (1H, s), 8.24-8.28 (2H, m), 8.53 (1H, s), 8.65 (1H，d, J=5.2 Hz)。 -704 - 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) 1304061 A7 B7Hz), 8.38 (1H, q, 1 = 4.4 Hz), 8.49 (1H, s), 8.62 (1H, d, J = 5.2 Hz) 〇 / Example 662 N6-ethyl-7-(芊氢) 4-(3-chloro-4-(((cyclopropylamine)))amine, phenoxy)-6-carboline #醯amine from 7-(benzyloxy)-4-(3-chloro -4-(((cyclopropylamino)carbonyl)amino)phenoxy 'yl)-6-threocol (1.056 g, 2·10 mmol) and 2M ethylamine-tetrahydrocyanate solution In the same manner as in Example 661, the title compound (1.022 g, 1.92 mmol, 91.8%) was obtained as white crystal. -701 - The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 _____B7 V. DESCRIPTION OF THE INVENTION (696) Di-j-NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.04 (3H, t, J = 7.2 Ηζ), 2·56 ( 1H,m), 3.25-3.31 (2H,m),5·39 (2H, s), 6.52 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H , dd, J=2.8, 8.8 Hz), 7.32-7.44 (3H, m), 7.47 (1H, d, J=2.8 Hz), 7.56 (2H, d, J=7.2 Hz), 7.59 (1H, s) , 7.97 (1H, s)5 8.26 (1H, d, J=8.8 Hz), 8.34 (1H, t, J=7.2 Hz), 8.49 (1H, s), 8·64 (1H,d,J=5.2 Hz). 663 methyl-4-(3-carb-4-((cyclopropylamine, oxime)amine) jasmonyl)-7-hydroxy-6-quinoxaline amide by the same method as in Example 83 From 6-methyl-7-(decyloxy)-4-((3-chloro-4-(((cyclopropylamino)carboxy)amino)phenoxy)&gt;6-4 retinoin 983 mg '1·90 mmol) gave the title compound (811 mg, 1.90 mmol, quantitative yield) as pale yellow crystals. iH-NMR spectrum (DMSO-d6) (5 (ppm): 0.42 (2H, m),0·65 (2H,m), 2.56 (1H, m), 2.85 (3H, s), 6.32 (1H, br), 7.18-7.24 (4H, m), 7.45 (1H, s), 7.96 (1H, s), 8.25 (1H, d, J = 9.2 Hz), 8.51 (1H, m), 8.81 (1H, s) 〇 Example 664 Μ·ethyl-4-(3-氪-4-( ((Cyclopropylamine)carbonyl)amino)mosyl-6-oxime-based gj-amine was obtained from N6-ethyl-7-(decyloxy)-4- in the same manner as in Example 83. _ (3 -Chloro-4 - (X (Cylan) carbonyl)amino)phenoxy)-6-quinolinecarboxamide (1·〇16 g, 1.91 mmol) gave the title of pale yellow crystal Compound ____- 702 - This demon sheet scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 Five DESCRIPTION invention (697) II. • 5 (845 mg, 1.91 mmol, quantitative yield). iH-NMR spectrum (DMSO-d6) 5 (ppm)·· 0·42 (2H, m), 0·65 (2H, m), 1.16 (3H, t, J=7.2 Hz), 2.56 (1H, m ), 3.36 (2H, m), 6.41 (1H, d, J=5.2 Hz), 7.15-7.35 (4H, m), 7.49 (1H, d, J=2.4 Hz), 7.97 (1H, s), 8.27 (1H, dd, J=4.0, 9.2 Hz), 8.60 (1H, d, J=5.2 Hz), 8,88 (LH, s), 12.68 (1H, br). Example 665 N6-Methyl-4-(3-chloro-4-((cyclopropylamine)carbonyl)amino)mosynyl)-7-(3-indole-leafyl)propoxy )-6- 口 杳 酿 酿 酿 from N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl))amino)phenoxy)-7-yl-6-π Quercetin (213.4 mg, 0.50 mmol) and 1-(3-chloropropionyl)pyrrolidine hydrochloride were obtained in the same manner as in Example 7 to give pale yellow, &lt; The title compound (78·4 mg, 0·146 mmol, 29.1%). — iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H, m), 0·65 (2H, m), 1.68 (4H, m), 1.99 (2H, m), 2.44 (4H, m ), 2.54-2.59 (3H, m), 2.83 (3H, d, J=4.8 Hz), 4.28 (2H, m), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J= 2.8 Hz), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.47 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.96 (1H, s)5 8.24-8.27 (2H, m), 8.53 (1H, s), 8.64 (1H, d, J = 5.2 Hz). Example 666 N6-ethyl-4-(3-chloro-4-(((cyclopropylamine)carbonyl))))))) ))-6-Kou Kui Lin Lin Broken Amine by N6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl))amino)phenoxy Base 7-hydroxy-6-quinoline carboxamide (213.4 __- 703 -__ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention ( 698 ) The title compound (85·0 mg, 0·1 54 mmol, 30.8%) was obtained as the title compound. iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H, m), 0.65 (2H, m), 1·16 (3H, t, J = 7.2 Hz), 1.68 (4H, m), 2 ·00 (2H, m), 2.44 (4H, m), 2.53-2.60 (3H, m), 3.32-3.36 (2H, m), 4.27 (2H, m), 6.51 (1H, d, J=5.2 Hz ), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.48 (1H, s), 7.96 (1H , s), , 8.24 - 8.27 (2H, m), 8.51 (1H, s)5 8.64 (1H, d, J = 5.2 Hz). Example 667 Ιϋν methyl- 4.-(3-chloro-4-(((cyclopropylamino)carbonyl)))))))))))))) Apricot 4 face was obtained from N6-methyl-4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-yl group by the same method as in Example 7. -6-Jun, linalylamine (426.9 mg, 1.00 mmol) and 4-methyl-1-benzenesulfonic acid (2R) oxiran-2-ylmethyl ester, the title compound 230.0 mg, 0.476 mmol, 47.6%) 〇W-NMR spectrum (DMSO-d6) (5 (ppm): 0·42 (2H, m), 0.65 (2H, m), 2.56 (1H, m), 2· 79-2·90 (2H,m),2·84 (3H,d,J=4.4 Hz), 3.47 (1H, m), 4.16 (1H, dd, J=6.0, 11.6 Hz), 4.63 (1H, Dd, J=2.4, 11.6 Hz), 6.52 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.47 ( 1H, d, J=2.8 Hz), 7.54 (ΙΗΓδ), 7;97 (1H, s), 8.24-8.28 (2H, m), 8.53 (1H, s), 8.65 (1H,d, J=5.2 Hz -704 - This paper size applies to Chinese National Standard (CNS) A4 specification (210x 297 mm) 1304061 A7 B7

699 實施例66^ 氯-企_(((環丙胺某）羰基）胺基）茉氣基）-7-(丄2 R)%馬L貌-2-基）甲氧基-6-p奎淋释酿胺 藉由與實施例7同樣之方法，從N6-乙基-4-(3-氯-4-(((環 丙胺基）羰基）胺基）冬氧基經基-6-α奎琳幾酿胺（44 0.9 mg ’ 1:00 mm〇i)及4-甲基-1-苯磺酸（2R)環氧乙烷-2-基甲 醋’得到為淡黃色結晶之標題化合物（235.4 mg，0.474 mmol，47.4%) 〇 iH-NMR光譜（DMSO-d6) 5 (ppm): 0.42 (2H，m)，0.65 (2H，m)， I. 15 (3H, t, J=7.2 Hz), 2.56 (1H, m), 2.82 (1H, m), 2.89 (1H, m), 3.28-3.36 (2H, m), 3.48 (1H, m), 4.17 (1H, dd, J=2.0; II. 2 Hz), 4.62 (1H, dd, J=2.4, 11.2 Hz), 6.52 (1H, d, J=5.2 '699 Example 66^ Chloro-ruthenium (((cyclopropylamine)carbonyl)amino)mosquito)-7-(丄2 R)% horse L-form-2-yl)methoxy-6-p-quine The liberated amine was obtained from N6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl))amino)oxyl-6-α by the same procedure as in Example 7.奎 几 酿 ( (44 0.9 mg ' 1:00 mm 〇 i) and 4-methyl-1-benzene sulfonic acid (2R) oxirane-2-yl ketone vinery to give the title compound as pale yellow crystal (235.4 mg, 0.474 mmol, 47.4%) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H, m), 0.65 (2H, m), I. 15 (3H, t, J=7.2 Hz), 2.56 (1H, m), 2.82 (1H, m), 2.89 (1H, m), 3.28-3.36 (2H, m), 3.48 (1H, m), 4.17 (1H, dd, J=2.0; II. 2 Hz), 4.62 (1H, dd, J=2.4, 11.2 Hz), 6.52 (1H, d, J=5.2 '

Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.53 (1H, s), 7.97 (1H, s), 8.24-8.30 (2H，m)，8.52 (1H，s)，8.65 (1H，d，J=5.2 Hz)。 實施例669 N6-—甲基- 4-(3-氯- 4-(((環丙胺基）羰基）胺某）策氫某）-7· ((2 R) - 2-¾基- 3- ( Ι-p比啥淀基）丙氣某）-6-峰〃林教酿胺 將N6-甲基- 4-(3 -氯- 4-(((環丙胺基）談基）胺基）苯氧基）_ 7 - ((2R)環乳乙燒-2-基）甲氧基-6-峻琳叛酿胺（225 mg， 0.466 mmol)，在氮氣蒙氣下溶於四氳呋喃（5.0 ml)中，添 加吡咯啶（1.0 ml)，並於室溫攪拌一整晚。將反應液減壓濃 縮，且付f於矽凝膠管柱層析（溶出液為乙酸乙酯：甲醇 _ ==95 : 5)，再將含有目的物之溶出份濃縮，濾取從乙酸乙酯 -705 - ^紙張尺度適用中國國家標準(CNS) A4規格(210x 297公董） 1304061 A7 B7 五、發明説明（700 ) - 中析出之結晶，藉由通風乾燥，得到為淡黃色結晶之標題 化合物（164.5 mg，0.297 mmol，63.7%) 0 W-NMR 光譜（DMSO-d6)5(ppm): 0.42 (2H，m)，0.65 (2H，m)， 1.67 (4H，m)，2.48-2.59 (6H，m)，2·66 (1H，dd，J=6.4，12.0 Hz)，2.85 (3H，d，J=4.8 Hz)，4.05 (1H，m)，4.16 (1H，dd， J=6.0，10.0 Hz)，4.34 (1H，dd，J=3.2，10.0 Hz)，5.24 (1H，d， J=4.8 Hz), 6.51 (1H, d, J=5.2 Hz), 7.18-7.25 (2H, m), 7.48 (1H, d, J=2.8 Hz), 7.54 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.50 (1H, q, J=4.8 Hz), 8.65 (1H, d, J=5.2 Hz), 8.71 (1H，s) 〇 實施例670 - N6-乙基-4-Π-氪-4-ΓΓί環丙胺某）羱某）胺基）茉氫某）-7--- ιΓΠ Γ T一 I I、•、一 ' ((2幻-2-蕤基-3-(1-吡咯啶某）丙氣基）-6-4啉卷醯胺 一 ：。 藉由與實施例669同樣之方法，從N6-乙基-4-( 3-氯-4-(((環丙胺基）羰基）胺基）苯氧基）-7-((2R)環氧乙烷-2-基） 甲氧基-6-喹啉羧醯胺（230 mg，0.463 mmol)，得到為淡黃 色結晶之標題化合物（146.0 mg，0.257 mmol，55.5%)。 iH-NMR光譜（DMSO-d6)5(ppm): 0.42 (2H，m)，0.65 (2H，m)， 1.16 (3H, t, J=7.2 Hz), 1.67 (4H, m), 2.47-2.58 (6H, m), 2.68 (1H, dd, J=6.8, 12.0 Hz), 3.30-3.40 (2H, m), 4.04 (1H, m), 4.19 (1H, dd, J=5.6, 9.6 Hz), 4.33 (1H, dd, J=3.2, 9.6 Hz), 5.18 (1H, d, J=4.8 Hz), 6.51 (1H, d, J=5.2 Hz), 7.18-7.25 (2H, m), T：48 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.53 (1H, m), 8.65 (1H, d, J=5.2 Hz), __- 706 -_ 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐） 1304061 A7 ___ _B7__ 五、發明説'~) &quot; '] 8.71 (1H，s) 〇 會施例670-1 N- (4- ((L_氰基7-(( 1-甲某-4-六氫p比症）甲氣基）-4- 4喊某丄 氳）-2- I苯基}N·-環丙某Μ 將&gt;1-(4-((6-氰基-7-(4-六氫吡啶甲氧基）-4-喹啉基）氧）-2-氟本-基）-Ν’·環丙基脲320 mg懸浮於四氫咬喃20 ml中， 然後於室溫攪拌下添加甲醛（37%水溶液）1 ml ,乙酸80 mg，繼而三乙醯氧基硼氫化鈉280 mg。攪拌20分鐘後，添 加2N氫氧化鈉水溶液及乙酸乙酯並萃取。將萃取液通過舖 上NH型矽凝膠之玻璃過濾器，藉由乙酸乙g旨：甲醇=2〇: 1 之混合溶媒將矽凝膠充分清洗。將有機溶媒合併且減壓餳 去。於殘餘物中添加乙酸乙酯且過濾，得到13〇 黃色' 固體。’ ' - ^-NMR (DMSO-d6) 5 (ppm): 0.35-0.45 (2H, m), 0.59-0.69 (2H，m)，1.32-1.46 (2H，m)，1.71-1.89 (5H，m)，2·14 (3H，s)， 2.49-2.59 (1H, m), 2.74-2.84 (2H, m), 4.12 (2H, d, J=5.2 Hz), 6·56 (1H，d，J=5.2 Hz)，6.80 (1H，s)，7.07 (1H，d，J=9.2 Hz)， 7.31 (1H, d, J=11.2 Hz), 7.55 (1H, s)5 8.16-8.27 (2H, m), 8.69 (1H，s)，8·70 (1H，d，J=5.2 Hz)。 中間體係以下述方法合成。 f 造例 670- 1- 1 一 4-(((4-(4-胺基-3-氣苯乳基）-6-氰基- 7-P杳说其）氣）甲基）· 1 -六氫117比峻教酸第二丁酉旨 將4-(4 -胺基-3 -氟苯氧基）-7-輕基-6-4琳甲腈5〇〇 mg、 ___- 707 -___ 本紙張尺度適用中國國家標準(cNS) A4規格(210x297公爱）Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.53 (1H, s), 7.97 ( 1H, s), 8.24-8.30 (2H, m), 8.52 (1H, s), 8.65 (1H, d, J = 5.2 Hz). Example 669 N6--methyl- 4-(3-chloro-4-((cyclopropylamino)carbonyl)amine))) ((2 R) - 2-3⁄4 base - 3- (Ι-p is more than 啥 基)) propylene -6) -6 〃 教 教 教 教 将 将 N 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 Phenoxy)-7-((2R)cyclo-ethidin-2-yl)methoxy-6-Junlin Amine (225 mg, 0.466 mmol), dissolved in tetrahydrofuran under nitrogen atmosphere ( In 5.0 ml), pyrrolidine (1.0 ml) was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: methanol _ == 95: 5), and the fractions containing the desired product were concentrated and filtered from ethyl acetate. Ester-705 - ^ Paper scale applicable to China National Standard (CNS) A4 specification (210x 297 dongdong) 1304061 A7 B7 V. Invention description (700) - Crystallized in the middle, obtained by air drying, the title of light yellow crystal Compound (164.5 mg, 0.297 mmol, 63.7%) 0 W-NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.67 (4H, m), 2.48-2.59 (6H,m),2·66 (1H,dd,J=6.4,12.0 Hz), 2.85 (3H,d,J=4.8 Hz), 4.05 (1H,m), 4.16 (1H,dd,J=6.0 , 10.0 Hz), 4.34 (1H, dd, J=3.2, 10.0 Hz), 5.24 (1H, d, J=4.8 Hz), 6.51 (1H, d, J=5.2 Hz), 7.18-7.25 (2H, m ), 7.48 (1H, d, J=2.8 Hz), 7.54 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.50 (1H, q, J=4.8 Hz) ), 8.65 (1H, d, J = 5.2 Hz), 8.71 (1H, s) 〇 Example 670 - N6-ethyl-4-Π-氪-4-ΓΓί cyclopropylamine) 羱))) Hydrogen)-7--- ιΓΠ Γ T-II,•, '((2 phanyl-2-mercapto-3-(1-pyrrolidine)propenyl)-6-4 oxalylamine: by the same procedure as Example 669, from N6-ethyl 4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)oxiran-2-yl)methoxy-6-quinoline Carboxylamidine (230 mg, 0.463 mmol) gave the title compound (146.0 mg, 0.27 mmol, 55.5%) as a pale yellow crystal. iH-NMR spectrum (DMSO-d6) 5 (ppm): 0.42 (2H, m) , 0.65 (2H, m), 1.16 (3H, t, J = 7.2 Hz), 1.67 (4H, m), 2.47-2.58 (6H, m), 2.68 (1H, dd, J=6.8, 12.0 Hz), 3.30-3.40 (2H, m), 4.04 (1H, m), 4.19 (1H, dd, J=5.6, 9.6 Hz), 4.33 (1H, dd, J=3.2, 9.6 Hz), 5.18 (1H, d, J=4.8 Hz), 6.51 (1H, d, J=5.2 Hz), 7.18-7.25 (2H, m), T:48 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.97 ( 1H, s), 8.26 (1H, d, J=9.2 Hz), 8.53 (1H, m), 8.65 (1H, d, J=5.2 Hz), __- 706 -_ This paper size applies to the Chinese National Standard (CNS) A4 size (210x 297 mm) 1304061 A7 ___ _B7__ V. Invention said '~) &quot; '] 8.71 (1H, s) 〇 would apply example 670-1 N- (4- ((L_ cyano 7-) ((1-A certain-4-hexahydrop ratio) Gas base)-4- 4 shout some 丄氲)-2- Iphenyl}N·-cyclopropyl Μ will be &gt; 1-(4-((6-cyano-7-(4-hexahydropyridine) Oxy)-4-quinolinyl)oxy)-2-fluorobenzyl)-oxime-cyclopropyl urea 320 mg was suspended in 20 ml of tetrahydroancillate, and then formaldehyde was added with stirring at room temperature (37). % aqueous solution) 1 ml, acetic acid 80 mg, followed by sodium ethoxide borohydride 280 mg. After stirring for 20 minutes, 2N aqueous sodium hydroxide solution and ethyl acetate were added and extracted. The extract was passed through a glass filter coated with a NH-type ruthenium gel, and the ruthenium gel was thoroughly washed by a mixed solvent of acetic acid: methanol = 2 〇: 1. The organic solvent is combined and decompressed sugar is removed. Ethyl acetate was added to the residue and filtered to give &lt ' ' - ^-NMR (DMSO-d6) 5 (ppm): 0.35-0.45 (2H, m), 0.59-0.69 (2H, m), 1.32-1.46 (2H, m), 1.71-1.89 (5H, m ), 2·14 (3H, s), 2.49-2.59 (1H, m), 2.74-2.84 (2H, m), 4.12 (2H, d, J=5.2 Hz), 6·56 (1H, d, J =5.2 Hz), 6.80 (1H, s), 7.07 (1H, d, J = 9.2 Hz), 7.31 (1H, d, J = 11.2 Hz), 7.55 (1H, s)5 8.16-8.27 (2H, m ), 8.69 (1H, s), 8.70 (1H, d, J = 5.2 Hz). The intermediate system was synthesized in the following manner. f Example 670- 1- 1 4-(((4-(4-Amino-3-phenylphenyl))-cyano-7-P杳)))))))))) Hexahydro 117 is more than 4-(4-amino-3-fluorophenoxy)-7-light-based-6-4 lenonitrile, 5 〇〇mg, ___- 707 -___ The paper scale applies to the Chinese National Standard (cNS) A4 specification (210x297 public)

裝 訂Binding

A7 B7 1304061 五、發明説明（7〇2) 4-(溴甲基）-1-六氫吡啶羧酸第三丁酯550 mg、碳酸鉀7〇〇 mg及二甲基甲醯胺5 ml，在60°C揽拌2小時。加水及乙酸乙 酯萃取，萃取液用硫酸鎂乾燥。濾去乾燥劑，於濾液中添 加矽凝膠，減壓餾去溶媒以吸著於矽凝膠上。將吸著反應 液之矽凝膠充填入裝有矽凝膠之乾燥管柱中並進行管柱層 析（己烷：乙酸乙酯=1 : 1，然後1 : 2，然後1 : 3，然後純 乙酸乙醋）。得到423 mg之褐色油狀物。 ^-NMR (DMSO-d6) δ (ppm): 1.20-1.32 (2H, m), 1.39 (9H, s), 1.75-1.83 (2H, m), 1.98-2.10 (1H, m), 2.67-2.88 (2H, m)5 3.94-4.05 (2H, m), 4.15 (2H, d, J=6.4 Hz), 5.25 (2H, bs), 6.51 (1H, d, J=5.2 Hz), 6.83-6.88 (2H, m), 7.06-7.11 (1H, m), 7.55 (1H，s)，8·69 (1H，s)，8.70 (1H，d, J=5.2 Hz)。 製造例670- 1-2 - izi (( 6-氰基二j二（3-氟-4- (7茉氣羰某）胺基）茉氣某）-7•岭4 基）氧）甲基）-1 -六氫吡啶藉醢第三丁酯 將4-(((4-(4-胺基-3-氟苯氧基）-6-氰基-7-峻琳基）氧）甲 基）-1-六氫吡啶羧酸第三丁酯523 mg、吡啶0.17 ml及四氫 吱喃10 ml在冰冷下授拌，且滴入氯甲酸苯醋。滴入終了後 立即移開冷浴，使回到室溫。攪捽1 5分鐘後，加水及乙酸 乙酯萃取。於萃取液中添加矽凝膠，減壓餾去溶媒以吸著 於矽凝膠上。將吸著反應液之矽凝膠充填入裝有矽凝膠之 乾燥管柱中並進行管柱層析（己烷：乙酸乙酯===1 : 1，然後 1 : 2，然後鈍乙酸乙酯）精製。得到490 mg之黃色粉末。 H-NMR (DMSO-d6) 5 (ppm): 1.20-1.32 (2H，m)，1·39 (9H，s)， ______- 708 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐） 1304061 A7 _ B7 五、發明説明（7〇3) 1 .云 1.75-1.83 (2H, m), 1.98-2.10 (1H, m), 2.70-2.85 (2H, m), 3.95- 4.04 (2H, m), 4.16 (2H, d, J=6.0 Hz), 6.64 (1H, d, J=5.2 Hz), 7.16-7.28 (4H, m), 7.38-7.46 (3H, m), 7.59 (1H, s), 7.80 (1H, dd, J=8.8 Hz, 8.8 Hz), 8.72 (1H, s), 8.75 (1H, d, J=5.2 Hz)，10.02 (1H，br s)。 製造例飞70-1-3 4二α_( 6-氰基-4-(4-(((環丙胺基）羰某）胺基氣茉氫基）· 7-喹啉基）氧）甲基）-1-六氪吡啶羧酸第三丁酯 將4-((( 6-氰基-4-( 3-氟-4-((苯氧羰基）胺基）苯氧基）-7-4淋基）氧）甲基）-1 -六氫吡啶叛酸第三丁酯490 mg、環丙 胺0.72 ml及四氫呋喃5 ml在60°C攪拌35分鐘。於反應溶液.. 中添加矽凝膠，減壓餾去溶媒以吸著於矽凝膠上。將吸著 反應液之碎凝膠充填入裝有梦凝膠之乾燥管柱中並進行管：27 柱層析（乙酸乙酯，然後乙酸乙酯：甲醇=20 : 1)精製。得 到340 mg之淡黃色固體。 ^-NMR (DMSO-d6) 5 (ppm): 0.37-0.44 (2H, m)5 0.59^0.69 (2H, m), 1.29-1.32 (2H, m), 1.39 (9H, s), 1.77-1.84 (2H, m), 1·99-2·11 (1H，m)，2·39·2·59 (1H，m)，2·59-2·87 (2H，m)， 3.96- 4.04 (2H，m)，4.16 (2H，d，J=6.4 Hz)，6·57 (1H，d，J-5.2 Hz)，6·80 (1H，d，J=2.8 Hz)，7.05-7.11 (lH，m)，7.31 (1H，dd， J=12.0 Hz, 2.8 Hz), 7.58 (1H, s), 8.19-8.27 (2H, m), 8.71 (1H，s)，8·73 (1H，d, J=5.2 Hz)。 製造例67ϋ=Τ-4 — N-(4J(6-氨某-7“4-六i.吡啶甲氣基）-4-p杏嗾某、氧 -709 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 一 一 13〇4〇61 A7 B7 五、發明説明（7〇4) 二 .5 1基）-N’-瑷丙某Μ 於4-(((6-氰基-4-(4-(((環丙胺基）羰基）胺基）-3-氟苯氧 基）-7-喹啉基）氧）甲基）-1-六氫吡啶羧酸第三丁酯340 mg中 添加三氟乙酸5 ml，並在室溫攪拌7分鐘。於反應溶液中添 加飽和小蘇打水及乙酸乙酯以萃取。將乙酸乙酯層用食鹽 水洗淨，以硫酸鈉乾燥。濾去乾燥劑，減壓餾去溶媒，得 到320 mg之淡黃色固體。 1 H-NMR (DMSO-d6) 5 (ppm): 0.37-0.44 (2H, m), 0.59-0.69 (2H, m), 1.47-1.59 (2H, m), 1.92-2.02 (2H, m), 2.14-2.25 (1H, m), 2.47-2.57 (3H, m), 2.87-2.98 (2H, m), 4.19 (2H, d, J=6.4 Hz)，6.59 (1H，d，J=5.2 Hz), 6.88 (1H，d，J=2.8 Hz); 7.05-7.10 (1H, m), 7.31 (1H, dd, J=12.0 Hz, 2.8 Hz), 7.63 &quot; (1H，s)，8·11 (1H，dd，J=9.2 Hz，9_2 Hz)，8.28 (1H，s)，8.73 : (1H，d，J=5.2 Hz)，8·74 (1H，s)。 實施例671 ii( 4· (3 -乙脲基）-氟苯氧基）-7-甲氣基π奎隻#酸^産旨 以與實施例11同樣之方法，將N-( 2-氟-4-(7-甲氧基甲 氧羰基-4-喹啉基）氧苯基）胺甲酸苯酯（〇·9 g)於二甲基亞石風 中’在室溫下用乙胺處理’得到為固體之標題化合物（〇6 g) 0 1H-NMR 光譜（DMSO-d6) 5 (ppm): 1·〇5 (3H，t，J=7 2 Hz) 一 3.07-3.15 (2H，m)，3·85 (3H，s)，3·96 (3H，s)，6 52 (1H d J=5.2 Ηζ)7—έ·5δ (1H, t, J=5.2 Hz), 7.04-7.08 (1H m) 7 31 一 (1H，dd，J=2.8 Hz，J=12 Hz)，7.51 (1H，s)，8.21 (1H t J=9 2 -710 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) !3〇4〇61A7 B7 1304061 V. Description of the invention (7〇2) 4-butyl bromide 4-(bromomethyl)-1-hexahydropyridinecarboxylate 550 mg, 7 mg of potassium carbonate and 5 ml of dimethylformamide Mix for 2 hours at 60 °C. Water and ethyl acetate were added for extraction, and the extract was dried over magnesium sulfate. The desiccant was filtered off, a hydrazine gel was added to the filtrate, and the solvent was distilled off under reduced pressure to adsorb onto the hydrazine gel. The hydrazine gel absorbing the reaction solution is filled into a dry column containing a hydrazine gel and subjected to column chromatography (hexane: ethyl acetate = 1: 1, then 1: 2, then 1: 3, then Pure acetic acid ethyl acetate). 423 mg of a brown oil were obtained. ^-NMR (DMSO-d6) δ (ppm): 1.20-1.32 (2H, m), 1.39 (9H, s), 1.75-1.83 (2H, m), 1.98-2.10 (1H, m), 2.67-2.88 (2H, m)5 3.94-4.05 (2H, m), 4.15 (2H, d, J=6.4 Hz), 5.25 (2H, bs), 6.51 (1H, d, J=5.2 Hz), 6.83-6.88 ( 2H, m), 7.06-7.11 (1H, m), 7.55 (1H, s), 8.69 (1H, s), 8.70 (1H, d, J = 5.2 Hz). Production Example 670- 1-2 - izi ((6-Cyano-di-j-(3-fluoro-4-(7-methane carbonyl)))))))))) -1 -hexahydropyridine, 4-(((4-(4-amino-3-fluorophenoxy)-6-cyano-7- cylinyl)oxy)methyl 1,3- hexahydropyridinecarboxylic acid tert-butyl ester 523 mg, pyridine 0.17 ml, and tetrahydrofuran 10 ml were mixed under ice cooling, and phenyl chloroformate was added dropwise. Immediately after the end of the instillation, remove the cold bath and return to room temperature. After stirring for 15 minutes, water and ethyl acetate were added for extraction. A ruthenium gel was added to the extract, and the solvent was distilled off under reduced pressure to absorb the ruthenium gel. The hydrazine gel absorbing the reaction solution was filled into a dry column containing a hydrazine gel and subjected to column chromatography (hexane: ethyl acetate ===1:1, then 1:2, then blister acetic acid) Ester) refined. A 490 mg yellow powder was obtained. H-NMR (DMSO-d6) 5 (ppm): 1.20-1.32 (2H,m),1·39 (9H,s), ______- 708 - This paper scale applies to China National Standard (CNS) Α4 specification (210X297 PCT) 1304061 A7 _ B7 V. INSTRUCTIONS INSTRUCTIONS (7〇3) 1 .Clouds 1.75-1.83 (2H, m), 1.98-2.10 (1H, m), 2.70-2.85 (2H, m), 3.95- 4.04 (2H , m), 4.16 (2H, d, J=6.0 Hz), 6.64 (1H, d, J=5.2 Hz), 7.16-7.28 (4H, m), 7.38-7.46 (3H, m), 7.59 (1H, s), 7.80 (1H, dd, J=8.8 Hz, 8.8 Hz), 8.72 (1H, s), 8.75 (1H, d, J=5.2 Hz), 10.02 (1H, br s). Production example fly 70-1-3 4 bis α-( 6-cyano-4-(4-((cyclopropylamino)carbonyl))))) )-1-hexylpyridinium carboxylic acid tert-butyl ester 4-(((6-cyano-4-(3-fluoro-4-((phenoxycarbonyl))amino)phenoxy)-7-4 Lysyloxy)methyl)-1 -hexahydropyridine tartrate butyl 490 mg, cyclopropylamine 0.72 ml and tetrahydrofuran 5 ml were stirred at 60 ° C for 35 minutes. A hydrazine gel was added to the reaction solution, and the solvent was distilled off under reduced pressure to adsorb on the hydrazine gel. The pulverized gel of the reaction solution was filled in a dry column equipped with a dream gel and purified by a column chromatography (ethyl acetate, then ethyl acetate:methanol = 20:1). A pale yellow solid of 340 mg was obtained. ^-NMR (DMSO-d6) 5 (ppm): 0.37-0.44 (2H, m)5 0.59^0.69 (2H, m), 1.29-1.32 (2H, m), 1.39 (9H, s), 1.77-1.84 (2H, m), 1·99-2·11 (1H,m),2·39·2·59 (1H,m),2·59-2·87 (2H,m), 3.96- 4.04 (2H , m), 4.16 (2H, d, J = 6.4 Hz), 6.57 (1H, d, J-5.2 Hz), 6·80 (1H, d, J = 2.8 Hz), 7.05-7.11 (lH, m), 7.31 (1H, dd, J = 12.0 Hz, 2.8 Hz), 7.58 (1H, s), 8.19-8.27 (2H, m), 8.71 (1H, s), 8.73 (1H, d, J =5.2 Hz). Production Example 67ϋ=Τ-4 — N-(4J(6-Ammonia-7"4-hexa.pyridylmethyl)-4-p apricot, oxygen-709 - This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1-13〇4〇61 A7 B7 V. Invention description (7〇4) II.5 1 base)-N'-瑷丙Μ 4- 4-(((6 -Cyano-4-(4-(((cyclopropylamino)carbonyl)amino)-3-fluorophenoxy)-7-quinolinyl)oxy)methyl)-1-hexahydropyridinecarboxylic acid 5 ml of trifluoroacetic acid was added to 340 mg of tributyl acrylate, and stirred at room temperature for 7 minutes. Saturated sodium bicarbonate and ethyl acetate were added to the reaction solution for extraction. The ethyl acetate layer was washed with saline to sulfuric acid. Drying with sodium. The desiccating agent was filtered off, and the solvent was evaporated to dryness to give a pale yellow solid (yield: DMSO-d6) 5 (ppm): 0.37-0.44 (2H, m), 0.59-0.69 (2H , m), 1.47-1.59 (2H, m), 1.92-2.02 (2H, m), 2.14-2.25 (1H, m), 2.47-2.57 (3H, m), 2.87-2.98 (2H, m), 4.19 (2H, d, J = 6.4 Hz), 6.59 (1H, d, J = 5.2 Hz), 6.88 (1H, d, J = 2.8 Hz); 7.05-7.10 (1H, m), 7.31 (1H, dd, J=12.0 Hz, 2.8 Hz), 7.63 &quot; (1H, s), 8·11 (1H, dd, J=9.2 Hz 9_2 Hz), 8.28 (1H, s), 8.73: (1H, d, J = 5.2 Hz), 8.74 (1H, s). Example 671 ii (4·(3-Ethylureido)-fluorobenzene Oxy(7-methoxy-4-(7-methoxymethoxycarbonyl-4-quinoline) was prepared in the same manner as in Example 11 to give the title compound. Phenyl oxyphenyl) phenyl carbamate (〇·9 g) was treated with ethylamine in dimethyl sulphate to give the title compound as a solid ( 〇 6 g) 0 1H-NMR spectrum (DMSO-d6) 5 (ppm): 1·〇5 (3H, t, J=7 2 Hz) A 3.07-3.15 (2H, m), 3.85 (3H, s), 3.96 (3H, s),6 52 (1H d J=5.2 Ηζ)7—έ·5δ (1H, t, J=5.2 Hz), 7.04-7.08 (1H m) 7 31 one (1H, dd, J=2.8 Hz, J =12 Hz),7.51 (1H,s),8.21 (1H t J=9 2 -710 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) !3〇4〇61

發明説明 705Invention description 705

Hz), 8.33 (1Η，br s)，8·55 (1Η，s)，8.67 (1Η，d，J=5.2 Hz)。 中間體係以下述方法合成。 製造例671- 1 U4 -硝基-3-氟苯氧基）-7-甲氣基-6-崎啦玲酸甲醋 藉由與製造例7同樣之操作’從4-氣-7-甲氧基-6-甲氧羰 基峻淋（2.51 g)，得到4-(4-硝基-3-氟苯氧基卜7-甲氧基-6_ 喳啉羧酸甲酯（2.44 g)。 々·NMR光譜（DMSO-d6)5(Ppm): 3.83 (3H，s)，3.99 (3H，s)， 6.93 (1H, d, 1=5.1 Hz), 7.30-7.33 (1H, m), 7.58 (1H, m), 7.65-7.69 (1H, m), 8.27-8.1 (1H, m), 8.44 (1H, s), 8.81 (1H, d，J=5.1 Hz)。 製造例671-7 1ΐ·( 4-胺基-3 -氟苯氧基）-7-甲氧基-6_ 4喊栽齡甲酿 ’一 藉由與製造例8同樣之操作，從4-(4-硝基-3-氟苯氧基）-7-甲氧基-6-喹啉羧酸甲酯（2.40 g)，得到4_(4_胺基-3-氟苯 氧基）-7-甲氧基-6-喹啉羧酸甲酯（1.54 g)。 iH-NMR 光譜（DMSO-d6)c5(ppm): 3.84 (3H，s)，3.95 (3H，s)， 5.21 (2H, br d), 6.46 (1H, d, J=5.1 Hz), 6.85-6.86 (2H, m), 7.09 (1H，d，J=11.9 Hz)，7.49 (1H，s)，8·55 (1H，s)，8·65 (1H， d，J=5.1 Hz)。 製造例671 K-(2-氣-4- (7-甲氣基-6-甲氧羰某-4- 4却其）氳茉某）胺甲 酸笨醋 藉由與製造例1 7同樣之操作，從4-(4-胺基-3-氟苯氧 -711 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061Hz), 8.33 (1Η, br s), 8·55 (1Η, s), 8.67 (1Η, d, J=5.2 Hz). The intermediate system was synthesized in the following manner. Production Example 671-1 U4-Nitro-3-fluorophenoxy)-7-methyl-based-6-succinic acid methyl ketone by the same operation as in Production Example 7 'from 4-gas-7-A Oxy-6-methoxycarbonyl radical (2.51 g) gave 4-(4-nitro-3-fluorophenoxyb 7-methoxy-6-carbolinecarboxylic acid methyl ester (2.44 g). NMR spectrum (DMSO-d6) 5 (Ppm): 3.83 (3H, s), 3.99 (3H, s), 6.93 (1H, d, 1 = 5.1 Hz), 7.30-7.33 (1H, m), 7.58 ( 1H, m), 7.65-7.69 (1H, m), 8.27-8.1 (1H, m), 8.44 (1H, s), 8.81 (1H, d, J = 5.1 Hz). Manufacturing Example 671-7 1ΐ·( 4-Amino-3-fluorophenoxy)-7-methoxy-6_ 4 shouting ageing 'One' by the same operation as in Production Example 8, from 4-(4-nitro-3-fluoro Methyl phenoxy)-7-methoxy-6-quinolinecarboxylate (2.40 g) afforded 4-(4-amino-3-fluorophenoxy)-7-methoxy-6-quinoline Methyl carboxylate (1.54 g). iH-NMR spectrum (DMSO-d6) c5 (ppm): 3.84 (3H, s), 3.95 (3H, s), 5.21 (2H, br d), 6.46 (1H, d , J=5.1 Hz), 6.85-6.86 (2H, m), 7.09 (1H,d,J=11.9 Hz), 7.49 (1H,s),8·55 (1H,s),8·65 (1H, d, J = 5.1 Hz). Manufacturing Example 671 K-(2-Gas-4-(7-Methane-6-A) Oxycarbonyl -4- 4 but 氲 某 ) 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 藉 藉 藉 藉 藉 藉 藉 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- China National Standard (CNS) A4 Specification (210 X 297 mm) 1304061

基）-7-甲氧基-6-喹啉羧酸甲酯（1·50 g)，得到N-(2_氟_4_ (7-甲氧基-6-甲氧羰基-4-喹啉基）氧苯基）胺甲酸苯酯（1.87 g) 0 j-NMR 光譜（CDCl3)5(ppm): 3·98 (3H，s)，4.05 (3H，s)， 6.49 (1H, d, J=5.3 Hz), 7.03-7.05 (2H, m), 7.22-7.28 (4H5 m), 7.50 (IH, s), 8.25 (1H, br s), 8.67 (1H, d, J=5.1 Hz), 8.77 (lH，s)〇 實施例672 jb (4- (3 -環丙脲基）-3 v氟苯氧基）-7-甲氳某p套说-籍酸甲 以與實施例11同樣之方法，將N-(2-氟-4-(7-甲氧基-6-甲-氧談基- 4-0奎淋基）氧苯基）胺甲酸苯酿（〇·9 g)於二甲基亞减_ 中，在室溫下用環丙胺處理，得到為固體之標題化^:物）¾ (0.5 g)。 W-NMR 光譜（0撾30-&lt;16)5(??111):0.37-0.41(211，111)，0.60_ 0.66 (2H，m)，2.51-2.57 (1H，m)，3.47 (3H，s)，3.59 (3H，s)， 6.52 (1H, d, J=5.6 Hz), 6.79-6.82 (1H, m), 7.05-7.10 (1H, m), 7.32 (1H, dd, J=2.8 Hz, J=11.6 Hz), 7.51 (1H, s), 8.17-8.24 (2H，m)，8·55 (1H，s)，8.30 (1H，d，J=5.6 Hz)。 實施例673 4-(4-(3-乙脲基3-氟笨氣基）-7-甲氧其4啉淼酩 以與實施例633同樣之方法，將4-(4-(3-乙脲基）-3-氟苯 氧基）-7-甲-乳基#奎淋-6-叛酸甲酿（600 mg)加水分解，得到 為固體之標題化合物（210 mg)。 -712 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（7〇7) 二 iH-NMR 光譜（DMSO-d6)5(ppm): 1·05 (3H，t，J=7.2 Hz)， 3.07-3.15 (2H, m), 3.96 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.77 (1H, t5 J=5.6 Hz), 7.03-7.09 (1H, m), 7.31 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.50 (1H, s), 8.21 (1H, t, J=9.2 Hz), 8.45 (1H, br s)，8·56 (1H，s)，8·67 (1H，d，J=5.2 Hz) o 實施例-674 4-(4-(3-璜丙脲某3-氣苯氣基）-7-甲氣基4啉-6-羧酸 以與實施例633同樣之方法，將4-(4-(3-環丙脲基）-3-氟 苯氧基）-7-甲氧基喹啉-6-羧酸甲酯（500 mg)加水分解，得 到為固體之標題化合物（220 mg)。 1H-NMR 光譜（01^30-(16)5(??111):0.38-0.43 (211，111)，0.61-0.67 (2H, m), 2.51-2.58 (1H, m), 3.95 (3H, s), 6.52 (1H, d, / J=5.2 Hz), 6.83 (1H, d, J=2.8 Hz), 7.05-7.09 (1H, m), 7^31 ^ (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.47 (1H, s), 8.20 (1H, t, J=9.2 Hz), 8.22-8.26 (1H, m), 8.46 (1H, s), 8.65 (1H, d, J=5.2 Hz)。 實施例675 4-(4-(3-乙脲基）-3-氣笨氣某）-7-甲氣基崦啉-6-藉酸甲氧 醯胺 以與實施例634同樣之方法，將4-(4-(3-乙脲基）_弘氟苯 氧基）-7-甲氧基喹啉-6-羧酸（65 mg)，以甲氧基胺、三乙 ' 胺及苯并三唑-1-基氧參（二甲胺基）鳞六氟磷酸鹽處理，得 到為固體之-標題化合物（21 mg)。 一 /H-NMR 光譜（DMSO-d6)5(PPm): 1.05 (3H, t, J=7.2 Hz)， ___-713 -____ ^纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) &quot;&quot; ~ &quot;&quot; — 1304061 A7 B7 五、發明説明（7〇8) 二 •七 3.08-3.15 (2H, m), 3.73 (3H, s), 3.97 (3H, s), 6.52 (1H, d, J=5.2 Hz)，6.56-6.61 (1H，m)，7.02-7.07 (1H，m)，7.30 (1H， dd, J=2.4 Hz, J=11.6 Hz), 7.48 (1H, s), 8.22 (1H, t, J=9.2 Hz)，8·33 (1H，br s)，8·41 (1H，s)，8·65 (1H，d，J=5.2 Hz)， 11.44 (1H，br s) o 實施例-676 4-(4-(3-乙脲基）-3-氟茉氣基）-7-甲氣基喹啉-6-藉酸順式-(2 -耽壞丙基）酿胺 以與實施例634同樣之方法，將4-(4-(3-乙脲基）-3-氟苯 氧基）-7-甲氧基4淋-6-幾酸（20 mg)，以順式-2-氟環丙 胺、三乙胺、苯并三唑-1-基氧參（二甲胺基）鱗六氟磷酸氪 處理，得到為固體之標題化合物（9 mg)。 - iH-NMR 光譜（DMSO-d6) 5 (ppm): 1.05 (3H，t，J=7.2 Hz)， 1.04-1.18 (2H，m)，2.87-2.95 (1H，m)，3.08-3.15 (2H，m)， 3.99 (3H, s), 4.69-4.74 (0.5H, m), 4.86-4.90 (0.5H, m), 6.52 (1H5 d5 J=5.2 Hz), 6.58 (1H, t, J=5.2 Hz), 7.02-7.07 (1H, m), 7.30 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.51 (1H, s), 8.21 (1H, t, J=9.2 Hz), 8.31-8.35 (1H, m), 8.45 (1H, d, J=4 Hz), 8.50 (1H, s), 8·65 (1H，d，J=5.2 Hz)。 實施例677 4-(4-(3-乙脲基）-3-氟笨氣基）-7-甲氣基4啉-6-藉酸（2-乙 ' 氣乙基）醯胺 以與實施例634同樣之方法，將4-(4-(3-乙脲基）-3-氟苯 一 氧基）-7-甲氧基喹啉-6-羧酸（50 mg)，以乙氧基乙胺、三 _- 714 -__ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（709) - 乙胺、苯并三唑-1-基氧參（二甲胺基）銹六氟磷酸鹽處理， 得到為固體之標題化合物（1 8 mg)。 iH-NMR 光譜（DMSO-d6) 5 (ppm): 1.05 (3H, t, J=7.2 Hz), 1.13 (3H, t5 J=7.2 Hz), 3.07-3.15 (2H, m), 3.46-3.57 (6H, m), 4.02 (3H, s), 6.52 (1H, d, J=5.2 Hz), 6.58 (1H, t, J=5.2 Hz), 7.02- 7.07 (1H, m), 7.30 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.51 (1H, s), 8.21 (1H, t, J=9.2 Hz), 8.31-8.35 (1H, m), 8.44 (1H, t，J=5.2 Hz)，8.61 (1H，s)，8.65 (1H，d，J=5.2 Hz)。 實施例678 4-(4-(3-乙脲基）-3-氣茉氳某）-7-甲氩某4啉-6-藉酸（2-氰 乙基）醯胺 _ 以與實施例634同樣之方法，將4-(4-(3-乙脲基）-3-氟苯 氧基）-7-甲氧基喹啉-6-羧酸（40 mg)，以氰基乙胺、三~乙 ^ 胺及苯并三唑-1-基氧參（二甲胺基）鳞六氟磷酸鹽處理，得 到為固體之標題化合物（29 mg)。 iH-NMR 光譜（DMSO-d6)5(ppm): 1·05 (3H，t，J=7.2 Hz)， 2.78 (2H, t, J=6.4 Hz), 3.07-3.15 (2H, m), 3.52-3.58 (2H, m), 4.01 (3H, s), 6.52 (1H, d, J=5.2 Hz), 6.56-6.61 (1H, m), 7.02- 7.07 (1H, m), 7.30 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.52 (1H，s)，8.21 (1H，t，J=9.2 Hz)，8.33 (1H，br s)，8.59 (1H，s)， 8·65 (1H，d，J=5.2 Hz)，8.72 (1H，t，J=6 Hz)。 實施例679 1-(4-( 7-笮_氣基-6-氨基4啉-4-某氣）-2-甲苯基）-3-乙脲 1 以與製造例17同樣之方法，從4-(4-胺基-3-甲苯氧基）-7- _-715 -_ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）Methyl-7-methoxy-6-quinolinecarboxylate (1·50 g) afforded N-(2-fluoro-4-[(7-methoxy-6-methoxycarbonyl-4-quinoline) Phenyl oxyphenyl) phenyl carbamate (1.87 g) 0 j-NMR spectrum (CDCl3) 5 (ppm): 3·98 (3H, s), 4.05 (3H, s), 6.49 (1H, d, J =5.3 Hz), 7.03-7.05 (2H, m), 7.22-7.28 (4H5 m), 7.50 (IH, s), 8.25 (1H, br s), 8.67 (1H, d, J=5.1 Hz), 8.77 (lH, s) 〇 Example 672 jb (4-(3-cyclopropionyl)-3 v-fluorophenoxy)-7-methyl hydrazine, a set of p-groups - the same method as in Example 11 , N-(2-Fluoro-4-(7-methoxy-6-methyl-oxoyl-4-0-quinolinyl)oxyphenyl)amine carboxylic acid benzene (〇·9 g) in dimethyl The mixture was treated with cyclopropylamine at room temperature to give the title compound (3:4). W-NMR spectrum (0 oz 30-&lt;16) 5 (?? 111): 0.37-0.41 (211, 111), 0.60_0.66 (2H, m), 2.51-2.57 (1H, m), 3.47 (3H) ,s),3.59 (3H,s), 6.52 (1H, d, J=5.6 Hz), 6.79-6.82 (1H, m), 7.05-7.10 (1H, m), 7.32 (1H, dd, J=2.8 Hz, J = 11.6 Hz), 7.51 (1H, s), 8.17-8.24 (2H, m), 8·55 (1H, s), 8.30 (1H, d, J = 5.6 Hz). Example 673 4-(4-(3-Ethylureido-3-fluoroindolyl)-7-methoxy-4-phenylindole In the same manner as Example 633, 4-(4-(3-B) Ureyl)-3-fluorophenoxy)-7-methyl-lacyl #Querine-6-Resin (600 mg) was hydrolyzed to give the title compound (210 mg) as a solid. Paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (7〇7) Di-iH-NMR spectrum (DMSO-d6) 5 (ppm): 1·05 (3H ,t,J=7.2 Hz), 3.07-3.15 (2H, m), 3.96 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.77 (1H, t5 J=5.6 Hz), 7.03- 7.09 (1H, m), 7.31 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.50 (1H, s), 8.21 (1H, t, J=9.2 Hz), 8.45 (1H, br s) ,8·56 (1H,s),8·67 (1H,d,J=5.2 Hz) o Example-674 4-(4-(3-Propanylurea 3-Hydroxybenzene)-7- Methane-based 4 oxo-6-carboxylic acid 4-(4-(3-cyclopropylureido)-3-fluorophenoxy)-7-methoxyquinoline was obtained in the same manner as in Example 633. The 6-carboxylic acid methyl ester (500 mg) was hydrolyzed to give the title compound (220 mg) as a solid. 1H-NMR spectrum (01^30-(16)5 (??111):0.38-0.43 (211,111 ) 0.61-0.67 (2H, m), 2.51-2.58 (1H, m), 3.95 (3H, s), 6.52 (1H, d, / J=5.2 Hz), 6.83 (1H, d, J=2.8 Hz), 7.05-7.09 (1H, m), 7^31 ^ (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.47 (1H, s), 8.20 (1H, t, J=9.2 Hz), 8.22- 8.26 (1H, m), 8.46 (1H, s), 8.65 (1H, d, J = 5.2 Hz). Example 675 4-(4-(3-ethylureido)-3-gas stupid) 7-Methoxypyroline-6-acid methoxy acetamide 4-(4-(3-ethylureido)-fluorophenyloxy)-7-methoxy in the same manner as in Example 634 Benzylquinoline-6-carboxylic acid (65 mg), treated with methoxyamine, triethylamine and benzotriazol-1-yloxyglycol (dimethylamino)scale hexafluorophosphate to give a solid - the title compound (21 mg). One/H-NMR spectrum (DMSO-d6) 5 (PPm): 1.05 (3H, t, J=7.2 Hz), ___-713 -____ ^The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) ) &quot;&quot; ~ &quot;&quot; — 1304061 A7 B7 V. Description of invention (7〇8) 2·7 3.08-3.15 (2H, m), 3.73 (3H, s), 3.97 (3H, s), 6.52 (1H, d, J=5.2 Hz), 6.56-6.61 (1H, m), 7.02-7.07 (1H, m), 7.30 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.48 (1H, s), 8.22 (1H, t, J=9.2 Hz), 8·33 (1H, br s), 8.41 (1H, s), 8·65 (1H, d, J = 5.2 Hz), 11.44 ( 1H, br s) o Example-676 4-(4-(3-Ethylurea)-3-fluoromolyla)-7-methyl quinolate-6-acid cis-(2- 耽Dilyl propyl) tyrosine 4-(4-(3-ethylureido)-3-fluorophenoxy)-7-methoxy-4-leaf-6-acid (4-(4-(3-ethylureido)-3-fluorophenoxy)-7-methoxy (in the same manner as in Example 634) Treated with cis-2-fluorocyclopropylamine, triethylamine, benzotriazol-1-yloxyglycol (dimethylamino) quinone hexafluorophosphate to give the title compound as a solid (9 mg ). - iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.05 (3H, t, J = 7.2 Hz), 1.04-1.18 (2H, m), 2.87-2.95 (1H, m), 3.08-3.15 (2H , m), 3.99 (3H, s), 4.69-4.74 (0.5H, m), 4.86-4.90 (0.5H, m), 6.52 (1H5 d5 J=5.2 Hz), 6.58 (1H, t, J=5.2 Hz), 7.02-7.07 (1H, m), 7.30 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.51 (1H, s), 8.21 (1H, t, J=9.2 Hz), 8.31- 8.35 (1H, m), 8.45 (1H, d, J=4 Hz), 8.50 (1H, s), 8·65 (1H, d, J = 5.2 Hz). Example 677 4-(4-(3-Ethylureido)-3-fluoroindolyl)-7-carbazyltetralin-6-acid (2-ethyl'-ethylethyl) decylamine Example 634, 4-(4-(3-ethylureido)-3-fluorophenyloxy)-7-methoxyquinoline-6-carboxylic acid (50 mg), ethoxy Ethylamine, three _- 714 -__ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (709) - Ethylamine, benzotriazol-1-yl Treatment with oxystilbene (dimethylamino) rust hexafluorophosphate gave the title compound (1 8 mg) as a solid. iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.05 (3H, t, J = 7.2 Hz), 1.13 (3H, t5 J = 7.2 Hz), 3.07-3.15 (2H, m), 3.46-3.57 ( 6H, m), 4.02 (3H, s), 6.52 (1H, d, J=5.2 Hz), 6.58 (1H, t, J=5.2 Hz), 7.02- 7.07 (1H, m), 7.30 (1H, dd , J=2.4 Hz, J=11.6 Hz), 7.51 (1H, s), 8.21 (1H, t, J=9.2 Hz), 8.31-8.35 (1H, m), 8.44 (1H, t, J=5.2 Hz ), 8.61 (1H, s), 8.65 (1H, d, J = 5.2 Hz). Example 678 4-(4-(3-ethylureido)-3-carbazone)-7-methylargon-4-phenyl-6-acid (2-cyanoethyl)guanamine _ 634 In the same manner, 4-(4-(3-ethylureido)-3-fluorophenoxy)-7-methoxyquinolin-6-carboxylic acid (40 mg) was obtained as cyanoethylamine. Treatment with tri-ethylamine and benzotriazol-1-yloxyglycol (dimethylamino) hexafluorophosphate gave the title compound (29 mg) as a solid. iH-NMR spectrum (DMSO-d6) 5 (ppm): 1·05 (3H, t, J = 7.2 Hz), 2.78 (2H, t, J = 6.4 Hz), 3.07-3.15 (2H, m), 3.52 -3.58 (2H, m), 4.01 (3H, s), 6.52 (1H, d, J=5.2 Hz), 6.56-6.61 (1H, m), 7.02- 7.07 (1H, m), 7.30 (1H, dd , J=2.4 Hz, J=11.6 Hz), 7.52 (1H, s), 8.21 (1H, t, J=9.2 Hz), 8.33 (1H, br s), 8.59 (1H, s), 8·65 ( 1H, d, J = 5.2 Hz), 8.72 (1H, t, J = 6 Hz). Example 679 1-(4-( 7-fluorenyl)-6-amino-4-phenyl-4-oxo-2-methylphenyl)-3-ethylurea 1 In the same manner as in Production Example 17, from 4 -(4-Amino-3-tolyloxy)-7- _-715 -_ This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

裝 訂Binding

k 1304061 A7 B7 五、發明説明（710 ) 芊氧基喹啉-6-甲腈（2 g)及氯碳酸苯酯，得到為固體之胺甲 酸酯（2.1 g).。繼而，以與實施例U同樣之方法，將胺甲酸 酯（1 g)於二甲基亞砜中，於室溫用乙胺處理，得到為固㈣ 之標題化合物（0.87 g)。 缸 j-NMR 光譜（DMSO-d6)5(Ppm): 1.57 (3H, t ’ Hz)， 2.20 (3H，s)，3.07-3.15 (2H，m), 5.43 (2H，s)，6.48j55 (2h m)，7.02 (1H，dd，J=2.8 Hz，J=8.8 Hz)，7.08 (1H h T ， Hz)，7·34-7·55 (5H，m)，7.68 (2H，s)，7.92 (1H，d，j=8 8 H 8·70 (1H，d，J=5.6 Hz)，8.74 (1H，s)。 Z)， 實施例680 E_(4_(6·氰至基峰啉-4-基氫）-2-甲芡其 以與製造例301-2同樣之方法，將' 喹啉-4-基氧）-2-甲苯基）-N，_乙脲（〇·8 g)於四氫呋喃中$氰 用鈀-碳脫芊基化，得到為固體之標題化合物（〇42幻。使 1H-NMR 光譜（DMSO-d6)5(ppm): 1·〇6 (3H，t，k 1304061 A7 B7 V. INSTRUCTION DESCRIPTION (710) Phenoxyquinolin-6-carbonitrile (2 g) and phenyl chlorocarbonate gave a solid urethane (2.1 g). Then, the title compound (0.87 g) was obtained as a solid (4). Cylinder j-NMR spectrum (DMSO-d6) 5 (Ppm): 1.57 (3H, t ' Hz), 2.20 (3H, s), 3.07-3.15 (2H, m), 5.43 (2H, s), 6.48j55 ( 2h m), 7.02 (1H, dd, J=2.8 Hz, J=8.8 Hz), 7.08 (1H h T , Hz), 7·34-7·55 (5H, m), 7.68 (2H, s), 7.92 (1H, d, j = 8 8 H 8·70 (1H, d, J = 5.6 Hz), 8.74 (1H, s). Z), Example 680 E_(4_(6·Cyanide to phenanthroline- 4-Hydroxy)-2-carboxamide In the same manner as in Production Example 301-2, 'quinolin-4-yloxy)-2-methylphenyl)-N,-ethylurea (〇·8 g) Dehydrogenation of the cyanide with palladium-carbon in tetrahydrofuran afforded the title compound as a solid (yield: </ br> </ br> </ br> </ br> </ br>

Hz) 2·20 (3H，s)，3.07-3.15 (2H，m)，6·37 (1H，d，J=5.2 ’ / z)，6.52 (1H，t，J=5.6 Hz)，7.01 (1H，dd，J=2.8 Hz, J=8.8 Hz) (1H，d，J=2.8 Hz)，7·35 (1H，s)，7·68 (1H，s)，7.93 (旧 〇8 J=8.8 Hz)，8·59 (1H，d，J=5.2 Hz)，8·61 (1H，s)。 ’ d’ 實施例681Hz) 2·20 (3H, s), 3.07-3.15 (2H, m), 6.37 (1H, d, J = 5.2 ' / z), 6.52 (1H, t, J = 5.6 Hz), 7.01 ( 1H, dd, J = 2.8 Hz, J = 8.8 Hz) (1H, d, J = 2.8 Hz), 7·35 (1H, s), 7.68 (1H, s), 7.93 (old 〇 8 J = 8.8 Hz), 8.59 (1H, d, J = 5.2 Hz), 8.61 (1H, s). 'd' Example 681

以與實施例7同樣之方法，從N-(4_(6_氰基_7•羥基喹π 4-基氧）-2-甲苯基）-Ν’-環丙基脲（41〇 mg)及4-溴乙基二&amp; 在、π氫 -716 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 A7 __ B7 五、發明説明（7n ) ~ ---- ~Ξ 吡啶-1-羧酸第三丁酯得到目的物後，再脫保護，得到為固 體之標題化合物（15 mg)。 1 H-NMR 光譜（DMSO-d6) 5 (ppm): 0.37-0.43 (2H，m) 〇 63 0·66(2Η，ιη)，1·44·1·56(2Η，πι)，1·92-1·98(2Η，ηι)，2ι1- 2·20 (1Η，m)，2.20 (3H”s)，2.51-2.58 (1Η，m)，2.85-2.94 (2Η， m), 3.15-3.45 (2H, m), 4.19 (2H, d, J=6.4 Hz), 6.51 (iH, d, J=5.2 Hz), 6.79 (1H, d, J=2.8 Hz), 7.04 (1H, dd, J=2.8 Hz, J=8.8 Hz), 7.10 (1H, d, J=2.8 Hz), 7.62 (1H, s), 7.64 (1H, s), 7.93 (1H, d, J=8.8 Hz), 8.71 (1H, d, J=5.2 Hz), 8.75 (1H, s) ° 實施例682 - N_-( 4-(6-氰基二7-(1-甲基-六氤毗啶-4-某甲氣某&gt;套啉-4-某 -:In the same manner as in Example 7, N-(4_(6-cyano-7)hydroxyquinoxa-4-yloxy)-2-methylphenyl)-indole-cyclopropyl urea (41 mg) and 4-Bromoethyldi-amp; π-hydrogen-716 - This paper scale applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 __ B7 V. Invention description (7n) ~ ---- ~ The title compound (15 mg) was obtained as a solid. 1 H-NMR spectrum (DMSO-d6) 5 (ppm): 0.37-0.43 (2H,m) 〇63 0·66(2Η,ιη),1·44·1·56(2Η,πι),1·92 -1·98(2Η, ηι), 2ι1- 2·20 (1Η, m), 2.20 (3H”s), 2.51-2.58 (1Η, m), 2.85-2.94 (2Η, m), 3.15-3.45 ( 2H, m), 4.19 (2H, d, J=6.4 Hz), 6.51 (iH, d, J=5.2 Hz), 6.79 (1H, d, J=2.8 Hz), 7.04 (1H, dd, J=2.8 Hz, J=8.8 Hz), 7.10 (1H, d, J=2.8 Hz), 7.62 (1H, s), 7.64 (1H, s), 7.93 (1H, d, J=8.8 Hz), 8.71 (1H, d, J = 5.2 Hz), 8.75 (1H, s) ° Example 682 - N_-(4-(6-Cyanobis 7-(1-methyl-hexa-pyridin-4-one) ; Phytosporin-4-some-:

C 氣）-2-甲茉基）-N’-環丙某胧 - 分 以與實施例670同樣之方法，從N-( 4-(6-氰基-7-(六氫吡 啶-4-基甲氧基）喹啉-4-基氧）-2-甲苯基）-Ν’-環丙基脲（1〇 mg)，得到為固體之標題化合物（3 mg)。 iH-NMR 光譜（〇1^3〇-(16)5(??111):0.38-0.44 (211，111)，0.61-0.67 (2H, m), 1.38-1.50 (2H, m), 1.78-1.85 (2H, m), 2.04-2.13 (1H，m)，2.20 (3H，s)，2.26 (3H，br s)，2·48-2·58 (1H， m), 2.84-2.99 (2H, m)5 3.04-3.54 (2H, m), 4.15 (2H, d, J=6 Hz), 6.50 (1H, d, J=5.2 Hz), 6.82 (1H, d, J=2.8 Hz), 7.04 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.10 (1H, d, J=2.4 Hz), 7.58 (1H, s), 7.66 (1H,^)7 7.93 (1H, d, J=8.8 Hz), 8.71 (1H, d, 1=5.2 Hz), 8·73 (1H，s)。 -717 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 B7 五、發明説明（712) 二 .三 實施例683 N-( 4-(6-氰基-7-(六氫吡啶-4-基甲氣基V套啉-4-基氣）-2-甲笨基）-N’-乙脲 以與實施例7同樣之方法，從N-(4-(6-氰基-7-羥基喹啉-4-基氧）-2-甲苯基）-Nf-乙脲（410 mg)及4-溴乙基-六氫吡 啶-1-羧酸第三丁酯得到目的物後，再脫保護，得到為固體 之標題化合物（15 mg)。 iH-NMR 光譜（DMSO-d6)5(ppm): 1·06 (3H，t，J=7.2 Hz)， 1.44-1.57 (2H，m)，1.93-1.99 (2H，m)，2.11-2.20 (1H，m)， 2.20 (3H, s), 2.88-2.98 (2H, m), 3.07-3.14 (2H, m), 3.15-3.45 (2H, m), 4.19 (2H, d, J=6 Hz), 6.51 (1H5 d, J=5.2 Hz), 6.57 (1H, t, J=5.6 Hz), 7.02 (1H, dd, J=2.4 Hz, J=8.8 Hz),-： 7.09 (1H, d, J=2.4 Hz), 7.62 (1H, s), 7.73 (1H, s), 7.94 (1H, d，J=8.8 Hz)，8.71 (1H，d，J=5.2 Hz)，8·74 (1H，s)。 實施例684 N- (4- ( 6-氰基-7- Π ·甲基-六獻外I:淀-4-基甲氣基）4淋-4-基 氣）-2-甲笨基）-N、乙某服 以與實施例670同樣之方法，從N-(4-(6-氰基-7-(六氫吡 啶-4-基甲氧基）喹啉-4-基氧）-2-甲苯基）-ίΤ-乙脲（15 mg)，得到為固體之標題化合物（5 mg)。 ^-NMR 光譜（DMSO-d6)5(ppm): 1·06 (3H，t，J=7.2 Hz)， 1.38-1.51 (2H，m)，1.78-1.86 (2H，m)，2.07-2.18 (1H，m)， 2.20 (3H^s&gt;v 2.28 (3H, br s), 2.89-2.97 (2H, m), 3.07-3.15 — (2H, m), 3.15-3.41 (2H, m), 4.15 (2H, d, J=6 Hz), 6.50 (1H, -718 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐）C gas)-2-methylmethyl)-N'-cyclopropanol--in the same manner as in Example 670, from N-(4-(6-cyano-7-(hexahydropyridine)-4- Methoxy)quinoline-4-yloxy)-2-methylphenyl)-indole-cyclopropylurea (1 mg) gave the title compound (3 mg). iH-NMR spectrum (〇1^3〇-(16)5(??111):0.38-0.44 (211,111), 0.61-0.67 (2H, m), 1.38-1.50 (2H, m), 1.78- 1.85 (2H, m), 2.04-2.13 (1H, m), 2.20 (3H, s), 2.26 (3H, br s), 2·48-2·58 (1H, m), 2.84-2.99 (2H, m)5 3.04-3.54 (2H, m), 4.15 (2H, d, J=6 Hz), 6.50 (1H, d, J=5.2 Hz), 6.82 (1H, d, J=2.8 Hz), 7.04 ( 1H, dd, J=2.4 Hz, J=8.8 Hz), 7.10 (1H, d, J=2.4 Hz), 7.58 (1H, s), 7.66 (1H,^)7 7.93 (1H, d, J=8.8 Hz), 8.71 (1H, d, 1=5.2 Hz), 8·73 (1H, s) -717 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) 1304061 A7 B7 V. INSTRUCTIONS INSTRUCTIONS (712) II. III. Example 683 N-(4-(6-Cyano-7-(hexahydropyridin-4-ylmethyl)V-carboxolin-4-yl gas)-2-A -N'-ethylurea in the same manner as in Example 7, from N-(4-(6-cyano-7-hydroxyquinolin-4-yloxy)-2-methylphenyl)-Nf- Ethyl urea (410 mg) and 4-bromoethyl-hexahydropyridine-l-carboxylic acid tert-butyl ester gave the title compound (m.p. DMSO-d6) 5 (ppm): 1·06 (3H, t, J = 7.2 Hz), 1. 44-1.57 (2H,m),1.93-1.99 (2H,m),2.11-2.20 (1H,m), 2.20 (3H, s), 2.88-2.98 (2H, m), 3.07-3.14 (2H, m ), 3.15-3.45 (2H, m), 4.19 (2H, d, J=6 Hz), 6.51 (1H5 d, J=5.2 Hz), 6.57 (1H, t, J=5.6 Hz), 7.02 (1H, Dd, J=2.4 Hz, J=8.8 Hz), -: 7.09 (1H, d, J=2.4 Hz), 7.62 (1H, s), 7.73 (1H, s), 7.94 (1H, d, J=8.8 Hz), 8.71 (1H, d, J = 5.2 Hz), 8.74 (1H, s). Example 684 N-(4-(6-Cyano-7- Π-methyl-hexa-exo I: ylide-4-ylmethyl) 4 lysyl-4-yl)-2-methylphenyl) -N, B, in the same manner as in Example 670, from N-(4-(6-cyano-7-(hexahydropyridin-4-ylmethoxy)quinolin-4-yloxy)- 2-Tolyl)- hydrazine-ethylurea (15 mg) gave the title compound (5 mg). ^-NMR spectrum (DMSO-d6) 5 (ppm): 1·06 (3H, t, J = 7.2 Hz), 1.38-1.51 (2H, m), 1.78-1.86 (2H, m), 2.07-2.18 ( 1H,m), 2.20 (3H^s&gt;v 2.28 (3H, br s), 2.89-2.97 (2H, m), 3.07-3.15 — (2H, m), 3.15-3.41 (2H, m), 4.15 ( 2H, d, J=6 Hz), 6.50 (1H, -718 - This paper size applies to Chinese National Standard (CNS) A4 size (210 x 297 mm)

訂Order

線 1304061 A7 B7 五、發明説明（713 ) d, J=5.2 Hz), 6.58 (1H, t, J=5.6 Hz), 7.03 (1H, dd5 J=2.8 Hz, J=8.8 Hz)，7·09 (1H，d, J=2.4 Hz), 7·58 (1H，s)，7.73 (1H，s)， 7.94 (1H，d，J==8.8 Hz)，8·79 (1H，d，J=5.2 Hz)，8 73 (ih， s) 〇 實施例697 M3-氣-4-(((乙胺基）羰基）胺某）茉氣某）-7- 基.6_皮 琳羧酸甲酯 將N-(2-氯-4-(7-甲氧基-6-甲氧羰基-4-喹啉基）氧苯基） 胺甲酸苯g旨（1.92 mg，4.00 mmol)，及2M乙胺（四氣咬喃溶 液）（4 ml)，於二甲基甲醯胺中，於室溫攪拌30分鐘。將反 應液分溶於乙酸乙酯及水中，有機層用水及飽和食鹽水洗 淨，用無水硫酸鎂乾燥，遽除乾燥劑，以及將濾液減麼餾 去。將得到之粗生成物懸浮於乙酸乙酯中，再將其以己烷 稀釋，濾取結晶及用己烷洗淨後，藉由通風乾燥，得到為 白色結晶之標題化合物（1.60 g，3.72 mmol，93%)。 h-NMR 光譜（DMSO-d6) 5(ppm)·· 1·09 (3H，t，J=7.4 Hz), 3.15 (2H, m), 3.87 (3H, s), 3.99 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.01 (1H, t, J=5.4 Hz), 7.25 (1H, dd, J=2.8, 9.0 Hz), 7.50 (1H, d, J=2.8 Hz), 7.54 (1H, s)5 8.08 (1H, s), 8.28 (1H, d，J=9.0 Hz)，8·58 (1H，s)，8·69 (1H，d，J=5.2 Hz) 〇 實施例698 4-(3-氯-4-(“乙胺基）羰基）胺某）苯氣基）-7-甲氡某-6-4 啉羧酸 於4-(3-氯-4-(((乙胺基）羰基）胺基）苯氧基）-7-甲氧基- -719 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（714 ) 6 -υ奎琳竣酸甲酉旨（150 g，3.49 mmol)中添加甲醇（14 ml)及2 當量濃度氫氧化鈉水溶液（7 ml)，並於60°C攪拌90分鐘。 將反應液放冷至室溫，添加2當量濃度鹽酸中和後，餾去甲 醇，滤取析出之白色結晶，充分水洗後，於60°C乾燥，得 到標題化合物（1.36 g，3.27 mmol，94%)。 iH-NMR 光譜（DMSO-d6) 5 (ppm): 1·09 (3H，t，J=7.4 Hz)， 3.15 (2H，m)，3·98 (3H，s)，6·53 (1H，d，J=5.0 Hz)，7·〇〇 (ih， t，J=5.4 Hz)，7.25 (1H，dd，J=2.8, 9.0 Hz)，7.48-7.53 (2H，m)， 8·08 (1H，s)，8·27 (1H，d，J=9.0 Hz)，8·54 (1H，s)，8·68 (1H， d，J=5.0 Hz)，13.12 (1H，br s)。 實施例699 基-4-(3-氯-4-((〔乙胺基）羰某）胺某）笨氫某 基-6-喹淋#醯胺 — 將4-(3-氣-4-(((乙胺基）羰基）胺基）苯氧基甲氧基_ 6-喹啉羧酸（1〇4 mg，0.250 mmol)溶於二甲基甲醯胺（3 ml) 中，於室溫依序添加40%甲胺-曱醇溶液（o.ioo ml)、三乙 胺（0.250 ml)及（1H-1，2,3-苯并三唑-1-基氧）（三（二甲胺基）） 鱗六氟磷酸鹽（221 mg，0.500 mmol)後，攪拌15小時。將 反應液分溶於乙酸乙酯及水中，有機層用水及飽和食鹽水 洗淨，用無水硫酸鎂乾燥。餾去溶媒後，懸浮於乙酸乙酯 中，再將其以己烷稀釋，濾取結晶後，藉由通風乾燥，得 到為白色結晶之標題化合物（79.0 g，〇· 184 mmol，74%) iH-NMR 光-譜（DMSO-d6)5(ppm): 1·〇8 (3H，t，J=7.4 Hz), 2.85 (3H, d, J=4.2 Hz), 3.15 (2H, m), 4.02 (3H, s), 6.53 (1H, -720 - l紙張尺度適财® S家標if (CNS) A4規格(210 X 297公爱)~： -----Line 1304061 A7 B7 V. Description of invention (713) d, J=5.2 Hz), 6.58 (1H, t, J=5.6 Hz), 7.03 (1H, dd5 J=2.8 Hz, J=8.8 Hz), 7.09 (1H,d, J=2.4 Hz), 7·58 (1H,s), 7.73 (1H,s), 7.94 (1H,d,J==8.8 Hz),8·79 (1H,d,J= 5.2 Hz), 8 73 (ih, s) 〇 Example 697 M3-gas-4-(((ethylamino)carbonyl)amine)))))))) N-(2-Chloro-4-(7-methoxy-6-methoxycarbonyl-4-quinolinyl)oxyphenyl) carbamic acid benzene g (1.92 mg, 4.00 mmol), and 2M ethylamine (Four gas urethane solution) (4 ml), stirred in dimethylformamide at room temperature for 30 minutes. The reaction solution was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated, and evaporated. The obtained crude product was suspended in ethyl acetate. EtOAc (EtOAc m. , 93%). H-NMR spectrum (DMSO-d6) 5 (ppm)··1·09 (3H, t, J=7.4 Hz), 3.15 (2H, m), 3.87 (3H, s), 3.99 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.01 (1H, t, J=5.4 Hz), 7.25 (1H, dd, J=2.8, 9.0 Hz), 7.50 (1H, d, J=2.8 Hz), 7.54 (1H, s)5 8.08 (1H, s), 8.28 (1H, d, J=9.0 Hz), 8·58 (1H, s), 8.69 (1H, d, J = 5.2 Hz) 〇Implementation Example 698 4-(3-Chloro-4-("ethylamino)carbonyl)amine a)phenylene)-7-carbamyl-6-4 carboxylic acid in 4-(3-chloro-4-( ((ethylamino)carbonyl)amino)phenoxy)-7-methoxy- -719 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention (714) 6 - υ υ 竣 竣 ( 150 150 (150 g, 3.49 mmol) was added methanol (14 ml) and a 2 N aqueous solution of sodium hydroxide (7 ml), and stirred at 60 ° C for 90 minutes. The reaction mixture was cooled to room temperature, and then added with aq. EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH %). iH-NMR spectrum (DMSO-d6) 5 (ppm): 1·09 (3H, t, J =7.4 Hz), 3.15 (2H,m),3·98 (3H,s),6·53 (1H,d,J=5.0 Hz),7·〇〇(ih, t,J=5.4 Hz), 7.25 (1H, dd, J=2.8, 9.0 Hz), 7.48-7.53 (2H, m), 8·08 (1H, s), 8·27 (1H, d, J=9.0 Hz), 8.54 ( 1H, s), 8.68 (1H, d, J = 5.0 Hz), 13.12 (1H, br s). Example 699 -4-(3-chloro-4-((ethylamino)carbonyl) Amine-hydrogenyl-6-quinolin #醯amine - 4-(3-carb-4-((ethylamino)carbonyl)amino)phenoxymethoxy-6-quinoline The carboxylic acid (1〇4 mg, 0.250 mmol) was dissolved in dimethylformamide (3 ml), and 40% methylamine-nonanol solution (o.ioo ml) and triethylamine (s) were added sequentially at room temperature. 0.250 ml) and (1H-1,2,3-benzotriazol-1-yloxy)(tris(dimethylamino))sodium hexafluorophosphate (221 mg, 0.500 mmol) were stirred for 15 hours. The reaction mixture was dissolved in ethyl acetate and water. After distilling off the solvent, the residue was taken from ethyl acetate. EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -NMR photo-spectrum (DMSO-d6) 5 (ppm): 1·〇8 (3H, t, J=7.4 Hz), 2.85 (3H, d, J=4.2 Hz), 3.15 (2H, m), 4.02 (3H, s), 6.53 (1H, -720 - l paper scale suitable for money® S standard if (CNS) A4 specification (210 X 297 public)~: -----

裝 訂Binding

1304061 A7 ______B7_ 五、發明説明（715 ) 二 d，J=5.2 Hz)，7.00 (1H，t，J=5.2 Ηζ)，7·22 (1H，dd，J=2.8, 9.21304061 A7 ______B7_ V. Description of invention (715) 2 d, J=5.2 Hz), 7.00 (1H, t, J=5.2 Ηζ), 7·22 (1H, dd, J=2.8, 9.2

Hz), 7.47 (1H, d, J=2.8 Hz), 7.52 (1H, s), 8.07 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.36 (1H, q, J=4.2 Hz), 8.59 (1H, s), 8.67 (1H，d，J=5.2 Hz) 〇 實施例700 ^•乙基-4-(3-氰.：：1二(（（乙胺某）羰基）胺基）笨氣某17_甲氧 基-6-4：淋#醯脖 藉由與貫施例699同樣之方法，從4-( 3-氯·4·(((乙胺基） 羰基）胺基）苯氧基)_7_甲氧基喹啉羧酸（1〇4 mg , 〇 25〇 mmol)及2·0Μ乙胺（四氫吱喃溶液），得到為白色結晶之標 題化合物（90.0 mg，0.203 mmo 卜 81%)。 一 W-NMR 光譜（DMSO-d6)5(ppm): 1·09 (3H，t，J=7.4 Hz)，乂: 1.15 (3H, t, J=7.2 Hz), 3.15 (2H, m), 3.28-3.38 (2H, m), 4.02 &quot; (3H, s), 6.53 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=5.4 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.51 (1H, s), 8.07 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.40 (1H, t, J=5.4 Hz), 8·54 (1H，s)，8·66 (1H，d，J=5.2 Hz)。 實施例701 Μ.·環丙基氣_K((乙胺基）羰基）胺某）苽氫甚）_7·甲 氧基-6- 4：淋#酿胺 藉由與實施例699同樣之方法，從4-(3-氯-4-(((乙胺基） 羰基）胺基）木氧基）-7-甲氧基-6-ρ奎琳竣酸（1〇4 mg，0.250 mmol)及環呙胺’得到為白色結晶之標題化合物（〇 mg， 〇· 1 82 mmol，73%)。 ___ - 721 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 _____ 五、發明説明（716 ) 一 1H-NMR光譜（DMSO-d6)5(ppm): 0.58 (2H, m)，0·71 (2H，m)， 1.08 (3H, t,.J=7.4 Hz), 2.87 (1H, m), 3.14 (2H, m), 3.99 (3H, s), 6.53 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=4.8 Hz), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.49 (1H, s), 8.07 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.34 (1H, d, J=4.0 Hz), 8.42 (1H，s)，8·66 (1H，d，J=5.2 Hz)。 實施例702 N 6 -甲乳基- 4- (3 -氣- 4- (((乙胺基）藥基）胺基）笨氣幕）-7-甲 氧基-6-4成淼S蒸胺 藉由與實施例699同樣之方法，從4-(3-氯-4-(((乙胺基） 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（104 mg，0.250 mmol)及甲氧基胺鹽酸鹽，得到為白色結晶之標題化合物 (52.0 mg，〇·117 mmol，47%) 〇 一 W-NMR 光譜（DMSO-d6) 5 (ppm): 1·〇9 (3H，t，J=7.4 Hz)， 3.15 (2H, m), 3.75 (3H, s), 4.00 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=5.4 Hz), 7.23 (1H, dd, 1=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 8.07 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.43 (1H, s), 8.67 (1H, d, J=5.2 Hz), 11.45 (1H, s) ° 實施例703 泌二,(2-甲氧乙基氣乙基）蕤某）基）苯氧 基）-7-甲氣基-6 -口奎?林為酿胺 藉由與實灰例699同樣之方法，從4-(3-氯-4-(((乙胺基）— 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（1〇4 mg , 〇 25〇 -722 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7Hz), 7.47 (1H, d, J=2.8 Hz), 7.52 (1H, s), 8.07 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.36 (1H, q, J=4.2 Hz), 8.59 (1H, s), 8.67 (1H, d, J = 5.2 Hz) 〇 Example 700 ^•ethyl-4-(3-cyano.::1 bis((ethylamine)carbonyl) Amino) stupid 17-methoxy-6-4: leaching from the 4-(3-chloro-4-((ethylamino)carbonyl) group by the same method as in Example 699 Amino)phenoxy)-7-methoxyquinolinecarboxylic acid (1,4 mg, 〇25 〇mmol) and EtOAc (EtOAc: EtOAc) Mg, 0.203 mmo, 81%). One W-NMR spectrum (DMSO-d6) 5 (ppm): 1·09 (3H, t, J = 7.4 Hz), 乂: 1.15 (3H, t, J = 7.2 Hz ), 3.15 (2H, m), 3.28-3.38 (2H, m), 4.02 &quot; (3H, s), 6.53 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=5.4 Hz) , 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.51 (1H, s), 8.07 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.40 (1H, t, J = 5.4 Hz), 8·54 (1H, s), 8.66 (1H, d, J = 5.2 Hz). Example 701 Μ.·Cyclopropyl gas _K ((ethylamino)carbonyl)amine)) hydrazine hydrogen) _7·methoxy-6 - 4: leaching of the amine from 4-(3-chloro-4-((ethylamino)carbonyl))amino)phenyloxy)-7-methoxy- 6-ρ quinine decanoic acid (1 〇 4 mg, 0.250 mmol) and cyclodecylamine afforded the title compound as a white crystals ( 〇mg, 〇·1 82 mmol, 73%). ___ - 721 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 _____ V. Description of invention (716) 1H-NMR spectrum (DMSO-d6) 5 (ppm): 0.58 ( 2H, m),0·71 (2H,m), 1.08 (3H, t,.J=7.4 Hz), 2.87 (1H, m), 3.14 (2H, m), 3.99 (3H, s), 6.53 ( 1H, d, J=5.2 Hz), 7.00 (1H, t, J=4.8 Hz), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.49 ( 1H, s), 8.07 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.34 (1H, d, J=4.0 Hz), 8.42 (1H, s), 8.66 (1H, d , J = 5.2 Hz). Example 702 N 6 -methyllacyl 4-(3- gas-4-(((ethylamino)))))))) Amine from 4-(3-chloro-4-((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid by the same procedure as Example 699 The title compound (52.0 mg, 117·117 mmol, 47%) was obtained as white crystals (m.p.). : 1·〇9 (3H,t,J=7.4 Hz), 3.15 (2H, m), 3.75 (3H, s), 4.00 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=5.4 Hz), 7.23 (1H, dd, 1=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 8.07 (1H, s) , 8.27 (1H, d, J=9.2 Hz), 8.43 (1H, s), 8.67 (1H, d, J=5.2 Hz), 11.45 (1H, s) ° Example 703 Bis, (2-methoxy Ethyl Ethyl Ethyl) Ethyl)Phenyloxy)-7-Methane-6-Methyl-N-Lin was made from 4-(3-chloro-) by the same method as ash 699. 4-(((Ethylamino)-carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (1〇4 mg , 〇25〇-722 - This paper size applies to China Standard (CNS) A4 size (210 X 297 mm) 1304061 A7 B7

mmol)及2_甲氧基乙胺，得到為白色結晶之標題化合物 (71.0 mg，Q.150 mmol，60%)。 lH-NMR 光譜（DMSO-d6)5(Ppm): 1〇8 3.15(2H，m)，3.3G(3H，S)，3.47_3.52(4H(，m)，U3(3Hj 6.54 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=5.4 Hz), 7.23 (1H, dd, J=2.8,9.2Hz)，7.48(1H，d，J=2.8Hz)，7.53(1H，s)，8.07 〇H，s)，8.27 (1H，d，J=9.2 Hz)，8 44 (m，叭 8 62 (m，”， 8.67 (1H, d, J=5.2 Hz) 〇 實施例704 &quot; 氟乙茱）-4-(3-氯-4-((丄_^£^^幾某）胺某）苽氫某 Z-甲氧基-6- p奎淋複酿胺 藉由與實施例699同樣之方法，從4_(3_氯4-(((乙胺基） 談基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（1〇4 mg，〇·250 mmol)及2-氟乙胺鹽酸鹽，得到為白色緒晶之標題化合物 (80.0 mg，0.174 mmol，69%)。 iH-NMR 光譜（DMSO-d6)5(ppm): 1.08 (3H，t，J=7.4 Hz)， 3.15 (2H，m)，3·59 (1H，m)，3.67 (1H，m)，4.03 (3H，s)，4.51 (1H，m)，4·63 (1H，m)，6.54 (1H，d，J=5.2 Hz)，7·00 (1H，t， J=5.4 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.53 (1H, s), 8.07 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.58-8·62 (2H，m)，8·67 (1H，d，J=5.2 Hz)。 實施例705 N6-((2Ry¾ri,-2-呋喃甲基）_4-r3-氳-4-(((乙胺基）羰基）胺 基）笨氫某）-7-甲氣基-6-裱啉游醯脍 -723 - _ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）The title compound (71.0 mg, Q. 150 mmol, 60%) was obtained as white crystal. lH-NMR spectrum (DMSO-d6) 5 (Ppm): 1〇8 3.15 (2H, m), 3.3G (3H, S), 3.47_3.52 (4H (, m), U3 (3Hj 6.54 (1H, d, J = 5.2 Hz), 7.00 (1H, t, J = 5.4 Hz), 7.23 (1H, dd, J = 2.8, 9.2 Hz), 7.48 (1H, d, J = 2.8 Hz), 7.53 (1H, s), 8.07 〇H, s), 8.27 (1H, d, J = 9.2 Hz), 8 44 (m, 叭 8 62 (m,", 8.67 (1H, d, J = 5.2 Hz) 〇 Example 704 &quot; fluoroacetamidine)-4-(3-chloro-4-((丄_^£^^)) amine 苽 hydrogen Z-methoxy-6-p-quinone complex amine by Example 699, in the same manner, from 4-(3-chloro-4-((ethylamino) yl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (1 〇 4 mg , 〇·250 mmol) and 2-fluoroethylamine hydrochloride gave the title compound (80.0 mg, 0.174 mmol, 69%) as white crystals. iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.08 (3H,t,J=7.4 Hz), 3.15 (2H,m),3·59 (1H,m), 3.67 (1H,m),4.03 (3H,s),4.51 (1H,m),4· 63 (1H,m), 6.54 (1H,d,J=5.2 Hz), 7·00 (1H,t, J=5.4 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H , d, J=2.8 Hz), 7.53 (1H, s), 8.07 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.58-8·62 (2H, m), 8.67 (1H, d, J = 5.2 Hz). Example 705 N6-((2Ry3⁄4ri,-2-furanmethyl)_4-r3-氲-4-( ((ethylamino)carbonyl)amino)hydrogen)-7-methyl-6-porphyrin-723 - _ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 PCT)

裝 訂Binding

線 1304061 A7 B7 五、發明説明（718) Γ rz: 藉由與實施例699同樣之方法，從4-(3-氣-4-(((乙胺基） m基）胺基）.苯氧基）-7-甲氧基-6-喳啉羧酸（104 mg, 〇 25() mmol)及R-四氫糠胺，得到為白色粉末之標題化合物（99 〇 mg，0.198 mmol，79%) 0 W-NMR 光譜（DMSO-d6)5(ppm): 1.08 (3H，t，j=74 HZ)， 1·62 (IH，m)，1.80-2.00 (3H，m)，3.15 (2H，m)，3.40 (2H，m)， 3.66 (1H，dd，J=3.6, 14.0 Hz)，3·81 (1H，dd，J=4.0, 14.0 Hz)， 3.99 (1H, m), 4.04 (3H, s), 6.54 (1H, d, J==5.2 Hz), 7.〇〇 (1H5 t, J-5.4 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.54 (1H, s), 8.07 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8.43 (1H，t，J=5.6 Hz)，8·61 (1H，s)，8·67 (1H，d，J=5.2 Hz)。- 實施例706 '·: K(2s)四氡士咬喃甲基葚、避早'音 基）表乳某）-7-甲氣基- 6-4 〃株幾酿胺 藉由與實施例699同樣之方法，從4-(3-氯-4-(((乙胺基） 羰基）胺基）苯氧基）-7-甲氧基喹啉羧酸（1〇4 mg，〇25() mmol)及S-四氫糠胺，得到為白色粉末之標題化合物（87 〇 mg，0.174 mmol，70%)。 實施例707 乙氧乙某V-4-(V氰二七（（（乙胺篡、璣某）胺某、茇氫 羞：.）-7-甲氧基-6_ g奎淋#疏fe 藉由與實施例699同樣之方法，從4-(3_氯-4-(((乙胺基) 羰基）胺基:）苯氧基）-7-甲氧基_6·喹啉羧酸（1〇4 mg，0.250 mmol)及2-乙氧基乙胺，得到為白色粉末之標題化合物（112 ____ - 724 嶋 本紙張尺度適用巾a S家標準(CNS) A4規格(21G X 297公 1304061 A7 B7 五、發明説明（719) 二 .*5 mg，0.239 mmol，95%) 〇 !H-NMR 光譜（DMSO-d6)5(ppm): 1.08 (3H，t，J=7.4 Hz)， 1.16 (3H, t, J=6.8 Hz), 3.15 (2H, m)3 3.45-3.56 (6H, m), 4.03 (3H，s)，6.54 (1H，d，J=5.2 Hz)，7.01 (1H，m)，7·23 (1H，dd， J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.54 (1H, s), 8.08 (1H, s), 8.27 (1H, dd, J=2.8, 9.2 Hz), 8.46 (1H, m), 8.64 (1H, d，J=2.0 Hz)，8·68 (1H，d，J=5.2 Hz) 〇 實施例708 M-...異丁氧基-4 - ( 3 -氯-4 “ (7乙胺基）蕤基）胺基）茉氳篡）-7-甲氧基-6-4啉羧醯胺 藉由與實施例699同樣之方法，從4-(3-氯-4-(((乙胺基_) 羰基）胺基）苯氧基）-7-甲氧基-6-喹啉羧酸（104 mg，0.250 _ mmol)及異丁氧基胺鹽酸鹽，得到為白色粉末之標題北合落一 物（64.0 mg，0.131 mmol，53%)。 W-NMR 光譜（DMSO-d6)5(ppm): 0.95 (6H，d，J=6.8 Hz)， 1.08 (3H, t5 J=7.4 Hz), 1.97 (1H, m), 3.15 (2H, m), 3.71 (2H, d, J=6.8 Hz), 3.99 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.00 (1H5 m), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.50 (1H, s), 8.08 (1H, s), 8.27 (1H, dd, J=2.8, 9.2 Hz), 8.36 (1H，s)，8·67 (1H, d, J=5.2 Hz), 11·36 (1H，br s)。 實施例709 ' 也二乙基-4-(3-氣-4-((丄甲胺基）羱甚&gt;|咹墓）苯氣基）_7_((21^ 二？-二乙腹基-2- :經基丙氧基）+ 〃林藉酿胺 - 在Ν6-乙基-4-(3-氯-4-(((甲胺基）羰基）胺基）苯氧基 -725 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公复）—-- 1304061 A7 B7 五、發明説明（720 ) 二 --Ξ #呈基-6-口奎淋叛酿胺（80.0 mg，0· 193 mmol)中，添加4-甲 基-1-苯橫酸（2R)環氧乙烷-2-基甲酯（66 mg，0.290 mmol)、碳酸鉀（32 mg，0.231 mmol)及二甲基甲醯胺（2 ml)，並於60°C攪拌7小時。繼而添加二乙胺（1 ml)，進一 步於60 °C攪拌一整晚。將反應液分溶於乙酸乙酯-四氫呋喃 (1 : 1)及水中，有機層用水及飽和食鹽水洗淨，用無水硫 酸鈉乾燥。將溶媒餾去，付諸於矽凝膠管柱層析（溶出液為 乙酸乙酯：甲醇=95 : 5)，再將含有目的物之溶出份濃縮 後，濾取從乙酸乙酯-己烷（1 : 1)中析出之結晶，藉由通風 乾燥，得到為白色結晶之標題化合物（51.7 mg，0.095 mmol，49·3%)。 _ iH-NMR 光譜（DMSO-d6)5(ppm): 0·94 (6Η，t，J=7.2 Ηζ)，- · .. 1.16 (3Η, t, 1=1.2 Hz), 2.40-2.60 (6H, m), 2.66 (3H, d, J=4.8 Hz), 3.20-3.40 (2H, m), 3.98 (1H, m), 4.19 (1H, dd, J=5.2, 10.0 Hz), 4.31 (1H, dd, J=3.2, 10.0 Hz), 5.09 (1H, d, J=4.8 Hz), 6.51 (1H, d, J=5.2 Hz), 6.86 (1H, q, J=4.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.52 (1H, s), 8.10 (1H, s), 8.23 (1H, d, J=9.2 Hz), 8.54 (1H, m), 8.65 (1H5 d, J=5.2 Hz)，8.73 (1H，s)。 實施例710 N6-乙基-4-(3-氣-4-(((乙胺基）羰基）胺某）宏氣基2R)_ -3·二乙胺基-2-爽基丙氧基）-6-p奎〃株卷酿胺 藉由與.虞-施例7〇9同樣之方法，從N6-乙基-4-(3-氯-4- — (((乙胺基）羰基）胺基）苯氧基）-7-羥基-6-喹啉羧醯胺（78.0 -726 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 _B7 五、發明説明（721 ) mg，0.182 mmol)，得到為白色結晶之標題化合物（44.5 mg，0.080 mmol，43.8%) 0 iH-NMR 光譜（DMSO-d6)(5(ppm): 〇·94 (6H，t，J=7.2 Hz)， 1.06 (3H, t, J=7.2 Hz), 1.16 (3H, t, J=7.2 Hz), 2.40-2.60 (6H, m)，3.12 (2H，m)，3.20-3.40 (2H，m)，3·98 (1H，m)，4.22 (1H， dd, J=5.6, 9.6 Hz), 4.31 (1H, dd, J=3.2, 9.6 Hz), 5.08 (1H, d, J=4.4 Hz), 6.51 (1H, d, J=5.2 Hz), 6.98 (1H, m), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.52 (1H, s), 8.05 (1H，s)，8·25 (1H，d，J=9.2 Hz)，8.54 (1H，m)，8·65 (1H，d， J=5.2 Hz)，8·73 (1H，s)。 實施例711Line 1304061 A7 B7 V. INSTRUCTION DESCRIPTION (718) Γ rz: From 4-(3-ethane-4-(((ethylamino))))) phenyloxy) by the same method as Example 699 -7-methoxy-6-carbolinecarboxylic acid (104 mg, 〇25 () mmol) and R-tetrahydrofuramide afforded the title compound as a white powder (99 〇mg, 0.198 mmol, 79% 0 W-NMR spectrum (DMSO-d6) 5 (ppm): 1.08 (3H, t, j = 74 HZ), 1·62 (IH, m), 1.80-2.00 (3H, m), 3.15 (2H, m), 3.40 (2H, m), 3.66 (1H, dd, J=3.6, 14.0 Hz), 3·81 (1H, dd, J=4.0, 14.0 Hz), 3.99 (1H, m), 4.04 (3H , s), 6.54 (1H, d, J==5.2 Hz), 7.〇〇(1H5 t, J-5.4 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d , J=2.8 Hz), 7.54 (1H, s), 8.07 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8.43 (1H, t, J=5.6 Hz), 8.61 (1H , s), 8.67 (1H, d, J = 5.2 Hz). - Example 706 '·: K(2s) 氡 咬 咬 葚 葚 避 避 避 避 避 避 -7 -7 -7 -7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 699, in the same manner, from 4-(3-chloro-4-((ethylamino)carbonyl)amino)phenoxy)-7-methoxyquinolinecarboxylic acid (1〇4 mg, 〇25 ( The title compound (87 mg, 0.174 mmol, 70%) was obtained as white powder. Example 707 Ethoxyethylene V-4-(V cyanide hexahydrate (((ethylamine oxime, 玑)) amine, 茇 hydrogen shy:.)-7-methoxy-6_ g 奎淋# From the same procedure as in Example 699, 4-(3-chloro-4-((ethylamino)carbonyl)amino:)phenoxy)-7-methoxy-6-quinolinecarboxylic acid ( 1〇4 mg, 0.250 mmol) and 2-ethoxyethylamine give the title compound as a white powder (112 ____ - 724 嶋 paper scale applicable towel a S standard (CNS) A4 specification (21G X 297 public 1304061 A7 B7 V. Description of the invention (719) II.*5 mg, 0.239 mmol, 95%) 〇! H-NMR spectrum (DMSO-d6) 5 (ppm): 1.08 (3H, t, J = 7.4 Hz), 1.16 ( 3H, t, J=6.8 Hz), 3.15 (2H, m)3 3.45-3.56 (6H, m), 4.03 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.01 (1H, m ), 7·23 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.54 (1H, s), 8.08 (1H, s), 8.27 (1H, dd, J=2.8, 9.2 Hz), 8.46 (1H, m), 8.64 (1H, d, J=2.0 Hz), 8.68 (1H, d, J=5.2 Hz) 〇Example 708 M-... Butyloxy-4 - (3-chloro-4" (7-ethylamino) decyl) amino) molybdenum)-7-methoxy-6-4 carboxycarboxamide by and with Example 699, from 4-(3-chloro-4-((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (104 mg, 0.250 _ mmol) and isobutoxylamine hydrochloride gave the title titled as a white powder (64.0 mg, 0.131 mmol, 53%). W-NMR spectrum (DMSO-d6) 5 (ppm): 0.95 (6H,d,J=6.8 Hz), 1.08 (3H, t5 J=7.4 Hz), 1.97 (1H, m), 3.15 (2H, m), 3.71 (2H, d, J=6.8 Hz), 3.99 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.00 (1H5 m), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.50 (1H, s), 8.08 (1H, s), 8.27 (1H, dd, J=2.8, 9.2 Hz), 8.36 (1H, s), 8.67 (1H, d, J=5.2 Hz), 11 · 36 (1H, br s). Example 709 ' Also diethyl-4-(3-carb-4-((methylamino) 羱 & 咹 咹 咹 咹 咹 咹 ) ) ) ) ) ) _ _ _ - - - - - - - - - - - - - - - - - - - - - 2-:-Phenylpropoxy)+ Eucalyptus-Acrylamine-In 6-Ethyl-4-(3-chloro-4-(((methylamino)carbonyl))amino)phenoxy-725- Paper scale applicable to China National Standard (CNS) A4 specification (210 X 297) - 1304061 A7 B7 V. Description of invention (720) II--Ξ #呈基-6-口奎淋叛胺(80.0 mg , 0· 193 mmol), 4-methyl-1-phenylphosphonic acid (2R) oxiran-2-ylmethyl ester (66 mg, 0.290 mmol), potassium carbonate (32 mg, 0.231 mmol) and Dimethylformamide (2 ml) was stirred at 60 ° C for 7 hours, then diethylamine (1 ml) was added, and the mixture was further stirred at 60 ° C overnight. Tetrahydrofuran (1:1) and water, the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and applied to a gel column chromatography (eluent was ethyl acetate:methanol = 95 : 5), after concentrating the fraction containing the target, the crystals precipitated from ethyl acetate-hexane (1:1) were collected by filtration. The title compound (51.7 mg, 0.095 mmol, 49.3%) was obtained as white crystals. </i>iH-NMR spectrum (DMSO-d6) 5 (ppm): 0·94 (6 Η, t, J = 7.2 Ηζ), - · .. 1.16 (3Η, t, 1=1.2 Hz), 2.40-2.60 (6H, m), 2.66 (3H, d, J=4.8 Hz), 3.20-3.40 (2H, m), 3.98 (1H, m), 4.19 (1H, dd, J=5.2, 10.0 Hz), 4.31 (1H, dd, J=3.2, 10.0 Hz), 5.09 (1H, d, J=4.8 Hz), 6.51 (1H, d, J=5.2 Hz), 6.86 (1H, q, J=4.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.52 (1H, s), 8.10 (1H, s), 8.23 (1H, d, J = 9.2 Hz), 8.54 (1H, m), 8.65 (1H5 d, J = 5.2 Hz), 8.73 (1H, s). N6-ethyl-4-(3- gas-4-((ethylamino)carbonyl)amine)) Macromethane 2R)_3·diethylamino-2-sylpropoxy)-6 -p-quine- sulphate-derived amine from N6-ethyl-4-(3-chloro-4-(((ethylamino))carbonyl)) Phenoxy)-7-hydroxy-6-quinolinecarboxamide (78.0 -726 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304061 A7 _B7 V. Description of invention (721 ) mg, 0.182 mmol) The title compound (44.5 mg, 0.080 mmol, 43.8%) was obtained as white crystals. iH-NMR spectrum (DMSO-d6) (5 (ppm): 〇·94 (6H, t, J = 7.2 Hz), 1.06 (3H , t, J = 7.2 Hz), 1.16 (3H, t, J = 7.2 Hz), 2.40-2.60 (6H, m), 3.12 (2H, m), 3.20-3.40 (2H, m), 3·98 ( 1H,m), 4.22 (1H, dd, J=5.6, 9.6 Hz), 4.31 (1H, dd, J=3.2, 9.6 Hz), 5.08 (1H, d, J=4.4 Hz), 6.51 (1H, d , J=5.2 Hz), 6.98 (1H, m), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.52 (1H, s), 8.05 (1H , s), 8·25 (1H, d, J = 9.2 Hz), 8.54 (1H, m), 8.65 (1H, d, J = 5.2 Hz), 8.73 (1H, s). Example 711

Km-4-.(3-氯甲胺基）羰某）胺某）茉氣某 2- #至基-3 - (1 - ρ比哈淀基）丙氣基）-6- g♦淋致酿胺 — 在N6-乙基-4-(3-氣-4-(((甲胺基）羰基）胺基）苯氧基）_7· 輕基-6- 4琳幾醯胺（80·0 mg，0.193 mmol)中，添加4-甲 基-1-苯磺酸（2R)環氧乙烷-2-基甲酯（66 mg，0.290 mmol)、碳酸鉀（32 mg，0.231 mmol)及二甲基甲醯胺（2 ml)，並於60°C攪拌7小時。將反應液放冷至室溫後，添加 吡咯啶（0.5 ml)，然後攪捽一整晚。將反應液分溶於乙酸乙 酯-四氫呋喃（1 ·· 1)及水中，將有機層用水及飽和食鹽水洗 淨’用無水硫酸鋼乾燥。將溶媒館去，付諸於碎凝膠管柱 層析（溶出液為乙酸乙酯：甲醇=95 : 5)，再將含有目的物 之溶出份篇褊後，濾取從乙酸乙酯-己烷（1 : 1)中析出之結 晶，藉由通風乾燥，得到為白色結晶之標題化合物（54 8 ___ - 727 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（722 ) 二 .三 mg，0.101 mmol，52.4%) 〇 iH-NMR 光譜（DMSO-d6) 5 (ppm): 1.16 (3H, t, J=7.2 Hz), 1.67 (4H, m), 2.40-2.60 (5H, m), 2.65-2.71 (4H, m), 3.20-3_40 (2H，m)，4.05 (1H，m)，4·19 (1H，dd，J=6.0，10.0 Hz)， 4.32 (1H，dd，J=3.6，10.0 Hz)，5.18 (1H，d，J=4.4 Hz)，6.52 (1H，d，J=4.0 Hz)，6.86 (1H，q，J=4.8 Hz)，7·22 (1H，d，J=9.2 Hz)，7.47 (1H，s)，7·52 (1H，s)，8·10 (1H，s)，8.23 (lH，d， J=9.2 Hz), 8.53 (1H, m), 8.65 (1H, d, J=4.0 Hz), 8.71 (1H, s) ° 實施例712 N6-乙基-4-(3-氯-4-(((乙胺基）羰基）胺基）苯氣基）-7-((2R) -2-羥基-3-(1-吡咯啶基）丙氣基6〃奎啉羧醯胺 …' 藉由與實施例711同樣之方法，從N6-乙基-4-(3-氯~-4- :::r (((乙胺基）羰基）胺基）苯氧基）-7-羥基-6-喹啉羧醯胺（78·0 mg，0.182 mmol)，得到為白色結晶之標題化合物（47.3 mg，0.085 mmol，46.8%)。 光譜（DMSO-d6)5(ppm): 1·06 (3H，t，J=7.2 Hz)， 1·16 (3H，t，J=7.2 Hz)，1·67 (4H，m)，2.40-2.60 (5H，m)，2.68 (1H, dd5 J=6.4, 12.0 Hz), 3.12 (2H, m), 3.35 (2H, m), 4.05 (1H，m)，4·19 (1H，dd，J=6.4，10.0 Hz)，4.32 (1H，dd，J=3.6， 10.0 Hz)，5.18 (1H，d，J=4,8 Hz)，6.51 (1H，d，J=5.2 Hz)， 一 6.98 (1H, m), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz)，H(lH，s)，8·05 (1H，s)，8.25 (1H，d，J=9.2 Hz)， 一 8.53 (1H，m)，8·65 (1H，d，J=5.2 Hz)，8·71 (1H，s)。 -728 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（723 ) 實施例713 Ν-(4:···(.Ι§_-氰基-7-(((2R)-3-(二乙胺產丄_2_ 鞀丙某）氲 崦啉基）氧）苯某）-Ν ’ -(嘧唑-2 -某）Μ 將4-(4-胺苯氧基）-6-氰基-7-(((2R)-3-(二乙胺基）_2•羥 丙基）氧）喹啉（105 mg，0.25 83 mmol)溶於二甲基亞颯〇 ml) 中’添加（魂哇-2-基）胺甲酸苯醋（60 mg，0.2712 mmol), 於85°C下加熱攪拌40分鐘。放冷至室溫後，於反應液中加 水’用乙酸乙酯-四氫吱喃萃取，以飽和食鹽水洗淨，用無 水硫酸鈉乾燥。將餾去溶媒之殘餘物溶於丙酮中，用乙趟 稀釋’濾取析出之沉殿物，以乙醚洗淨後，藉由通風乾 燥，得到為淡黃色粉末之標題化合物（75 mg , 〇.14〇8 mmol，54.51%) 〇 iH-NMR 光譜（DMSO-d6) 5 (ppm): 〇·96 (6H，t，J=7.〇 ΉΖ)， 2.41-2.68 (6H，m)，3·96 (1H，m)，4·21 (1H，dd，J=5.2，10·〇Km-4-.(3-chloromethylamino)carbonyl)amine() a certain 2-# to base-3 - (1 - ρ thanhadyl)-propenyl)-6-g♦ Amine amine - in N6-ethyl-4-(3-carb-4-(((methylamino)carbonyl))amino)phenoxy)_7· light -6-6 linalamine (80·0 Add 4-methyl-1-benzenesulfonic acid (2R) oxirane-2-ylmethyl ester (66 mg, 0.290 mmol), potassium carbonate (32 mg, 0.231 mmol) and two in mg, 0.193 mmol) Methylformamide (2 ml) was stirred at 60 ° C for 7 hours. After allowing the reaction to cool to room temperature, pyrrolidine (0.5 ml) was added, followed by stirring overnight. The reaction mixture was dissolved in ethyl acetate-tetrahydrofuran (1··1) and water, and the organic layer was washed with water and saturated brine. The solvent was removed and subjected to crushing gel column chromatography (eluent was ethyl acetate:methanol = 95:5), and then the dissolution product containing the desired product was taken, and then filtered from ethyl acetate-hexane. The crystals precipitated from the alkane (1:1) are dried by air to give the title compound as white crystals (54 8 ___ - 727 - the paper size applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of the invention (722) 2. 3 mg, 0.101 mmol, 52.4%) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.16 (3H, t, J=7.2 Hz), 1.67 (4H , m), 2.40-2.60 (5H, m), 2.65-2.71 (4H, m), 3.20-3_40 (2H, m), 4.05 (1H, m), 4·19 (1H, dd, J=6.0, 10.0 Hz), 4.32 (1H, dd, J=3.6, 10.0 Hz), 5.18 (1H, d, J=4.4 Hz), 6.52 (1H, d, J=4.0 Hz), 6.86 (1H, q, J= 4.8 Hz), 7.22 (1H, d, J = 9.2 Hz), 7.47 (1H, s), 7·52 (1H, s), 8·10 (1H, s), 8.23 (lH, d, J = 9.2 Hz), 8.53 (1H, m), 8.65 (1H, d, J = 4.0 Hz), 8.71 (1H, s) ° Example 712 N6-ethyl-4-(3-chloro-4-(( (ethylamino)carbonyl)amino)phenylene)-7-((2R)-2-hydroxy-3-(1-pyrrole) Pyridyl)propenyl 6 quinoid carboxy guanamine ...' by the same procedure as in Example 711, from N6-ethyl-4-(3-chloro~-4-:::r ((ethylamine) Carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide (78·0 mg, 0.182 mmol) afforded the title compound (47.3 mg, 0.085 mmol, 46.8%) Spectrum (DMSO-d6) 5 (ppm): 1·06 (3H, t, J = 7.2 Hz), 1·16 (3H, t, J = 7.2 Hz), 1·67 (4H, m), 2.40 -2.60 (5H,m), 2.68 (1H, dd5 J=6.4, 12.0 Hz), 3.12 (2H, m), 3.35 (2H, m), 4.05 (1H, m), 4·19 (1H, dd, J=6.4,10.0 Hz), 4.32 (1H, dd, J=3.6, 10.0 Hz), 5.18 (1H, d, J=4, 8 Hz), 6.51 (1H, d, J=5.2 Hz), a 6.98 (1H, m), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), H(lH, s), 8·05 (1H, s), 8.25 ( 1H, d, J = 9.2 Hz), an 8.53 (1H, m), 8.65 (1H, d, J = 5.2 Hz), 8.71 (1H, s). -728 - This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Inventive Note (723) Example 713 Ν-(4:···(.Ι§_-Cyanide -7-(((2R)-3-(diethylamine 丄_2_ 鼗)) porphyrin) oxy) benzene)-Ν '-(pyrazole-2 - a) Μ 4 (4-Aminophenoxy)-6-cyano-7-((2R)-3-(diethylamino)_2•hydroxypropyl)oxy)quinoline (105 mg, 0.25 83 mmol) was dissolved In the dimethyl hydrazine ml), '(SOW-2-yl) hydroxyacetic acid benzene vinegar (60 mg, 0.2712 mmol) was stirred and stirred at 85 ° C for 40 minutes. After cooling to room temperature, water was added to the reaction mixture, which was extracted with ethyl acetate-tetrahydrofuran, washed with saturated brine and dried over anhydrous sodium sulfate. The residue of the solvent was dissolved in acetone and diluted with ethyl acetate. The precipitated material was collected by filtration, washed with diethyl ether, and then evaporated to give the title compound as a pale yellow powder (75 mg, 〇. 14〇8 mmol, 54.51%) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 〇·96 (6H, t, J=7.〇ΉΖ), 2.41-2.68 (6H, m), 3· 96 (1H,m),4·21 (1H,dd,J=5.2,10·〇

Hz), 4.31 (1H, dd, J=3.2, 10.0 Hz), 4.92 (1H, br s), 6.52 (1H, d, J=5.2 Hz), 7.10 (1H, d, J=3.6 Hz), 7.27 (2H, d, J=9.0 Hz), 7.37 (1H, d, J=3.6 Hz), 7.61 (1H? s), 7.63 (2H, d, J=9.0 Hz), 8·72 (1H，d, J=5.2 Hz)，8.76 (1H，S)，9.15 (1H，br s)。 起始物質係以下述方法合成。 製造例713-1 4 - ( 4 -胺表乳基）-6-氨基-7-趙基p杳成 使用從製造例5得到之7-苄氧基-6-氰基(4_硝苯氧基） 喹啉，依恶梨造例21之方法，將苄基脫保護得到之6-氰基-7-羥基-4-(4-硝苯氧基）喹啉（1·23 g , 4.00 mmol)，以製造 -729 - 本紙張尺度通用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（724 ) 例21同樣地將硝基還原，得到為黃褐色結晶之標題化合物 (0.864 g，3.1160 mmol，77.90%) 〇 ’H-NMR 光譜（CDCl3)(HPpm): 5.18 (2H，卜 s)，6 36 (ih，山 J=5.2 Hz), 6.65 (2H, d, J=8.4 Hz), 6.92 (2H, d, J=8.4 Hz), 7.38 (1H，s)，8.60 (1H，d，J=5.2 Hz)，8·62 (1H s)。 製造树713-2 4·-.(·4-胺苯氧基）-6-氰基^基）甲氫其為 企 將4-(4-胺苯氧基）-6-氰基-7-幾基4：琳（277 mg , 1.00 mmol)溶於二甲基甲醯胺（3.0 ml)中，在室溫下添加氫化鋼 (40 mg，1.00 mmol，60%於油中）且攪拌。於其中添加4甲 基-1-苯磺酸（2R)-環氧乙烷-2-基甲酯（228 mg，1.00 /: mmol)，在60°C下加熱攪拌5小時。放冷至室溫後，將反應 液分溶於乙酸乙酯及水中。將有機層以飽和食鹽水洗淨， 用無水硫酸鈉乾燥，藉由將溶媒餾去，得到為黃褐色固體 之標題化合物（322 mg，0.97 mmol，97%)。 iH-NMR 光譜（DMSO-d6)6(ppm): 2.82 (1H，dd，J=2.8，4.8 Hz)，2·93 (1H，dd，J=4.8, 4·8 Hz)，3·48 (1H，m)，4·17 (1H，dd， J=6.63 12.0 Hz), 4.71 (1H, dd, J=2.0, 12.0 Hz), 5.20 (2H, m), 6.49 (1H, d, J=5.2 Hz), 6.68 (2H, d, J=8.8 Hz), 6.96 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.71 (1H, d, J=5.2 Hz), 8.76 (1H, s) ° 製造例71H . 4-(4-胺茉氣某）-6-氨某-3-(二乙胺基1-2-.幾 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） -730 - 1304061 A7 B7 五、發明説明（725 ) 二 .•5 氧）口奎淋 使用4-(4-胺苯氧基）-6-氰基-7-(( 2R)-環氧乙烷-2-基）甲 氧峻淋（297 mg，0.8900 mmol)，以與製造例429-2同樣之方 法，得到為淡黃色油狀物之標題化合物（105 mg，0.2583 mmol，29.02%)。 iH-NMR 光譜（匸〇(：13)5(??111):1.08(611，1】=7.0 1^)，1.50-2.50 (1H, br s), 2.55-2.76 (6H, m), 3.79 (2H, br s), 4.15 (1H, m), 4.24 (2H, d, J=4.8 Hz), 6.46 (1H, d, J=5.4 Hz), 6.77 (2H, d, J=8.8 Hz), 6.96 (2H, d, J=8.8 Hz), 7.48 (1H? s)? 8.64 (1H, d，J=5.4 Hz)，8·69 (1H，s)。 實施例714 · N:(4-((6-氰基_7-“（2R)-2-蕤某-3-(毗呔冷-u某）丙某/·' 氳)-4- 4:啉基）氣）笨基）-&gt;Γ -(達唑-2-某、碑 一 將4-(4-胺苯氧基）-6-氰基-7-((2R)-環氧乙烷-2-基）甲氧 基4:淋（322 mg，0.966 mmol)及嘧唑-2-基胺甲酸苯酯（25 5 mg，1.26 mmol)於二甲基亞颯（2 ml)中及85 °C攪拌4小時。 將反應液分溶於乙酸乙酯-四氫呋喃混合溶媒及水中，有機 層用水及飽和食鹽水洗淨後，用無水硫酸鐵乾燥。滤除乾 燥劑，將濾液減壓餾去。於室溫下將所得之生成物及四氫 吡咯（343 mg，4.83 mmol)於二甲基甲醯胺（3 ml)中擾拌15 分鐘，將反應液分溶於乙酸乙酯與水中、有機層以水、飽 --和食鹽水洗淨後’以無水硫酸鎂乾燥之。濾除乾燥劑後減 壓餘去滤遂”。將得到之粗生成物付諸於♦凝膠管柱層析（溶 -出液為乙酸乙酯：甲醇=15 : 1)，再將含有目的物之溶出份 -731 - ^紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) —’ ---- 1304061 A7 _____B7 ____五、發明説明（726 ) 二 濃縮，懸浮於乙酸乙酯中，再將其以己烷稀釋，濾取結晶 及用己垸洗.淨後’藉由通風乾燥，得到為淡黃色結晶之標 題化合物（45 mg，0·085 mmol，9%)。 iH-NMR 光譜（DMSO-d6) 5 (ppm): 1·67 (4H，m)，2.40-2.60 (5H，m)，2.73 (1H，dd，J=6.4，12.4 Hz)，4.03 (1H，m)，4·22 (1H, dd, J=6.0, 10.0 Hz), 4.33 (1H, dd, J=3.2, 10.0 Hz), 5.04 (1H，d，J=5.2 Hz)，6·54 (1H，d，J=5.2 Hz)，7·12 (1H，d，J=3.6 Hz), 7.27-7.32 (2H, m), 7.38 (1H, d, J=3.6 Hz), 7.62-7.69 (3H，m)，8.74 (1H，d，J=5.2 Hz)，8.77 (1H，s)，9.25 (1H，br s)， 10.73 (1H，br s) 〇 實施例715 — { 6-氰某-4-「4- ( 3 -噻唑-2_某睥篡）笨氣基i,杳嗾-7_某氣甲 ' 基}六氫峨咬-1 -棱酸第三丁酯 以與實施例713同樣地，將4-(4-(4-胺苯氧基）-6-氰基-喹 啉基氧甲基）-六氫吡啶-1-羧酸第三丁酯（225 mg)在二甲 基亞颯中，與噻唑基胺甲酸苯酯一起於8〇°C加熱，得到 為固體之標題化合物（240 mg)。 1H-NMR 光譜（DMSO-d6) 5 (ppm): 1.19-1.32 (2H，m)，139 (9H，s)，1.75-1.84 (2H，m)，2.01-2.11 (1H, m)，2.66-2.87 (2H m)，3.94-4.04 (2H，m)，4.17 (2H，d，J=5.6 Hz)，6.52 (iH，d J=5.2 Hz), 7.11 (1H, d, J=3.2 Hz), 7.27 (2H, d3 J=8.8 Hz) 7.37 (1H, d, J=3.2 Hz), 7.58 (1H, s), 7.62 (2H, d, J-8.8 Hz) 8.71 (1Η，4··&gt;5·2 Hz), 8·75 (1H，s)，9.14 (1H，br s)。 ’ 〜 中間體係以下述方法合成。 • 732 -Hz), 4.31 (1H, dd, J=3.2, 10.0 Hz), 4.92 (1H, br s), 6.52 (1H, d, J=5.2 Hz), 7.10 (1H, d, J=3.6 Hz), 7.27 (2H, d, J=9.0 Hz), 7.37 (1H, d, J=3.6 Hz), 7.61 (1H? s), 7.63 (2H, d, J=9.0 Hz), 8·72 (1H,d, J = 5.2 Hz), 8.76 (1H, S), 9.15 (1H, br s). The starting materials were synthesized in the following manner. Production Example 713-1 4 - (4-Amino-Episyl)-6-Amino-7-Zhaojip was prepared using 7-benzyloxy-6-cyano (4-nitrophenoxy) obtained in Production Example 5. Deprotection of benzyl group to 6-cyano-7-hydroxy-4-(4-nitrophenoxy)quinoline (1·23 g , 4.00 mmol) according to the method of Example 21 ) - To manufacture - 729 - This paper scale Common Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Inventive Note (724) Example 21 Similarly, the nitro group is reduced to give a yellow-brown crystal The title compound (0.864 g, 3.1160 mmol, 77.90%) 〇'H-NMR spectrum (CDCl3) (HPpm): 5.18 (2H, s), 6 36 (ih, mountain J = 5.2 Hz), 6.65 (2H, d, J = 8.4 Hz), 6.92 (2H, d, J = 8.4 Hz), 7.38 (1H, s), 8.60 (1H, d, J = 5.2 Hz), 8.62 (1H s). Manufacture of tree 713-2 4·-.(·4-Aminophenoxy)-6-cyanomethyl)methylhydrogen which is 4-(4-aminophenoxy)-6-cyano-7- A few groups of 4: Lin (277 mg, 1.00 mmol) were dissolved in dimethylformamide (3.0 ml), and hydrogenated steel (40 mg, 1.00 mmol, 60% in oil) was added at room temperature and stirred. 4 methyl-1-benzenesulfonic acid (2R)-oxiran-2-ylmethyl ester (228 mg, 1.00 /: mmol) was added thereto, and the mixture was stirred under heating at 60 ° C for 5 hours. After allowing to cool to room temperature, the reaction mixture was dissolved in ethyl acetate and water. The organic layer was washed with EtOAc EtOAc EtOAc. iH-NMR spectrum (DMSO-d6) 6 (ppm): 2.82 (1H, dd, J = 2.8, 4.8 Hz), 2.93 (1H, dd, J = 4.8, 4·8 Hz), 3·48 ( 1H,m),4·17 (1H,dd, J=6.63 12.0 Hz), 4.71 (1H, dd, J=2.0, 12.0 Hz), 5.20 (2H, m), 6.49 (1H, d, J=5.2 Hz), 6.68 (2H, d, J=8.8 Hz), 6.96 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.71 (1H, d, J=5.2 Hz), 8.76 (1H, s) ° Manufacturing Example 71H. 4-(4-Amine Mosquito)-6-Ammonia-3-(diethylamino 1-2-. Several paper scales applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -730 - 1304061 A7 B7 V. INSTRUCTIONS (725) II.•5 Oxygen) Methyl quinine using 4-(4-aminophenoxy)-6-cyano-7-(( 2R) - oxirane-2-yl)methanesulfonate (297 mg, 0.8900 mmol), m. 29.02%). iH-NMR spectrum (匸〇(:13)5(??111):1.08(611,1]=7.0 1^), 1.50-2.50 (1H, br s), 2.55-2.76 (6H, m), 3.79 (2H, d, J=4.8 Hz), 6.46 (2H, d, J=5.4 Hz), 6.96 (2H, d, J=8.8 Hz), 7.48 (1H? s)? 8.64 (1H, d, J=5.4 Hz), 8.69 (1H, s). Example 714 · N:(4-( (6-Cyano-7-"(2R)-2-蕤--3-(Pi-cold-u)) 某/·' 氲)-4- 4: phenyl) gas) stupid)-&gt ;Γ-(Dazol-2-one, indole 4-(4-aminophenoxy)-6-cyano-7-((2R)-oxiran-2-yl)methoxy 4 : leaching (322 mg, 0.966 mmol) and phenyl pyrazole-2-ylcarbamate (25 5 mg, 1.26 mmol) in dimethyl hydrazine (2 ml) and stirring at 85 ° C for 4 hours. The mixture is dissolved in ethyl acetate-tetrahydrofuran mixed solvent and water, and the organic layer is washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant is filtered off, and the filtrate is evaporated under reduced pressure. And tetrahydropyrrole (343 mg, 4.83 mmol) was scrambled in dimethylformamide (3 ml) for 15 minutes, and the reaction solution was dissolved in ethyl acetate and water. The organic layer was washed with water, saturated- and brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and then decompressed to remove the filtrate. The crude product was applied to a gel column chromatography. (Solution-exitate is ethyl acetate: methanol = 15:1), and the content of the solution containing the target -731 - ^ paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) - ' --- - 1304061 A7 _____B7 ____ V. Inventive Note (726) Two concentrates, suspended in ethyl acetate, diluted with hexane, filtered for crystallization and washed with hexane. After drying, by drying in air, The title compound (45 mg, 0·085 mmol, 9%) of pale yellow crystals. iH-NMR spectrum (DMSO-d6) 5 (ppm): 1·67 (4H, m), 2.40-2.60 (5H, m) , 2.73 (1H, dd, J=6.4, 12.4 Hz), 4.03 (1H, m), 4·22 (1H, dd, J=6.0, 10.0 Hz), 4.33 (1H, dd, J=3.2, 10.0 Hz) ), 5.04 (1H, d, J = 5.2 Hz), 6.54 (1H, d, J = 5.2 Hz), 7·12 (1H, d, J = 3.6 Hz), 7.27-7.32 (2H, m) , 7.38 (1H, d, J = 3.6 Hz), 7.62-7.69 (3H, m), 8.74 (1H, d, J = 5.2 Hz), 8.77 (1H, s), 9.25 (1H, br s), 10.73 (1H , br s) 〇Example 715 — { 6-Cyanide-4-"4-(3-thiazole-2_ 睥篡) stupid base i, 杳嗾-7_a gas a 'yl} hexahydroanthracene In the same manner as in Example 713, 4-(4-(4-aminophenoxy)-6-cyano-quinolinyloxymethyl)-hexahydropyridine was occluded in the same manner as in Example 713. The title compound (240 mg) was obtained as a solid title compound (240 mg). 1H-NMR spectrum (DMSO-d6) 5 (ppm): 1.19-1.32 (2H, m), 139 (9H, s), 1.75-1.84 (2H, m), 2.01-2.11 (1H, m), 2.66- 2.87 (2H m), 3.94-4.04 (2H, m), 4.17 (2H, d, J = 5.6 Hz), 6.52 (iH, d J = 5.2 Hz), 7.11 (1H, d, J = 3.2 Hz), 7.27 (2H, d3 J=8.8 Hz) 7.37 (1H, d, J=3.2 Hz), 7.58 (1H, s), 7.62 (2H, d, J-8.8 Hz) 8.71 (1Η,4··&gt;5 · 2 Hz), 8·75 (1H, s), 9.14 (1H, br s). The intermediate system was synthesized in the following manner. • 732 -

裝 iyInstall iy

k A7 B7 1304061 五、發明説明（727 ) 噑造例715_1 Γ 4- (4-胺笨氣基）-6-氨+嗾-六氫口比咬二1-幾. 鸹第三丁酯 以與實施例713-2同樣地，將4-(4-胺苯氧基）-7-羥喹啉-6-甲腈（0.32g)在二甲基甲醯胺中，用氫化鈉處理後，與4-溴乙基-六氫吡啶-1 -羧酸第三丁酯反應’得到為固體之標 題化合物（225 mg)。 iH-NMR 光譜（DMSO-d6) 5 (ppxn): (2H，m)，1.39 (9H，s)，1.75-1.82 (2H，m)，1.98-2.10 (1H，m)，2.62-2.92 (2H， m), 3.94-4.03 (2H, m), 4.15 (2H, d, J=6 Hz), 5.16-5.21 (2H, m)，6·45 (1H，d，J=5.2 Hz)，6·65 (2H，d，J=8.8 Hz)，6·93 (2H、 d，J=8.8 Hz)，7.55 (1H，s)，8·68 (1H，d，J=5.2 Hz)，8.70 (1H， s) 〇 — 實施例716 1-(4-(6-氰基-7-(六氫吡啶-4-某甲氣基）喹啉-4-基氣）茇 基唑-2-基）脲 以與實施例670-4同樣地，將4-(6-氰基-4-(4-(3-噻唑-2-基脲基）-苯氧基）-喹啉-7-基氧甲基）-六氫吡啶-1-羧酸第三 丁酯（240 mg)在三氟乙酸中脫保護，得到為固體之標題化 合物（220 mg)。 W-NMR 光譜（0以80-(16)5(|)1)111):1.46-1.59 (211，111)，1.87-1.96 (2H, m), 2.06-2.18 (1H, m), 2.78-2.89 (2H, m), 3.08-3.38 (2H,^n&gt;, 4,13 (2H, d, J=6 Hz), 6.43 (1H, d, J=5；2 Hz), 7.07 (1H, d, J=3.2 Hz), 7.20 (2H, d, J=9.2 Hz), 7.36 (1H, d, 733 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 B7 五、發明説明（728 ) 二， J=3.2 Hz), 7.57 (1H, s), 7.68 (2H, d, J=9.2 Hz), 8.63 (1H3 d, J=5.2 Hz), 8·71 (1H，s)，9·82 (1H，br) 〇 實施例717 hi 4_ ( 6-氰基-7_ (1 -甲六氣咄啶基甲氣某u杏啉· 4·基氣） 塞基）_3_(嘧唑某）月尿 以與實施例670同樣地，從i-(4-(6-氰基(六氫吡啶·‘ 基甲氧基）喹啉-4-基氧）苯基）-3-〇塞唑-2-基）脲（220 mg), 得到為固體之標題化合物（5 1 mg)。 iH-NMR 光譜（0?480-(16)5咖111):1.35-1.48 (211，111)，1.75-1.85 (2H, m)5 1.89-1.96 (1H, m), 2.18 (3H, br s), 2.79-2.86 (2H, m), 3.18-3.38 (2H, m), 4.15 (2H, d, J=5.6 Hz), 6.52 (1H, d, J=5.2 Hz), 7.10 (1H, d, J=3.2 Hz), 7.27 (2H, d, J=9.2 Hz),-. 7.37 (1H, d, 1=3.2 Hz), 7.58 (1H, s), 7.63 (2H, d, J=9.2 Hz), 8·72 (1H，d，J=5.2 Hz)，8·76 (1H，s)，9·20 (1H，br)。 實施例71 8 N:,(4-(6-胺甲蘼基-7-甲氣基-4-4淋某）氳-2-三氟甲笨某）-乙某驿 將乙胺2N四氫呋喃溶液（〇·ΐ〇 ml)加入二甲基亞颯（〇.5 ml) 中，於其中溶解（4-(6-胺甲醯基-7-甲氧基-4-喳啉基）氧-2-二氟甲苯基）胺甲酸苯酯（25 mg)且揽拌1〇分鐘。於此反應 溶液中添加水及乙酸乙酯，濾取析出之結晶，得到標題化 ' 合物（5.0 mg)。 1 H-NMR 4DMSO-d6) 5 (ppm): 1.08 (3H, t, J=7.2 Hz), 3.10- 一 3.18 (2H, m)5 4.04 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.00-7.07 ______- 734 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)k A7 B7 1304061 V. INSTRUCTIONS (727) 噑 715 715_1 Γ 4- (4-Amine stupid)-6-ammonia-嗾-hexahydro-port ratio bite two to several. 鸹T-butyl ester Example 713-2 Similarly, 4-(4-aminophenoxy)-7-hydroxyquinoline-6-carbonitrile (0.32 g) was treated with sodium hydride in dimethylformamide. Reaction of tert-butyl 4-bromoethyl-hexahydropyridine-1 -carboxylate to give the title compound (225 mg). iH-NMR spectrum (DMSO-d6) 5 (ppxn): (2H, m), 1.39 (9H, s), 1.75-1.82 (2H, m), 1.98-2.10 (1H, m), 2.62-2.92 (2H , m), 3.94-4.03 (2H, m), 4.15 (2H, d, J=6 Hz), 5.16-5.21 (2H, m), 6·45 (1H, d, J=5.2 Hz), 6· 65 (2H,d,J=8.8 Hz),6·93 (2H, d, J=8.8 Hz), 7.55 (1H, s), 8.68 (1H, d, J=5.2 Hz), 8.70 (1H , s) 〇 - Example 716 1-(4-(6-Cyano-7-(hexahydropyridine-4-methyl) quinolin-4-yl) oxazol-2-yl)urea In the same manner as in Example 670-4, 4-(6-cyano-4-(4-(3-thiazol-2-ylureido)-phenoxy)-quinolin-7-yloxymethyl - hexahydropyridine-1-carboxylic acid tert-butyl ester (240 mg) was deprotected in trifluoroacetic acid to afford the title compound (220 mg). W-NMR spectrum (0 to 80-(16)5(|)1) 111): 1.46-1.59 (211,111), 1.87-1.96 (2H, m), 2.06-2.18 (1H, m), 2.78- 2.89 (2H, m), 3.08-3.38 (2H,^n&gt;, 4,13 (2H, d, J=6 Hz), 6.43 (1H, d, J=5; 2 Hz), 7.07 (1H, d , J=3.2 Hz), 7.20 (2H, d, J=9.2 Hz), 7.36 (1H, d, 733 - This paper size applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) 1304061 A7 B7 Five , invention description (728) 2, J = 3.2 Hz), 7.57 (1H, s), 7.68 (2H, d, J = 9.2 Hz), 8.63 (1H3 d, J = 5.2 Hz), 8·71 (1H, s), 9·82 (1H, br) 〇 Example 717 hi 4_ (6-Cyano-7_(1-methylhexahydropyridinylmethyl a certain apricotine·4·base gas) Seki)_3_( Pyrimidine, urea, in the same manner as in Example 670, from i-(4-(6-cyano(hexahydropyridine)' methoxy)quinolin-4-yloxy)phenyl)-3- The oxozol-2-yl)urea (220 mg) gave the title compound (5 1 mg). iH-NMR spectrum (0?480-(16)5 coffee 111): 1.35-1.48 (211,111), 1.75-1.85 (2H, m)5 1.89-1.96 (1H, m), 2.18 (3H, br s ), 2.79-2.86 (2H, m), 3.18-3.38 (2H, m), 4.15 (2H, d, J=5.6 Hz), 6.52 (1H, d, J=5.2 Hz), 7.10 (1H, d, J=3.2 Hz), 7.27 (2H, d, J=9.2 Hz),-. 7.37 (1H, d, 1=3.2 Hz), 7.58 (1H, s), 7.63 (2H, d, J=9.2 Hz) , 8·72 (1H, d, J = 5.2 Hz), 8.76 (1H, s), 9·20 (1H, br). Example 71 8 N:, (4-(6-aminocarbamimid-7-methyl-l--4-yl), 氲-2-trifluoromethyl]-ethyl bromide 2N tetrahydrofuran solution (〇·ΐ〇ml) was added to dimethyl hydrazine (〇.5 ml) where it was dissolved (4-(6-aminocarbamido-7-methoxy-4-indolyl)oxy-2 Phenyl-difluoromethylphenyl)carbamate (25 mg) was stirred for 1 minute. Water and ethyl acetate were added to the reaction solution, and the precipitated crystals were filtered to give the title compound (5.0 mg). 1 H-NMR 4 DMSO-d6) 5 (ppm): 1.08 (3H, t, J = 7.2 Hz), 3.10 - a 3.18 (2H, m)5 4.04 (3H, s), 6.54 (1H, d, J= 5.2 Hz), 7.00-7.07 ______- 734 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)

裝 訂Binding

k 1304061 A7 B7 五、發明説明（729 ) 二 (1H，m)，7.51-7.63 (3H，m)，7·74 (1H，br s)，7·82-7·88 (2H， m)，8.06-8.13 (1Η，m)，8.66-8.70 (2Η，m)。 實施例719 N-「4- ( 6-胺甲醯基-7-甲氧某g林某）氣基-2_三氣甲炎 某1-N、甲基脲 於甲-胺2N四氫呋喃溶液（1.00 ^1)中添加[4-(6-胺甲醯基-7-甲氧基-4-喹啉基）氧基-2-三氟甲苯基]胺甲酸苯酯（25 mg) 且攪捽10分鐘。濾取析出之結晶，用四氫呋喃洗淨，得到 標題化合物（10 mg)。 ^-NMR (DMSO-d6) 6 (ppm): 2.68 (3H, d, J=4.0 Hz), 4.04 (3H，s)，6·54 (1H，d，J=5.6 Hz)，6·87-6·94 (1H，m)，7.51-7.63 (3H, m), 7.75 (1H, br s), 7.86 (1H, br s), 7.90 (1H, br s),- 8.03-8.09 (1H，m)，8.66-8.70 (2H，m) 〇 — Ί 實施例720 N-(4-(7_-—字皇基-6-氰基巧奎琳-4-某氧）-2,3-二甲芝甚 環丙脲 於二甲基甲酿胺（10 ml)中添加環丙胺（1 ml)，再於其中 添加（4-(7-芊氧基-6-氰基-喹啉-4-基氧）-2,3-二甲苯基）胺 甲酸苯酯（1.99g)且在室溫攪拌10分鐘。於其中加入水（3〇 ml)及乙酸乙酯（30 ml)，濾取析出之結晶，將其用乙酸乙 酯洗淨，得到標題化合物（1660 mgp - lH-NMR (DMSO-d6) δ (ppm): 0.40-0.45 (2Η, m)9 〇 62-0 67 (2H，m)，2^3 (3H，s)，2.16 (3H，s)，2.52-2.59 (ih，m) 5 47 - (2H，s)，6·33 (1H，d，J=5.2 Hz), 6.68-6.74 (1H，m)，7 〇〇 (m -735 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) &quot; '^ --—-k 1304061 A7 B7 V. INSTRUCTIONS (729) II (1H, m), 7.51-7.63 (3H, m), 7.74 (1H, br s), 7·82-7·88 (2H, m), 8.06-8.13 (1Η, m), 8.66-8.70 (2Η, m). Example 719 N-"4-(6-Aminomethylmercapto-7-methoxyl-glin) gas-based-2_trioxanone 1-N, methylurea in methyl-amine 2N tetrahydrofuran solution ( [4-(6-Aminomethylhydrazino-7-methoxy-4-quinolinyl)oxy-2-trifluoromethyl] phenyl carbamate (25 mg) was added to 1.00 ^1) and stirred After 10 minutes, the crystals were crystallized, crystallised eluted eluted eluted elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut ,s),6·54 (1H,d,J=5.6 Hz),6·87-6·94 (1H,m),7.51-7.63 (3H, m), 7.75 (1H, br s), 7.86 ( 1H, br s), 7.90 (1H, br s), - 8.03-8.09 (1H, m), 8.66-8.70 (2H, m) 〇 - 实施 Example 720 N-(4-(7_--字皇基Add Cyclopropylamine (1 ml) to dimethyl ketoamine (10 ml) and add it to -6-cyanoquinone-4-oxygen-2,3-dimethylglycol (4-(7-Methoxy-6-cyano-quinolin-4-yloxy)-2,3-xylyl)carboxamide (1.99 g) and stirred at room temperature for 10 min. Water (3 ml) and ethyl acetate (30 ml) were added, and the crystals which precipitated were collected by filtration. Compound (1660 mgp - lH-NMR (DMSO-d6) δ (ppm): 0.40-0.45 (2Η, m)9 〇62-0 67 (2H,m), 2^3 (3H,s), 2.16 ( 3H,s),2.52-2.59 (ih,m) 5 47 - (2H,s),6·33 (1H,d,J=5.2 Hz), 6.68-6.74 (1H,m),7 〇〇(m -735 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) &quot; '^ ----

訂Order

13040611304061

d, J=8.8 Hz), 7.35-7.49 (3H, m), 7.52-7.73 (5H, m), 8.69 (1H, d, J=5.2 Hz), 8.76 (1H, s) 起始物係以下述2個步驟合成。 製造例720-1 iz丄4-胺基-273-__^^^上_ 7·字氫某_ 6_氨某喹啉 將從·柬永化成購入之4_胺基-2,3-二甲酚（2·8〇 g)溶於二甲 基亞颯（15 ml)中，然後在室溫下緩慢加入6〇%氫化鈉（816 mg)並攪袢20分鐘。添加7_苄氧基_4_氯氰基喹啉（3〇 g)，在100 C攪摔下加熱4小時。放冷至室溫，將反應液分 落於乙酸乙酯及水，將有機層以水、1N氫氧化鈉水溶液及 飽和食鹽水洗淨，用無水硫酸鈉乾燥。將溶媒餾去，得到 足粗生成物用乙酸乙酯洗淨，得到為淡褐色結晶之標題化' 合物（1.72 g)。 — A-NMR (DMSO-d6)&lt;5(ppm): 1.91 (3H，s)，2·01 (3H，s)， 4.83-4.90 (2H, m), 5.44 (2H, s), 6.30 〇Η, d, J=5.2 Hz), 6.60 (1H, d, J=8.4 Hz), 6.73-6.79 (1H, m), 7.33-7.47 (3H, m), 7,51-7.58 (2H, m), 7.67 (1H, s), 8.65 (1H, d, J=5.2 Hz),V8〇 (1H, s) 製造例720-2d, J=8.8 Hz), 7.35-7.49 (3H, m), 7.52-7.73 (5H, m), 8.69 (1H, d, J=5.2 Hz), 8.76 (1H, s) Starting materials are as follows 2 steps to synthesize. Production Example 720-1 iz丄4-Amino-273-__^^^上_ 7·Word Hydrogen _ 6_Ammonia Quinoline will be purchased from the Cambodian 4~Amino-2,3-II The cresol (2.8 g) was dissolved in dimethyl hydrazine (15 ml), and then 6 〇% sodium hydride (816 mg) was slowly added at room temperature and stirred for 20 minutes. 7-Benzyloxy_4_chlorocyanoquinoline (3 〇 g) was added and heated under stirring at 100 C for 4 hours. The mixture was allowed to cool to room temperature, and the mixture was evaporated to ethyl acetate and water. The solvent was evaporated to give a crude material (yield: EtOAc) — A-NMR (DMSO-d6) &lt; 5 (ppm): 1.91 (3H, s), 2·01 (3H, s), 4.83-4.90 (2H, m), 5.44 (2H, s), 6.30 〇 Η, d, J=5.2 Hz), 6.60 (1H, d, J=8.4 Hz), 6.73-6.79 (1H, m), 7.33-7.47 (3H, m), 7,51-7.58 (2H, m) , 7.67 (1H, s), 8.65 (1H, d, J=5.2 Hz), V8〇(1H, s) Manufacturing Example 720-2

Ll_ (7_卞乳基ϋ基嗤淋-4-基氧上笨某1脖甲酩 苯酯 ' 藉由實施例141 - 1 f己載之方法’從4- ( 4-胺基_ 2 3 -甲苯 氧基）-7-菜氧基-6-氰基喹淋（1.72 g)得到為淡褐色結晶之 一 _ 標題化合物（1.99 g)。 __ - 736 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公ϋ 一 ---- 1304061 A7 B7Ll_(7_卞乳基ϋ基嗤 -4--4-yloxy 上上一一一甲甲苯苯' by the method of Example 141 - 1 f loaded 'from 4-(4-amino- 2 3 -Tolyloxy)-7-oxoethoxy-6-cyanoquinone (1.72 g) was obtained as one of pale brown crystals _ title compound (1.99 g). __ - 736 - This paper scale applies to Chinese national standards (CNS) A4 size (210 X 297 mm - one---- 1304061 A7 B7

五、發明説明（731 ) H-NMR (CDCI3) 5 (ppm): 2.02 (3H, s), 2.13 (3H, s), 5.36 (2H，s)，6·32 (1H，d，J=5.2 Hz)，6.78 (1H，br s)，7.00 (1H，d， J=8.8 Hz), 7.20-7.80 (12H, m), 8.62 (1H, d, J=5.2 Hz), 8.78 (1H, s) 實施例721 N-f2,3 -二甲基-4-(6-氰基- 7-#p杳淋-4-基氣）茉基 丙脲 將N-[4-(7-苄氧基-6-氰基喳啉-4-基氧）-2,3-二甲苯基卜 N* -環丙月尿（1600 mg)加入四氫吱喃（400 ml)中，進一步添加 鈀-碳（2000 mg)，在氫氣氣流下於室溫攪拌一整夜。藉由 過濾除去鈀-碳，用二甲基甲醯胺洗淨後，將濾液減壓濃 縮，得到標題化合物（827 mg)。 ~ : ^-NMR (DMSO-d6) 5 (ppm): 0.40-0.46 (2H, m)/〇.62-〇.67 ：^ (2H, m), 2.03 (3H, s), 2.16 (3H, s), 2.54-2.60 (1H, m), 6.20 (1H，d，J=5.2 Hz)，6.68 (1H，d，J=3.2 Hz), 7.00 (1H，d，J=8.8 Hz)，7.39 (1H，br s)，7.65 (1H，d，J=8.8 Hz)，7.69 (1H，s)， 8·59 (1H，d，J=5.2 Hz)，8.71 (1H，s) 〇 實施例722 N- (4-(6-氰基- 7- (3 -p比哈症-1-基丙氣某）g奎淋-4-基氧基）二 2,3-二甲茉基）-N、環丙脲 於二甲基甲醯胺（2 ml)中添加以實施例721合成之N-[2,3- ' 二甲基-4-(6-氰基-7-羥喹啉-4-基氧）苯基]-Ν’-環丙基脲 (100 mg)^-l-(3-氯丙基）吡啶鹽酸鹽（95 mg)及碳酸卸（150 一 mg)，在60°C加熱7小時。在該反應液中加入水且以乙酸乙 737 -本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 --- 一 ^ ^ 五、發明説明（732 ) 二 酉旨萃取’有機層依序以水及飽和食鹽水洗淨後，用無水硫 酸鈉乾燥，，且減壓餾去溶媒。將得到之粗生成物用乙酸乙 酯洗淨，得到為淡黃色結晶之標題化合物（49 mg)。 iH-NMR (CDC13) (5(ppm): 0.38-0.44 (2H，m)，0.59-0.66 (2H， m)，1.64-1.71 (4H，m)，1·94-2·0〇 (2H，m)，2.01 (3H，s)，2.14 (3H，s)，2.40-2.60 (7H，m)，4.33 (2H，t，J=6.4 Hz)，6.30 (1H， d, J=5.6 Hz), 6.82 (1H, br s), 6.99 (1H, d, J=8.8 Hz), 7.58 (1H，s)，7.64 (1H，d，J=8.8 Hz)，7·69 (1H，br s)，8.67 (1H，d， J=5.6 Hz)，8.80 (1H，s)。 _ : 實施例723 N- (4- (6-着·基-7- ((2R) - 2 -疫基-3 -叶b洛淀· 1 基丙氧口杳 味-4-基氣）-2,3•二甲苯基）-Ν·_瑷而胍 ·二 於义（4-(6_氰基-7_((21〇-環氧乙烷-2-基）甲氧基-嗜4/:备 基氧）_2,3_二甲苯基）-Ν’ -環丙月尿（110 mg)中添加四氣咬 喃（2.0 ml)及外1:洛淀（0.20 ml)並在60°C加熱2小時。將此反 應溶液放冷後，濾取析出之結晶，得到為淡褐色結晶之標 題化合物（18 mgp h-NMR (DMSO-d6) 5 (ppm): 0.40-0.46 (2H，m)，0.62-0 68 (2H，m)，1.65-1.73 (4H，m)，2·03 (3H，s)，2·16 (3H，s)，2·45_ 2·70 (7H，m)，4.00麵4·08 (1H，m)，4.22 (1H，dd，J=l〇.4，5 6 Hz), 4.32 (1H, dd, J=10.4, 3.6 Hz), 5.04 (1H, d, J=4.4 Hz) 、 6.32 (1H, d, J=5.6 Hz), 6.67-6.72 (1H, m), 7.02 (1H, d, J^8 8 Hz), 7.61-7:72 (3H, m), 8.69 (1H, d, J=5.6 Hz), 8.82 (1H 一 s) ° -738 - 本紙張尺度適用中國國家標準(CNS) A4规格(210 x 297公釐) 1304061 A7 ______ B7 五、發明説明（733 ) — 7&quot; .-Ξ 起始物係以下述方法合成。 製造例723-1 N-(_4_-,(6-氰基-7-((2jl)-環氧乙烷基）甲氳4啉-4-篡氧U 2,3-二甲苯某）-Ν’-環丙Μ 將Ν-(2,3-二甲基-4-(6_氰基-7-羥基-喳啉-4-基氧）_苯 基）-Ν’-環丙基脲（476 mg)加入二甲基甲醯胺（4 ml)中。於 其中添加對甲苯續酸（2R)-縮水甘油酯（3 65 mg)及碳酸奸 (340 mg)，然後在50 C加熱4小時。於此反應溶液中加入水 且用乙酸乙g旨萃取。將有機層用水及飽和食鹽水依序洗淨 後，用我水硫酸納乾燥，並減壓館去溶媒。將得到之粗生 成物用乙酸乙酯洗淨，得到為淡黃色結晶之標題化合物 (270 mg) 〇 ' lH-NMR (DMSO-d6) 5 (ppm): 0.40-0.46 (2H, m), 0.62-0.68 (2H, m), 2.03 (3H, s), 2.16 (3H? s), 2.52-2.60 (1H, m), 2.80-2.96 (2H, m), 3.45-3.52 (1H, m), 4.18 (1H, dd, J-11.6, 6.4 Hz), 4.73 (1H, dd, J=11.6, 2.0 Hz), 6.34 (1H, d, J=5.6 Hz), 6.69-6.74 (1H, m), 7.01 (1H, d, J=8.8 Hz), 7.61-7.75 (2H, m), 7·95 (1H，br s)，8.70 (1H，d，J=5.6 Hz)，8·85 (1H，s)。 實施例724 (4- ( 6-氰基-7- ((2R) - 2-藉基-3-六氫p比峻-1-甚丙氣某 4-基氧）-2,3-二甲苯某）-N、環丙脈 ' 於N-(4-(6-氰基-7-((2R)-環氧乙烷-2-基）甲氧基奎啉. 4-基氧）-2^二甲苯基）-Ν’-環丙脲（80 mg)中添加四氫吱喃 一 (2 ·0 ml)及六氫p比淀（0.20 ml)，並在60 °C加熱4小時。將此 -739 - 本紙俵尺度適用中國國家標準(CNS) A4規格(210 X 297公ί) ' ---- 1304061 A7 _ B7 五、發明説明（734 ) &quot; 反應溶液放冷後，濾取析出之結晶，得到為淡褐色結晶之 標題化合物（5 0 mg)。 1H_NMR (DMSO-d6) 5 (ppm): 0.40-0.46 (2H，m)，0.62-0.68 (2H，m)，1.30-1.55 (6H，m)，2.03(3H，s)，2.16(3H，s)，2.30-2.70 (7H，m)，4·00-4·09 (1H，m)，4·22 (1H，dd，J=10.4，5.6 Hz)，4·32 (1H，dd，J=10.4, 3·6 Hz)，4·95 (1H，d，J=4.0 Hz)， 6.32 (1H, d, J=5.6 Hz), 6.71-6.74 (1H, m), 7.02 (1H, d5 J=8.8V. INSTRUCTIONS (731) H-NMR (CDCI3) 5 (ppm): 2.02 (3H, s), 2.13 (3H, s), 5.36 (2H, s), 6.32 (1H, d, J=5.2 Hz), 6.78 (1H, br s), 7.00 (1H, d, J = 8.8 Hz), 7.20-7.80 (12H, m), 8.62 (1H, d, J = 5.2 Hz), 8.78 (1H, s) Example 721 N-f2,3-dimethyl-4-(6-cyano-7-#p杳--4-yl gas) jasperylurea N-[4-(7-benzyloxy- 6-Cyanoporphyrin-4-yloxy)-2,3-dimethylphenyl-N*-cyclopropanil (1600 mg) was added to tetrahydrofuran (400 ml), further adding palladium-carbon (2000) (mg), stirring overnight at room temperature under a stream of hydrogen. The palladium-carbon was removed by filtration, washed with dimethylformamide, and the filtrate was concentrated under reduced pressure to give the title compound (827 mg). ~ : ^-NMR (DMSO-d6) 5 (ppm): 0.40-0.46 (2H, m) / 〇.62-〇.67 :^ (2H, m), 2.03 (3H, s), 2.16 (3H, s), 2.54-2.60 (1H, m), 6.20 (1H,d,J=5.2 Hz), 6.68 (1H,d,J=3.2 Hz), 7.00 (1H,d,J=8.8 Hz), 7.39 ( 1H, br s), 7.65 (1H, d, J = 8.8 Hz), 7.69 (1H, s), 8·59 (1H, d, J = 5.2 Hz), 8.71 (1H, s) 〇 Example 722 N - (4-(6-Cyano- 7-(3 -pbiha)-1-ylpropanol)g quinolin-4-yloxy)di 2,3-dimethylmethyl)-N, N-[2,3- 'Dimethyl-4-(6-cyano-7-hydroxyquinoline-4-) synthesized in Example 721 was added to propylformamide in dimethylformamide (2 ml). Phenyloxy)phenyl]-indole-cyclopropyl urea (100 mg) ^-l-(3-chloropropyl)pyridine hydrochloride (95 mg) and carbonic acid (150 mg) at 60 ° C Heat for 7 hours. Add water to the reaction solution and apply the Chinese National Standard (CNS) A4 specification (210 X 297 mm) to the standard of acetic acid 737 - paper. 1304061 A7 --- one ^ ^ five, invention description (732 ) The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated. The obtained crude product was washed with ethyl acetate. iH-NMR (CDC13) (5 (ppm): 0.38-0.44 (2H, m), 0.59-0.66 (2H, m), 1.64-1.71 (4H, m), 1·94-2·0〇 (2H, m), 2.01 (3H, s), 2.14 (3H, s), 2.40-2.60 (7H, m), 4.33 (2H, t, J = 6.4 Hz), 6.30 (1H, d, J = 5.6 Hz), 6.82 (1H, br s), 6.99 (1H, d, J=8.8 Hz), 7.58 (1H, s), 7.64 (1H, d, J = 8.8 Hz), 7·69 (1H, br s), 8.67 (1H, d, J = 5.6 Hz), 8.80 (1H, s). _: Example 723 N-(4-(6-的基基-7-((2R)-2-)-epoxy-3-leaf b洛丁·1 丙丙氧口杳味-4-base gas)-2,3•xylyl)-Ν·_瑷和胍·二于义(4-(6_cyano-7_(21 〇-Ethylene oxide-2-yl)methoxy-isophilic 4/:substituted oxygen)_2,3-dimethylphenyl)-Ν'-cyclopropene urea (110 mg) was added with four gas spurs ( 2.0 ml) and the outer 1: Loduce (0.20 ml) and heated at 60 ° C for 2 hours. After cooling the reaction solution, the precipitated crystals were filtered to give the title compound (18 mg p h-NMR (DMSO-d6) 5 (ppm): 0.40-0.46 (2H, m), 0.62-0 68 (2H, m), 1.65-1.73 (4H, m), 2·03 (3H, s), 2.16 (3H, s), 2·45_ 2·70 (7H, m), 4.00 face 4·08 (1H,m), 4.22 (1H,dd,J=l〇.4,5 6 Hz), 4.32 (1H, dd, J=10.4, 3.6 Hz), 5.04 (1H, d, J=4.4 Hz), 6.32 (1H, d, J=5.6 Hz), 6.67-6.72 (1H, m), 7.02 (1H, d, J^8 8 Hz), 7.61-7:72 (3H, m), 8.69 (1H, d , J=5.6 Hz), 8.82 (1H a s) ° -738 - This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 ______ B7 V. Invention description (733 ) — 7&quot; .-Ξ The starting material was synthesized in the following manner. Production Example 723-1 N-(_4_-,(6-Cyano-7-((2jl)-oxiranyl)methylindole-4-pyridin-4-indole) Oxygen U 2,3-xylene one)-Ν'-cyclopropene Ν-(2,3-dimethyl-4-(6-cyano-7-hydroxy-indololin-4-yloxy)_ Phenyl)-indole-cyclopropyl urea (476 mg) was added to dimethylformamide (4 ml). To this was added p-toluene acid (2R)-glycidyl ester (3 65 mg) and carbonic acid (340 mg), followed by heating at 50 C for 4 hours. Water was added to the reaction solution and extracted with acetic acid. The organic layer was washed with water and saturated brine in that order, and then dried with sodium sulphate in water, and decompressed to remove the solvent. The obtained crude product was washed with ethyl acetate toield crystals eluted eluted elut elut elut elut elut elut elut elut elut elut -0.68 (2H, m), 2.03 (3H, s), 2.16 (3H? s), 2.52-2.60 (1H, m), 2.80-2.96 (2H, m), 3.45-3.52 (1H, m), 4.18 (1H, dd, J-11.6, 6.4 Hz), 4.73 (1H, dd, J=11.6, 2.0 Hz), 6.34 (1H, d, J=5.6 Hz), 6.69-6.74 (1H, m), 7.01 ( 1H, d, J = 8.8 Hz), 7.61-7.75 (2H, m), 7·95 (1H, br s), 8.70 (1H, d, J = 5.6 Hz), 8.85 (1H, s). Example 724 (4-(6-Cyano-7-((2R)-2-hexyl-3-hexahydrop to jun-1-propene gas 4-yloxy)-2,3-xylene a)-N, cyclopropane' in N-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxyquinoline. 4-yloxy)-2 ^Xylphenyl)-Ν'-cyclopropanil (80 mg) was added with tetrahydrofuran-one (2.0 ml) and hexahydro-p-precipitate (0.20 ml) and heated at 60 °C for 4 hours. This -739 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 ί) ' ---- 1304061 A7 _ B7 V. Invention description (734 ) &quot; After the reaction solution is cooled, it is filtered and precipitated. The title compound (50 mg) was obtained as pale brown crystals. 1H_NMR (DMSO-d6) 5 (ppm): 0.40-0.46 (2H, m), 0.62-0.68 (2H, m), 1.30-1.55 ( 6H, m), 2.03 (3H, s), 2.16 (3H, s), 2.30-2.70 (7H, m), 4·00-4·09 (1H, m), 4·22 (1H, dd, J =10.4, 5.6 Hz), 4·32 (1H, dd, J = 10.4, 3·6 Hz), 4.95 (1H, d, J = 4.0 Hz), 6.32 (1H, d, J = 5.6 Hz) , 6.71-6.74 (1H, m), 7.02 (1H, d5 J=8.8

Hz)，7.62-7.70 (2H，m)，7.73 (1H，br s)，8.69 (1H，d，J=5.6Hz), 7.62-7.70 (2H, m), 7.73 (1H, br s), 8.69 (1H, d, J=5.6

Hz), 8.82 (1H, s) 〇 實施例725 义（4-(6-氨某-7-(3-二乙胺基_(210-2-羥基_丙氫基）4嗾_ 4-基氡2,3-二甲苯基）-Ν’-環丙某Μ 」 於Ν-(4_(6_氰基-7_((2R)-環氧乙烷基）甲氧基-喹Ί 4-基氧）-2,3 -二曱苯基）-Ν、環丙基脲（80 mg)中添加四氫吱 喃（2.0 ml)及二乙胺（0·50 ml)，在60°C加熱6小時。將此反 應溶液放冷後，滤取析出之結晶，得到為淡褐色結晶之標 題化合物（32 mg)。 lH-NMR (DMSO-d6) 5 (ppm): 0.40-0.46 (2H, m)? 0.62-0.69 (2H, m), 0.98 (6H, t, J=7.2 Hz), 2.03 (3H, s), 2.16 (3H, s)5 2.40-2.70 (7H，m)，3.90-4.02 (1H，m)，4·22 (1H，dd，J=i〇.4， 5.6 Hz), 4.32 (1H, dd3 J=10.4, 3.6 Hz), 4.93 (1H, d, J=4.〇 'Hz), 8.82 (1H, s) 〇 Example 725 (4-(6-Amino-7-(3-diethylamino)-(210-2-hydroxy-propylhydro) 4嗾-4-yl氡2,3-Dimethylphenyl)-Ν'-cyclopropyl Μ" Ν-(4_(6-Cyano-7_((2R)-oxiranyl)methoxy-quinoline 4-yl) Oxygen-2,3-diphenylene)-indole, cyclopropyl urea (80 mg), tetrahydrofuran (2.0 ml) and diethylamine (0.5 ml) were added and heated at 60 °C. After the reaction solution was allowed to cool, the crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystalssssssssssssssssssssssssssss 0.62-0.69 (2H, m), 0.98 (6H, t, J=7.2 Hz), 2.03 (3H, s), 2.16 (3H, s)5 2.40-2.70 (7H, m), 3.90-4.02 (1H , m), 4·22 (1H, dd, J=i〇.4, 5.6 Hz), 4.32 (1H, dd3 J=10.4, 3.6 Hz), 4.93 (1H, d, J=4.〇 '

Hz)，6·32 (1H，d，J=5.6 Hz)，6·71-6·74 (1H，m)，7·02 (1H，d， J=8.8 Ηζ)τ-7λ61-7·70 (2H，m)，7.72 (1H，br s)，8·69 (1H，d， 一 J=5.6 Hz)，8.82 (1H，s)。 -740 - 本紙張尺度適财S S家標準(CNS) A4規格297公董) ^ ：- 1304061 A7 B7 五、發明説明（735 ) — 實施例726 N6-乙基-7-芊氣基-4-(3-氣-(4-((甲胺某）羰基）胺基）苯氧 基）-6-崦啉藉醯胺 將N6-乙基-4-(4-胺基-3-氯苯氧基）-7-芊氧基-6-喹啉羧 酿胺（870 mg，1.94 mmol)及 p 比淀（460 mg，5.82 mmol)溶於 二甲基甲醯胺（10 ml)中，於冰冷下添加氯甲酸苯酯（456 mg，2.91 mmol)並於室溫攪拌18小時。將反應液分溶於乙 酸乙酯及水中，有機層用水及飽和食鹽水洗淨後，用無水 硫酸鎂乾燥。濾除乾燥劑，將濾液減壓餾去。將得到之粗 生成物一部份（460 mg，0.810 mmol)及40%甲胺-甲醇溶液 (0.810 ml)於二甲基甲醯胺（5 ml)中，於室溫攪拌30分鐘。_ 將反應液分溶於乙酸乙酯及水中，將有機層用水及飽和食'二 鹽水洗淨後，用無水硫酸鎂乾燥。濾除乾燥劑，將滤液減ν : 壓餾去。將得到之粗生成物懸浮於乙酸乙酯中，再將其以 己烷稀釋，濾取結晶及用己烷洗淨後，藉由通風乾燥，得 到為白色結晶之標題化合物（359 mg ’ 0·711 mmol，74%)。 W-NMR 光譜（DMSO-d6)c5(Ppm): 1·07 (3H，t，J=7.4 Hz)， 2·68 (3H，d，J=4.0 Hz)，3.30 (2H，m)，5·41 (2H，S)，6·54 (1H， d，J=5.2 Hz)，6.89 (1H，m)，7·23 (1H，dd，J=2.8, 9.2 Hz)， 7.34-7.40 (1H, m), 7.40-7.49 (3H, m), 7.55-7.60 (2H, m), 7.61 (1H，s)，8.13 (1H，s)，8.25 (1H，dd，J=3.2，9.2 Hz)，8.36 (1H，t，J=5.2 Hz)，8.51 (1H，s)，8.66 (1H，d，JN5.2 Hz)。 起始物象以下述方法合成。 一 製造例726-1 -741 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1304061 A7 _________ Β7 五、發明説明（736 ) 二、 .三 Ν6-·_ζ^基苄氧茱·4_氣-6-崦喊藉醯眩 於7-卞氧基·4-酮基-l，4-二氫喳啉羧酸苯酯（2.32 g , 6 ·2 5 mmol)中添加亞硫醯氯（1() ^1)及觸媒量之二甲基甲醯 胺，並於攪拌下加熱回流2小時。將反應液減壓濃縮，以甲 苯共滞2次後，將殘餘物溶於二甲基甲醯胺（丨〇 mi)及三乙 胺（5 ml)之混合溶媒中，在冰水浴冷卻下，慢慢地添加2M 乙胺（四氫呋喃溶液）（6.25 ml，12·5 mmol)，且於室溫攪拌 3小時。將反應液分溶於乙酸乙酯及水中，有機層用氨水、 水及飽和食鹽水洗淨，用無水硫酸鎂乾燥。餾去溶媒，添 加乙酸乙酯繼而添加乙醚使結晶化，濾取結晶且通風乾 燥，得到為黃色結晶之標題化合物（723 mg，2.12 mmol 34%) ° ·、 ^-NMR 光譜（DMSO-d6) 5 (ppm): 1·08 (3H，t，J=7.2 Ηζ)， Ί 3.30 (2H, m), 5.41 (2H, s), 7.34-7.39 (1H, m), 7.40-7.46 (2H, m), 7.54-7.59 (2H, m), 7.66 (1H, d, J=4.8 Hz), 7.70 (1H, s), 8.36 (1H，s), 8·42 (1H, m), 8·81 (1H，d，J=4.8 Hz) 〇 製造例726-2 Ν6·乙基- 4- (4 -胺基·3_氯笨氣基氣基·6· 口奎淋，酿胺 將4-胺基-3-氯紛（379 mg，2.64 mmol)溶於二甲基亞颯 (10 ml)中，然後在室溫慢慢地添加氫化鈉（106 mg，2.64 mmol)且攪拌30分鐘。添加N6-乙基-7-苄氧基-4-氯-6-4淋 ' 羧醯胺（720 mg，2.11 mmol)，在l〇〇°C攪拌下加熱2小時。 放冷至室温-，將反應液分溶於乙酸乙酯及水中，有機層用 一 氨水溶液、水及飽和食鹽水洗淨’用無水硫酸鈉乾燥。餾 -742 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公D 'Hz),6·32 (1H,d,J=5.6 Hz),6·71-6·74 (1H,m),7·02 (1H,d, J=8.8 Ηζ)τ-7λ61-7·70 (2H, m), 7.72 (1H, br s), 8.69 (1H, d, a J = 5.6 Hz), 8.82 (1H, s). -740 - This paper scale is suitable for SS standard (CNS) A4 specification 297 dongdong) ^ :- 1304061 A7 B7 V. Description of invention (735) - Example 726 N6-ethyl-7-helium-based -4- (3-Ga-(4-((methylamine)carbonyl)amino)phenoxy)-6-carboline by decylamine N6-ethyl-4-(4-amino-3-chlorophenoxy Base)-7-decyloxy-6-quinolinecarboxylamine (870 mg, 1.94 mmol) and p-precipitate (460 mg, 5.82 mmol) dissolved in dimethylformamide (10 ml) in ice cold Phenyl chloroformate (456 mg, 2.91 mmol) was added and stirred at room temperature for 18 h. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was evaporated under reduced pressure. A portion (460 mg, 0.810 mmol) of a crude product and a 40% methylamine-methanol solution (0.810 ml) were obtained in dimethylformamide (5 ml) and stirred at room temperature for 30 min. _ The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtrate is reduced by ν: distillation. The obtained crude product was suspended in ethyl acetate. EtOAc (m.) 711 mmol, 74%). W-NMR spectrum (DMSO-d6) c5 (Ppm): 1·07 (3H, t, J = 7.4 Hz), 2·68 (3H, d, J = 4.0 Hz), 3.30 (2H, m), 5 ·41 (2H,S),6·54 (1H, d,J=5.2 Hz), 6.89 (1H,m),7·23 (1H,dd,J=2.8, 9.2 Hz), 7.34-7.40 (1H , m), 7.40-7.49 (3H, m), 7.55-7.60 (2H, m), 7.61 (1H, s), 8.13 (1H, s), 8.25 (1H, dd, J = 3.2, 9.2 Hz), 8.36 (1H, t, J = 5.2 Hz), 8.51 (1H, s), 8.66 (1H, d, JN5.2 Hz). The starting material was synthesized in the following manner. A manufacturing example 726-1 -741 - This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 _________ Β7 V. Invention description (736) II. .3Ν6-·_ζ^ Benzyl oxime ·4_气-6- 崦 醯 醯 醯 醯 醯 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 Chloro(1()^1) and a catalytic amount of dimethylformamide were heated and refluxed for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in toluene, and the residue was dissolved in dimethylformamide ( 丨〇mi) and triethylamine (5 ml). 2M Ethylamine (tetrahydrofuran solution) (6.25 ml, 12·5 mmol) was slowly added and stirred at room temperature for 3 hr. The reaction mixture was dissolved in ethyl acetate and water. The solvent was evaporated, and ethyl acetate was added, then ethyl ether was added to crystallize, crystals were crystallized, and crystals were evaporated to give the title compound (723 mg, 2.12 mmol, 34%) as a yellow crystal, and NMR spectrum (DMSO-d6) 5 (ppm): 1·08 (3H, t, J=7.2 Ηζ), Ί 3.30 (2H, m), 5.41 (2H, s), 7.34-7.39 (1H, m), 7.40-7.46 (2H, m ), 7.54-7.59 (2H, m), 7.66 (1H, d, J=4.8 Hz), 7.70 (1H, s), 8.36 (1H, s), 8·42 (1H, m), 8·81 ( 1H,d,J=4.8 Hz) 〇Production Example 726-2 Ν6·Ethyl 4- 4-(4-Amino·3_Chloro-based gas group·6·Methyl quinone, 4-amino group Benzyl chloride (379 mg, 2.64 mmol) was dissolved in dimethyl hydrazine (10 ml), then sodium hydride (106 mg, 2.64 mmol) was slowly added at room temperature and stirred for 30 min. Ethyl-7-benzyloxy-4-chloro-6-4 lysine carboxy carbamide (720 mg, 2.11 mmol), heated under stirring at 1 ° C for 2 hours. Dissolved in ethyl acetate and water, and the organic layer was washed with an aqueous ammonia solution, water and saturated brine. 'Dry with anhydrous sodium sulfate. Distillate -742 - This paper scale applies to China National Standard (CNS) A4 (210 X 297 well-D '

裝 訂Binding

1304061 A7 ____ B7 五、發明説明（737 ) 去溶媒，懸浮於乙酸乙酯中，再將其以己烷稀釋，濾取結 晶’藉由通風乾燥，得到為褐色結晶之標題化合物（870 mg，1·94 mmol，92%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): ι·〇7 (3H，t，J=7.2 Hz)， 3.30 (2H，m)，5·40 (2H，s)，5·43-5·49 (2H，m)，6.47 (1H，d， J=5.2 Hz), 6.91 (1H, d, J=8.8 Hz), 7.01 (1H, dd, J=2.8, 8.81304061 A7 ____ B7 V. INSTRUCTIONS (737) Desolvation of the solvent, suspended in ethyl acetate, which was diluted with hexanes, and crystallized by filtration to give the title compound (870 mg, 1 · 94 mmol, 92%) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): ι·〇7 (3H, t, J = 7.2 Hz), 3.30 (2H, m), 5·40 (2H, s),5·43-5·49 (2H,m), 6.47 (1H,d, J=5.2 Hz), 6.91 (1H, d, J=8.8 Hz), 7.01 (1H, dd, J=2.8, 8.8

Hz)，7·24 (1H，d，J=2.8 Hz)，7.34-7.39 (1H，m)，7·41-7·46 (2H，m)，7.55-7.60 (3H，m)，8.36 (1H，t，J=5.2 Hz)，8.52 (1H， s)，8·62 (1H，d，J=5.2 Hz) 〇 ~ 實施例727 ΝΑ-,乙基_7_—字氧基-4-(3_氣-(_H(乙胺基）羰基）胺某）茇氧 基）-6-4琳#酿胺 將N6-乙基-4-(4-胺基-3-氯苯氧基）-7-爷氧基-6- p奎淋致令， 醯胺（870 mg，1.94 mmol)及吡啶（460 mg，5.82 mmol)溶於 二甲基甲醯胺（10ml)中，冰冷下添加氯甲酸苯酯（456 mg， 2_91 mmol)，於室溫攪拌18小時。將反應液分溶於乙酸乙 酯及水中，有機層用水及飽和食鹽水洗淨後，用無水硫酸 鎂乾燥，濾除乾燥劑，將濾液減壓餾去。將得到之粗生成 物一部份（460 mg，0.810 mmol)及2M乙胺-四氫呋喃溶液 (4.05 ml)於二甲基甲醯胺（5 ml)中及室溫下授拌3〇分鐘。 將反應液分溶於乙酸乙酯及水中，有機層用水及飽和食鹽 ' 水洗淨後’用無水硫酸鎂乾燥，濾除乾燥劑，將濾液減壓 餾去。將得-到之粗生成物懸浮於乙酸乙酯中，再將其以己 一 燒稀釋’滤取結晶及用己燒洗淨後’藉由通風乾燥，得到 -743 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 ____B7__._ 五、發明説明（738 ) 為白色結晶之標題化合物（347 mg，0.669 mmol，83%)。 iH-NMR 光譜（DMSO-d6) 5 (ppm): 1.03-1.11 (6H，m)，3·14 (2H，m)，3·30 (2H，m)，5·41 (2H，s)，6.54 (1H，d，J=5.2 Hz)， 7.01 (1H, m), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.34-7.40 (1H, m), 7.41-7.49 (3H, m), 7.55-7.60 (2H, m), 7.61 (1H, s), 8.07 (1H, s), 8.27 (1H, dd, J=3.2, 9.2 Hz), 8.36 (1H, t, J=5.2 Hz), 8.51 (1H，s)，8.66 (1H，d，J=5.2 Hz)。 實施例728 N6-乙某-4-(3-氯-4-(((甲胺基）蕤基）胺基）苯氧基）-7•羥 基-6-4啉藉醯胺 藉由與實施例83同樣之方法，從N6-乙基-7-苄氧基-4, (3_氯-(4-((甲胺基）羰基）胺基）苯氧基）-6-喳啉羧醯胺（344 mg，0.681 mmol)，得到為黃色結晶之標題化合物（253 mg，0.609 mmol，90%) ° iH-NMR 光譜（DMSO-d6)5(ppm): 1.18 (3H, t，J=7.2 Hz)， 2.68 (3H, d, J=4.4 Hz), 3.38 (2H, m), 6.42 (1H, d, J=5.2 Hz), 6.88 (1H, q, J=4.4 Hz), 7.25 (1H, dd, J=2.8, 9.2 Hz), 7.31 (1H, s), 7.49 (1H, d, J=2.8 Hz), 8.13 (1H, s), 8.27 (1H, d, J=9.2 Hz)，8.61 (1H，d，J=5.2 Hz)，8.89 (1H，s)。 實施例729 N6-乙某-4-(3-氪-4-α(乙胺基）羰基）胺基）笨氣基7-羥 基- 6-4g株竣酿胺 藉由與虞-施例83同樣之方法，從N6-乙基-7-苄氧基-心 (3-氯-(4-((乙胺基）羰基）胺基）苯氧基）-6-喹啉羧醯胺（332 -744 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（739 ) 二 mg，0.640 mmol)，得到為黃色結晶之標題化合物（247 mg，0.576 ipmol，90%) 〇 j-NMR 光譜（DMSO-d6)5(ppm): 1.08 (3H，t，J=7.2 Hz)， 1.18 (3H, t, J=7.2 Hz), 3.14 (2H, m), 3.39 (2H, m), 6.42 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=5.2 Hz), 7.25 (1H, dd, J=2.8, 9.2 Hz), 7,30 (1H, s), 7.49 (1H, d, J=2.8 Hz), 8.08 (1H, s), 8.29 (1H，d，J=9.2 Hz)，8.61 (1H，d, J=5.2 Hz)，8.90 (1H，s)。 實施例730 N6-乙H(3-氯-4-(((甲胺某）羰基）胺某）茉氫某 甲_基-4:立氫ρ比咬基）甲氣某）_ 6- 4淋複酿胺 將Ν6-乙基-4-(3-氯-4-(((甲胺基）羰基）胺基）苯氧基）-7， 經基- 6-p奎琳幾酿胺（8〇·〇 mg，0· 193 mmol)、4-(溴甲基）--: 1-六氫吡啶羧酸第三丁酯（80·5 mg，0.289 mmol)及碳酸鉀Hz),7·24 (1H,d,J=2.8 Hz),7.34-7.39 (1H,m),7·41-7.46 (2H,m),7.55-7.60 (3H,m),8.36 ( 1H, t, J = 5.2 Hz), 8.52 (1H, s), 8.62 (1H, d, J = 5.2 Hz) 〇~ Example 727 ΝΑ-, ethyl_7_--oxy-4-( 3_Gas-(_H(ethylamino)carbonyl)amine)) oxime)-6-4 Lin# N6-ethyl-4-(4-amino-3-chlorophenoxy)- 7-toloxy-6-p-quinone, decylamine (870 mg, 1.94 mmol) and pyridine (460 mg, 5.82 mmol) were dissolved in dimethylformamide (10 ml). Phenyl ester (456 mg, 2_91 mmol) was stirred at room temperature for 18 h. The reaction liquid was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated. A portion (460 mg, 0.810 mmol) of the obtained crude product and a 2M ethylamine-tetrahydrofuran solution (4.05 ml) were stirred in dimethylformamide (5 ml) at room temperature for 3 min. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with water and saturated brine &lt The obtained crude product is suspended in ethyl acetate, and then diluted with a single-burning solution, 'filtered and crystallized and washed with hexanes', dried by airing to obtain -743 - the paper size is applicable to China Standard (CNS) A4 size (210 X 297 mm) 1304061 A7 ____B7__._ V. Description of the invention (738) The title compound (347 mg, 0.669 mmol, 83%). iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.03-1.11 (6H, m), 3·14 (2H, m), 3·30 (2H, m), 5·41 (2H, s), 6.54 (1H,d,J=5.2 Hz), 7.01 (1H, m), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.34-7.40 (1H, m), 7.41-7.49 (3H, m) , 7.55-7.60 (2H, m), 7.61 (1H, s), 8.07 (1H, s), 8.27 (1H, dd, J=3.2, 9.2 Hz), 8.36 (1H, t, J=5.2 Hz), 8.51 (1H, s), 8.66 (1H, d, J = 5.2 Hz). Example 728 N6-ethyl-4-(3-chloro-4-(((methylamino)) yl)amino)phenoxy)-7-hydroxy-6-4 phenyl hydrazine Example 83, in the same manner, from N6-ethyl-7-benzyloxy-4, (3-chloro-(4-((methylamino)carbonyl)amino)phenoxy)-6-carbolinecarboxylate The title compound (253 mg, 0.609 mmol, 90%) eluted eluted eluted eluted eluted eluted eluted Hz), 2.68 (3H, d, J=4.4 Hz), 3.38 (2H, m), 6.42 (1H, d, J=5.2 Hz), 6.88 (1H, q, J=4.4 Hz), 7.25 (1H, Dd, J=2.8, 9.2 Hz), 7.31 (1H, s), 7.49 (1H, d, J=2.8 Hz), 8.13 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.61 ( 1H, d, J = 5.2 Hz), 8.89 (1H, s). Example 729 N6-By 4-(3-indole-4-α(ethylamino)carbonyl)amino) stupid 7-hydroxy-6-4 g strain of an amine by means of hydrazine - Example 83 In the same manner, from N6-ethyl-7-benzyloxy-heart (3-chloro-(4-((ethylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide (332) -744 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of the invention (739) 2 mg, 0.640 mmol), the title compound (247 mg, 0.576 ipmol, 90%) 〇j-NMR spectrum (DMSO-d6) 5 (ppm): 1.08 (3H, t, J = 7.2 Hz), 1.18 (3H, t, J = 7.2 Hz), 3.14 (2H, m ), 3.39 (2H, m), 6.42 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=5.2 Hz), 7.25 (1H, dd, J=2.8, 9.2 Hz), 7,30 (1H, s), 7.49 (1H, d, J=2.8 Hz), 8.08 (1H, s), 8.29 (1H,d,J=9.2 Hz), 8.61 (1H,d, J=5.2 Hz), 8.90 (1H, s). Example 730 N6-B-H (3-chloro-4-((methylamine)carbonyl)amine)))):::::::::::::::::::::::::::: The phosphonium amine will be 6-ethyl-4-(3-chloro-4-(((methylamino))carbonyl))amino)phenoxy)-7, via -6-p-quine 8〇·〇mg, 0· 193 mmol), 4-(bromomethyl)-: 1-tert-butyl 1-hexahydropyridinecarboxylate (80·5 mg, 0.289 mmol) and potassium carbonate

(33.3 mg，0.241 mmol)於二甲基甲醯胺（1 ml)中，在 60°C 加熱攪拌15小時。將反應液分溶於乙酸乙酯及水中，有機 層用水及飽和食鹽水洗淨後，用無水硫酸鎂乾燥，濾除乾 燥劑’將濾液減壓餾去。將得到之生成物溶於三氟乙酸（i ml) ’在室溫攪拌丨小時後，將反應液減壓濃縮，將殘餘物 溶於甲醇中，將三乙胺滴入以中和。餾去溶媒，將殘餘物 於四氫呋喃（2 ml) -甲醇（2 ml)之混合溶媒中，於室溫下依 序添加37%甲醛水溶液（〇·360 ml)、乙酸（0.070 ml)及氰基 ' 硼氫鈉（36.3 mg，〇·579 mmol)，攪拌15分鐘。於反應液中 添加驗性本-凝膠且濃縮後，付諸於矽凝膠管柱層析，將目 —— 的物溶出份減壓濃縮，將得到之粗生成物懸浮於乙酸乙酯 __ - 745 · 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（740 ) 二 中，再將其以己烷稀釋，濾取結晶及用己烷洗淨後，藉由 通風乾燥，.得到為白色結晶之標題化合物（57.5 mg，0.109 mmol，57%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): 1·16 (3H，t，J=7.2 Hz)， 1.38 (2H, m), 1.72-1.92 (5H, m), 2.17 (3H, s), 2.68 (3H, d, J=4.4 Hz), 2.81 (2H? m), 3.36 (2H, m), 4.11 (2H, d, J=6.0 Hz), 6.53 (1H, d, J=5.2 Hz), 6.87 (1H3 m), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.46 (1H, d, J=2.8 Hz), 7.49 (1H, s), 8.12 (1H, s), 8.20-8.28 (2H, m), 8.50 (1H, s), 8.65 (1H, d, J=5.2 Hz) 〇 實施例731 _ 及6-乙基-4-(3-氣-4-(((乙胺基）羰某）胺基）苽氫基\ -jg基-4-六氫吡啶基）甲氧基）-6-喹啉羧醯胺 - ：:::- 將N6-乙基- 4-(3 -氯- 4-(((乙胺基）談基）胺基）苯氧基）_7_ 羥基-6-喹啉羧醯胺（78.0 mg，0.182 mmol)、4-(溴甲基）-1-六氫p比淀幾酸第三丁酿（75.9 mg，0.273 mmol)及碳酸却 (31.4 mg，0.228 mmol)於二甲基甲醯胺（1 ml)中，在 6〇°c 加熱攪拌15小時。將反應液分溶於乙酸乙酯及水中，有機 層用水及飽和食鹽水洗淨後，用無水硫酸鎂乾燥，滤除乾 燥劑，將濾液減壓餾去。將得到之生成物溶於三氟乙酸（i ml)中’在皇溫授摔1小時後’將反應液減壓濃縮，將殘餘 一 物溶於甲醇中，並滴入三乙胺以中和。餾去溶媒，將殘餘 物溶於四義呋喃《2 ml) -甲醇（2 ml)之混合溶媒中，於室溫 一 下依序添加37%甲醛水溶液（0.340 ml)、乙酸（0.070 ml)及 ___- 746 - 本紙張尺度適用中國S家標準(CNS) A4規格(21GX 297公釐)&quot;&quot; &quot; --- 1304061(33.3 mg, 0.241 mmol) in dimethylformamide (1 ml) was stirred and stirred at 60 ° C for 15 hours. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and filtered. The obtained product was dissolved in trifluoroacetic acid (1 ml). After stirring at room temperature for a few hours, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol, and triethylamine was dropped to neutralize. The solvent was distilled off, and the residue was added to a mixture solvent of tetrahydrofuran (2 ml)-methanol (2 ml), and then a mixture of 37% aqueous formaldehyde (〇·360 ml), acetic acid (0.070 ml) and cyano group were added at room temperature. 'Sodium borohydride (36.3 mg, 〇·579 mmol), stirred for 15 minutes. After adding the gelatin gel to the reaction solution and concentrating, it was subjected to column chromatography on a gel column, and the residue of the product was concentrated under reduced pressure, and the obtained crude product was suspended in ethyl acetate. _ - 745 · This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (740) Second, dilute it with hexane, filter and crystallize The title compound (57.5 mg, 0.109 mmol, 57%) was obtained as white crystals eluted with EtOAc (m.). , J=7.2 Hz), 1.38 (2H, m), 1.72-1.92 (5H, m), 2.17 (3H, s), 2.68 (3H, d, J=4.4 Hz), 2.81 (2H? m), 3.36 (2H, m), 4.11 (2H, d, J=6.0 Hz), 6.53 (1H, d, J=5.2 Hz), 6.87 (1H3 m), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.46 (1H, d, J=2.8 Hz), 7.49 (1H, s), 8.12 (1H, s), 8.20-8.28 (2H, m), 8.50 (1H, s), 8.65 (1H, d, J= 5.2 Hz) 〇Example 731 _ and 6-ethyl-4-(3-carb-4-(((ethylamino)carbonyl))amino)hydrazine-based -jgyl-4-hexahydropyridyl )methoxy)-6-quinoline carboxamide - ::::- N6-ethyl- 4- (3-Chloro-4-((ethylamino)-yl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide (78.0 mg, 0.182 mmol), 4-(bromomethyl)- 1-hexahydro p is the third acid (75.9 mg, 0.273 mmol) and carbonic acid (31.4 mg, 0.228 mmol) in dimethylformamide (1 ml), heated and stirred at 6 ° C 15 hours. The reaction mixture was dissolved in ethyl acetate and water, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The obtained product was dissolved in trifluoroacetic acid (1 ml), and the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol, and triethylamine was added dropwise to neutralize. . The solvent was distilled off, and the residue was dissolved in tetrahydrofuran "2 ml"-methanol (2 ml) in a mixture solvent, and 37% aqueous formaldehyde (0.340 ml), acetic acid (0.070 ml) and _ __- 746 - This paper size applies to China S Standard (CNS) A4 specification (21GX 297 mm)&quot;&quot;&quot; --- 1304061

氰基硼氫鈉（34.3 mg，0.546 mmol)，並攪拌15分鐘。於反 應液中添加驗性矽凝膠且濃縮後，付諸於矽凝膠管柱層 析’將目的物溶出份減壓濃縮，將得到之粗生成物懸浮於 乙酸乙ί旨中’再將其以己烷稀釋，濾取結晶及用己烷洗淨 後’藉由通風乾燥，得到為白色結晶之標題化合物（58. i mg，0.108 mmol，59%) 〇 H-NMR 光請（DMSO-d6)5(ppm): 1.08 (3H，t，J=7.2 Hz)， 1.16 (3H, t, J=7.2 Hz), 1.38 (2H, m), 1.72-1.92 (5H, m), 2.17 (3H，s)，2.81 (2H，m)，3.14 (2H，m)，3·35 (2H，m)，4.10 (2H， d, J=6.0 Hz), 6.53 (1H, d5 J=5.2 Hz), 7.00 (1H, m), 7.22 (1H, dd，J=2.8, 8.8 Hz)，7.47 (1H，d，J=2.8 Hz)，7.49 (1H，s)，8.07 (1H，s)，8.22-8.29 (2H，m)，8.50 (1H，s)，8.66 (1H，d，J=5.2Sodium cyanoborohydride (34.3 mg, 0.546 mmol) was stirred for 15 min. An anthraquinone gel was added to the reaction solution and concentrated, and then applied to a gel column chromatography. The target product was concentrated under reduced pressure, and the obtained crude product was suspended in acetic acid. The title compound (5. D6) 5 (ppm): 1.08 (3H, t, J = 7.2 Hz), 1.16 (3H, t, J = 7.2 Hz), 1.38 (2H, m), 1.72-1.92 (5H, m), 2.17 (3H , s), 2.81 (2H, m), 3.14 (2H, m), 3·35 (2H, m), 4.10 (2H, d, J = 6.0 Hz), 6.53 (1H, d5 J = 5.2 Hz), 7.00 (1H, m), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.47 (1H, d, J=2.8 Hz), 7.49 (1H, s), 8.07 (1H, s), 8.22-8.29 (2H,m), 8.50 (1H,s),8.66 (1H,d,J=5.2

Hz)。 — 實施例732 Νϋ_氧基-了-爷氧基_4_(3•氣- 乙胺基）辨基）脖篡、草 氧基）-6- 4淋#臨胺 將N6-甲氧基-4-(4-胺基-3-氯苯氧基）-7-苄氧基-6_喳啉 致酿胺（81.0 mg，0.180 mmol)及 ρ 比淀（32.0 mg，〇·4〇4 mmol) 溶於二甲基甲酿胺（2 ml)中，於冰冷下添加氯甲酸苯酿 (42.3 mg，0.270 mmol)後，於室溫揽拌30分鐘。於反應液 中添加2M乙胺-四氫呋喃溶液（0.270 ml)，進一步於室溫下 ' 攪捽30分鐘。將反應液分溶於乙酸乙酿及水中，有機層用 水及飽和^^鹽水洗淨後，用無水硫酸鍰乾燥，滤除乾燥 — 劑，將濾液減壓餾去。將得到之粗生成物懸浮於乙鍵中， -747 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7Hz). - Example 732 Νϋ 氧基 oxy-----yloxy_4_(3•--ethylamino) discriminating) 篡 篡, oxalooxy)-6- 4 leaching #临胺N6-methoxy- 4-(4-Amino-3-chlorophenoxy)-7-benzyloxy-6-carboline-induced amine (81.0 mg, 0.180 mmol) and ρ-precipitate (32.0 mg, 〇·4〇4 mmol) Dissolved in dimethyl ketoamine (2 ml), added with chloroformic acid benzene (42.3 mg, 0.270 mmol) under ice-cooling, and stirred at room temperature for 30 min. A 2 M ethylamine-tetrahydrofuran solution (0.270 ml) was added to the reaction mixture, and the mixture was further stirred at room temperature for 30 minutes. The reaction solution was dissolved in ethyl acetate and water, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and filtered, and evaporated. The obtained crude product is suspended in the B bond, -747 This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7

再將其以己烷稀釋’濾取結晶及用己烷洗淨後，藉由通風 乾燥，得到為白色結晶之標題化合物（68 5 mg , 〇 mmol，73%) 〇 H-NMR 光 if(DMSO-d6)5(ppm): ι·〇8 (3H，t，J=7.2 Hz) 3.15 (2H, m), 3.72 (3H, s)3 5.40 (2H, s), 6.54 (1H, d, J=5i2 Hz), 7.01 (1H, m), 7.22 (lH, dd, J=2.8, 9.2 Hz), 7.32-7,37 (1H，m)，7.40-7.46 (2H，m)，7 47 (1H, d, J=2 8 Hz)，7 53_ 7.60 (3H, m), 8.07 (1H, s), 8.27 (1H, dd, J=3.2, 9.2 Hz), 8.34 (1H，s)，8·65 (1H，d，J=5.2 Hz)，11.53 (1H，br s)。 · 起始物質係以下述方法合成。 製造例732-1 ΝΑ-甲氧基苄氧基4啉藉醯胺 於7宇氧基4酮基-i，4_二氧奎琳叛酸苯酿（2,32—g， 6·25 mmol)中添加亞硫醯氯（1〇㈤”及觸媒量之二甲基甲醯 胺，然後於攪拌下加熱回流2小時。將反應液減壓濃縮，以 甲苯共沸2次後，將殘餘物溶於二甲基甲醯胺（2〇瓜丨）及三 乙胺（20 ml)之混合溶媒中，在冰水浴冷卻下，添加甲氧胺 鹽酸鹽（10.4 g，125 mmol)，且於室溫攪捽18小時。將反應 液分落於乙酸乙酯及水中，將有機層用水及飽和食鹽水洗 淨後，用無水硫酸鎂乾燥。餾去溶媒後，付諸於矽凝膠管 柱層析，將目的物溶出份減壓濃縮，終後將得到之粗生成 物懸浮於乙酸乙酯中，再將其以己烷稀釋，濾取結晶及用. 己烷洗淨後-，藉由通風乾燥，得到為白色結晶之標題化合 物（392 mg，1.14 mmol，18%) 〇 -748 -The title compound (68 5 mg, 〇mmol, 73%) was obtained as white crystals (yield: EtOAc). -d6)5(ppm): ι·〇8 (3H,t,J=7.2 Hz) 3.15 (2H, m), 3.72 (3H, s)3 5.40 (2H, s), 6.54 (1H, d, J =5i2 Hz), 7.01 (1H, m), 7.22 (lH, dd, J=2.8, 9.2 Hz), 7.32-7,37 (1H,m), 7.40-7.46 (2H,m),7 47 (1H , d, J=2 8 Hz), 7 53_ 7.60 (3H, m), 8.07 (1H, s), 8.27 (1H, dd, J=3.2, 9.2 Hz), 8.34 (1H, s), 8.65 (1H, d, J = 5.2 Hz), 11.53 (1H, br s). · The starting materials were synthesized in the following manner. Manufactured Example 732-1 ΝΑ-methoxybenzyloxy 4 porphyrin decylamine was synthesized on 7 oxy-4-keto-i,4 dioxopyridinyl phenolic acid (2,32-g, 6.25 mmol) Add ruthenium chloride (1 〇 (5)" and a catalytic amount of dimethylformamide, and then heat to reflux for 2 hours with stirring. The reaction solution is concentrated under reduced pressure, and after azeotropy twice with toluene, residue The product was dissolved in a mixed solvent of dimethylformamide (2 guanidine) and triethylamine (20 ml), and methoxyamine hydrochloride (10.4 g, 125 mmol) was added under cooling in an ice water bath, and After stirring for 18 hours at room temperature, the reaction mixture was separated into ethyl acetate and water, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. Column chromatography, the target extract was concentrated under reduced pressure, and the obtained crude product was suspended in ethyl acetate, then diluted with hexane, filtered, and washed with hexane. The title compound (392 mg, 1.14 mmol, 18%) was obtained as white crystals.

1304061 A7 B7 五、發明説明（743) 二、 H-NMR光譜（DMSO-d6)(5(ppm): 3.72 (3H，s)，5.41 (2H，s)， 7.32-7.38 (1H, m), 7.40-7.46 (2H, m)5 7.52-7.56 (2H, m), 7.64-7.70 (2H, m), 8.22 (1H, s), 8.82 (1H, d, J=4.8 Hz), 11·60 (1H，br s) 〇 製造例732-2 mJL·氧基-4 胺基-3 -氯茉氩某H芊氫某-6 _ g套啉藉醯 霞 將4-胺基-3-氯紛（408 mg，2·84 mmol)溶於二甲基亞颯 (10 ml)中’在室溫慢慢地添加氫化鈉（j 14 mg，2.84 mmol) 且擾拌30分鐘。添加N6-甲氧基_7-苄氧基_4·氯_6_喳啉羧 酿胺（388 mg，1·14 mmol)，在100 °C及撥拌下加熱18小 時。放冷至室溫，將反應液分溶於乙酸乙酯及水中，有機 層用水及飽和食鹽水洗淨，然後用無水硫酸鎂乾燥。扁去 么媒後’付諸於碎凝膠管柱層析，將目的物溶出份減壓濃 縮’將得到之粗生成物懸浮於乙酸乙酯中，再將其以己烷 稀釋，濾取結晶及用己烷洗淨後，藉由通風乾燥，得到為 白色結晶之標題化合物（81 ·〇 mg，0· 1 80 mmol，16%)。 W-NMR 光譜（CDCl3)(5(ppm): 3·81 (3H，s)，4·22 (2H，br s)， 5·43 (2H，s)，6.68 (1H，d，J=6.2 Hz)，6.88 (1H，d，J=8.8 Hz)， 6.94 (1H, dd, 1=2.8, 8.8 Hz), 7.16 (1H, d, J=2.8 Hz), 7.41- 7.58 (5H，m)，8.14 (1H，s)，8.66 (1H，d，J=6.2 Hz)，9·35 (1H， s)，10.19 (1H，s) 〇 實施例一 甲氧基-.IdJ-氣-4-(((乙胺某）羰基）胺基）茇氳某7-羥 - _ —_- 749 -___一 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（744) 某-6〃杏4羧醯胺 藉由與實施例83同樣之方法，從N6-甲氧基-7-芊氧基-4-(3-氣-(4-((乙胺基）羰基）胺基）苯氧基）-6-喹啉羧醯胺 (68·3 mg，0.131 mmol)，得到為黃色結晶之標題化合物 (43.3 mg，0.101 mmol，77%) 〇 iH-NMR 光譜（DMSO-d6)5(ppm): 1.08 (3H，t，J=7.2 Hz)， 3.14 (2H, m), 3.76 (3H, s), 6.43 (1H, d, J=5.2 Hz), 7.00 (lH, t，J=5.2 Hz)，7.25 (1H，dd，J=2.8，9.2 Hz)，7.34 (1H，br s)， 7.48 (1H, d, J=2.8 Hz), 8.07 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.60 (1H，d，J=5.2 Hz)，8.64 (1H，s)。 實施例734 ίϋ-甲基-4-(—3-氯環丙胺基）羰某）胺基）茉氫某2^ 甲氧乙氣基）-6- 4啉#醯胺 一 使用甲胺之甲醇溶液，以與實施例249同樣之方式，得到 目的物。 1 H-NMR(DMSO-d6) 5 (ppm): 0.38-0.44 (2H, m), 2.62-2.68 (2H, m), 2.50-2.60 (1H, m), 2.85 (3H, d, J=4.8 Hz), 3.37 (3H, s)5 3.79 (2H, t, J-4.4 Hz), 4.39 (2H, t, J=4.4 Hz), 6.52 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.4 Hz), 7.23 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.48 (1H, d, J=2.4 Hz), 7.55 (1H, s), 7.96 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8.35 (1H, q, J=4.8 Hz), 8.65 (1H, d, J=5.2 Hz)，8·66 (1H，s)。 實施例731 - - 乙基-4_(3-氟-4-(((環丙胺某）羰基）胺基）茉氳某V7- _____- 750 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 ___ B7 _____ 五、發明説明（745) 二 (2-甲氣乙氣某）-6-崦啉羧醯胺 使用乙胺之四氫呋喃溶液，以與實施例249同樣之方式’ 得到目的物。 lH-NMR(DMSO-d6) (5 (ppm): 0.38-0.44 (2H, m), 2.62-2.68 (2H, m), 1.15 (3H, t, J=7.2 Hz), 2.50-2.60 (1H, m), 3.27-3.40 (2H, m), 3.36 (3H, s), 3.79 (2H, t, J=4.4 Hz), 4.39 (2H, t, J=4.4 Hz), 6.51 (1H, d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=8.8 Hz, 2.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.54 (1H, s), 7.96 (1H, s)3 8.26 (1H, d, J=8.8 Hz), 8.34 (1H, t, J=4.8 Hz)，8·65 (1H，d，J=5.6 Hz)，8·68 (1H，s)。 實施例736 - ·. Ν-(2·氣-4-(6-氨基-7-Π-Π-六氤毗忒某）丙氣基）-4-4咏_ ' 基）氣茉某環丙脲 一 ：:: 藉由與實施例7同樣之方法，從N-C4-(6-氰基-7-羥基-4-喹啉基）氧-2-氯苯基）-N’-環丙脲（500 mg，1·60 mmol)及1-(3-氯丙基）六氫吡啶鹽酸鹽，得到為淡黃色結晶之標題化 合物（102.2 mg，0.197 mmol，12.3%)。 &quot;H-NMR 光譜（DMSO-d6)(5(ppm): 0.42 (2H，m)，0·65 (2H，m)， 1·37 (2H，m)，1·48 (2H，m)，1.96 (2H，m)，2.34 (4H，m)， 2.43-2.49 (4H，m)，2·56 (1H，m)，4.31 (2H，m)，6·57 (1H，d， J=5.2 Hz), 7.19 (1H, d, J=2.8 Hz), 7.25 (1H, dd, J=2.8, 8.8 Hz), 7.49 (1H, d, J=2.8 Hz), 7.59 (1H, s), 7.98 (1H, s), 8.27 (1H，d，J=^8 Hz)，8.71-8.74 (2H，m) 〇 ’ 實施例737 _____- 751 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A71304061 A7 B7 V. Description of the invention (743) 2. H-NMR spectrum (DMSO-d6) (5 (ppm): 3.72 (3H, s), 5.41 (2H, s), 7.32-7.38 (1H, m), 7.40-7.46 (2H, m)5 7.52-7.56 (2H, m), 7.64-7.70 (2H, m), 8.22 (1H, s), 8.82 (1H, d, J=4.8 Hz), 11·60 ( 1H, br s) 〇 Production Example 732-2 mJL·oxy-4 Amino-3-Chloro argon A H 芊 hydrogen -6 _ g zoline by 醯 醯 将 胺 胺 胺 胺 4- 408 mg, 2.84 mmol) dissolved in dimethyl hydrazine (10 ml). Slowly add sodium hydride (j 14 mg, 2.84 mmol) at room temperature and stir for 30 min. Add N6-methoxy _7-Benzyloxy_4·chloro-6-porphyrin carboxychiral amine (388 mg, 1.14 mmol), heated at 100 ° C for 18 hours with stirring. Allow to cool to room temperature and separate the reaction solution. It is dissolved in ethyl acetate and water, and the organic layer is washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. 'The obtained crude product was suspended in ethyl acetate, and it was diluted with hexane, and the crystals were collected by filtration and washed with hexane, and dried by air to give white crystals. Compound (81 · 〇mg, 0·1 80 mmol, 16%). W-NMR spectrum (CDCl3) (5 (ppm): 3·81 (3H, s), 4·22 (2H, br s), 5·43 (2H, s), 6.68 (1H, d, J = 6.2 Hz), 6.88 (1H, d, J = 8.8 Hz), 6.94 (1H, dd, 1=2.8, 8.8 Hz), 7.16 (1H , d, J=2.8 Hz), 7.41- 7.58 (5H,m), 8.14 (1H,s), 8.66 (1H,d,J=6.2 Hz),9·35 (1H, s),10.19 (1H, s) 〇 Example 1-methoxy-.IdJ-gas-4-(((ethylamine)carbonyl)amino) 茇氲7-hydroxy- ___- 749 -___ a paper scale for China National Standard (CNS) A4 Specification (210X 297 mm) 1304061 A7 B7 V. Inventive Note (744) A-6-Apricot 4 Carboxamide The same procedure as in Example 83, from N6-methoxy-7 - methoxy-4-(3-carbo-(4-((ethylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide (68·3 mg, 0.131 mmol), The title compound of the title compound (43.3 mg, 0.101 mmol, 77%) 〇iH-NMR spectrum (DMSO-d6) 5 (ppm): 1.08 (3H, t, J = 7.2 Hz), 3.14 (2H, m), 3.76 (3H, s), 6.43 (1H, d, J=5.2 Hz), 7.00 (lH, t, J=5.2 Hz), 7.25 (1H, dd, J=2.8, 9.2 Hz), 7.34 (1H, d, J = 2.8 Hz), 8.07 (1H, s), 8.27 (1H, d, J = 9.2 Hz), 8.60 (1H, d, J = 5.2 Hz) , 8.64 (1H, s). Example 734 ϋ 甲基-methyl-4-(-3-chlorocyclopropylamino)carbonyl)amino) japan hydrogen 2 methoxyethoxy)-6- 4 porphyrin #醯amine-methanol using methylamine The object was obtained in the same manner as in Example 249. 1 H-NMR (DMSO-d6) 5 (ppm): 0.38-0.44 (2H, m), 2.62-2.68 (2H, m), 2.50-2.60 (1H, m), 2.85 (3H, d, J=4.8 Hz), 3.37 (3H, s)5 3.79 (2H, t, J-4.4 Hz), 4.39 (2H, t, J=4.4 Hz), 6.52 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.4 Hz), 7.23 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.48 (1H, d, J=2.4 Hz), 7.55 (1H, s), 7.96 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8.35 (1H, q, J=4.8 Hz), 8.65 (1H, d, J=5.2 Hz), 8.66 (1H, s). Example 731 - - Ethyl-4_(3-fluoro-4-(((cyclopropylamine)carbonyl)))) A V7- _____- 750 - This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210X297 mm) 1304061 A7 ___ B7 _____ V. Description of the invention (745) II (2-methyl ethane) -6-porphyrin Carboxamide A solution of ethylamine in tetrahydrofuran was used in the same manner as in Example 249. Obtained the objective. lH-NMR (DMSO-d6) (5 (ppm): 0.38-0.44 (2H, m), 2.62-2.68 (2H, m), 1.15 (3H, t, J = 7.2 Hz), 2.50- 2.60 (1H, m), 3.27-3.40 (2H, m), 3.36 (3H, s), 3.79 (2H, t, J=4.4 Hz), 4.39 (2H, t, J=4.4 Hz), 6.51 (1H , d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=8.8 Hz, 2.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.54 ( 1H, s), 7.96 (1H, s)3 8.26 (1H, d, J=8.8 Hz), 8.34 (1H, t, J=4.8 Hz), 8·65 (1H, d, J=5.6 Hz), 8.68 (1H, s). Example 736 - ·. Ν-(2·Ga-4-(6-Amino-7-Π-Π-六氤别忒)) Propylene)-4-4咏_ 'base) gas chlorocyclopropaneurea::: by the same method as in Example 7, from N-C4-(6-cyano-7-hydroxy-4-quinolinyl)oxy-2-chloro Phenyl)-N'- Propan-urea (500 mg, 1 · 60 mmol) and 1- (3-chloropropyl) piperidine hydrochloride, to give the title compound as pale yellow crystals (102.2 mg, 0.197 mmol, 12.3%). &quot;H-NMR spectrum (DMSO-d6) (5 (ppm): 0.42 (2H, m), 0·65 (2H, m), 1·37 (2H, m), 1·48 (2H, m) , 1.96 (2H, m), 2.34 (4H, m), 2.43-2.49 (4H, m), 2·56 (1H, m), 4.31 (2H, m), 6·57 (1H, d, J= 5.2 Hz), 7.19 (1H, d, J=2.8 Hz), 7.25 (1H, dd, J=2.8, 8.8 Hz), 7.49 (1H, d, J=2.8 Hz), 7.59 (1H, s), 7.98 (1H, s), 8.27 (1H, d, J=^8 Hz), 8.71-8.74 (2H, m) 〇' Example 737 _____- 751 - This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7

於4-(4-硝苯氧基）噻吩并[2,3_d]嘧啶25〇 中，添加鐵 粉37〇mg、氯化銨75〇mg、乙醇3〇ml及水3mi，在8㈡代 攪拌2 · 5 U 4讓其回至至溫後，添加四氯咬喃，用碎藥土 過濾，於濾液中加乙酸乙酯及水並分液萃取。將有機層用 飽和食鹽水洗淨，用無水硫酸鈉乾燥，以棉栓過濾，濃縮 至乾，得到胺化合物182 mg。將其之70 mg於甲苯4 ml及乙 腈4 ml中回流使溶解，添加異氰酸3_氟苯酯（列以丨）且攪摔i 小時。放置至室溫，濾取析出之結晶，乾燥後，得到標題 化合物73 mg。 W-NMR 光譜（DMSO-d6) 5 (ppm): 6.72-6.80 (1H，m)，7.12 (1H，d，J=7.7 Ηζ)，7·22 (2H，d，J=7.7 Hz)，7.28 (1H，dd，- · 1=14.2 Hz, 7.1 Hz), 7.49 (1H, dv J=14.2 Hz), 7.52 (2H； d9 ^ J=7.7 Hz)，7.64 (1H，dd，J=6.5 Hz，1·5 Hz)，7·84 (1H，d， J=6.5 Hz)，8·60 (1H，s)，9.00 (1H，s)，9.10 (1H，S)。 中間體係以下述方法合成。 製造例737-1 4-(4-硝苯氣基吩并f2,3-dl嘧啶 於 Seans Acad· Sci·，Ser，C( 1967)264(2)207 中記載之化合 物4-氯p塞吩并[2,3-d]嘧啶302 mg中，添加4-硝基紛600 mg、碳酸鉀1.2g及二甲基甲醯胺2 ml，在130°C攪摔30小時 — 後，回至室溫，加水並用乙酸乙酯-四氫味喃混合溶液分液 年取’濃’至乾’將得到之固體以乙酸洗淨，得到榡題化 -合物250 mg 〇 -752 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱） A7 B7 1304061 五、發明説明（747) 二 lH-NMR (DMSO-d6) 5 (ppm): 7.63 (2H, d, J=8.7 Hz), 7.68 (1H, d, J=6.1 Hz), 8.00 (1H, d, J=6.1 Hz), 8.35 (2H, d, J=8.7 Hz)，8·65 (1H，s)。 f施例73 8 氟苯基）-嚷吩并[2,3-dlp密淀-4-某氧基）笨基）In 4-(4-nitrophenoxy)thieno[2,3_d]pyrimidine 25〇, add 37〇mg of iron powder, 75〇mg of ammonium chloride, 3〇ml of ethanol and 3mi of water, and stir in 8 (two) generation 2 · 5 U 4 After returning to the temperature, add tetrachloromethane, filter with crushed soil, add ethyl acetate and water to the filtrate and extract with liquid separation. The organic layer was washed with brine, dried over anhydrous sodium sulfate 70 mg of this was dissolved in 4 ml of toluene and 4 ml of acetonitrile to dissolve, and 3-fluorophenyl isocyanate (listed in hydrazine) was added and stirred for 1 hour. After standing at room temperature, the precipitated crystals were collected by filtration. W-NMR spectrum (DMSO-d6) 5 (ppm): 6.72-6.80 (1H, m), 7.12 (1H, d, J = 7.7 Ηζ), 7.22 (2H, d, J = 7.7 Hz), 7.28 (1H, dd, -1 = 14.2 Hz, 7.1 Hz), 7.49 (1H, dv J = 14.2 Hz), 7.52 (2H; d9 ^ J = 7.7 Hz), 7.64 (1H, dd, J = 6.5 Hz, 1·5 Hz), 7·84 (1H, d, J=6.5 Hz), 8·60 (1H, s), 9.00 (1H, s), 9.10 (1H, S). The intermediate system was synthesized in the following manner. Production Example 737-1 4-(4-Nitrobenzene-based phenantho-f2,3-dl-pyrimidine in Seans Acad. Sci., Ser, C (1967) 264(2) 207, 4-chloro-p-phene And [2,3-d]pyrimidine 302 mg, add 4-nitro 600 mg, potassium carbonate 1.2 g and dimethylformamide 2 ml, stir at 130 ° C for 30 hours - after returning to the room Warm, add water and use ethyl acetate-tetrahydrofuran mixed solution to separate the liquid and take 'concentrated' to dry'. The solid obtained is washed with acetic acid to obtain the title compound 250 mg 〇-752. China National Standard (CNS) A4 Specification (210 X 297 public) A7 B7 1304061 V. Description of Invention (747) Two lH-NMR (DMSO-d6) 5 (ppm): 7.63 (2H, d, J=8.7 Hz) , 7.68 (1H, d, J=6.1 Hz), 8.00 (1H, d, J=6.1 Hz), 8.35 (2H, d, J=8.7 Hz), 8·65 (1H, s) f Example 73 8 fluorophenyl)-non-pheno[2,3-dlp-dense-4-anoxy) stupid base)

Wl.- 從實施例737記載之胺化合物90 mg，使用異氰酸4-氟苯 酯（90# 1)，藉由實施例737同樣之方法，得到標題化合物 - 一 - 92 mg 0 W-NMR 光譜：（DMSO-d6) 7·12 (2H，t，J=9.6 Hz)，7.20 (2H，d， J=8.6 Hz), 7.46 (2H, dd, J=9.6 Hz, 5.2 Hz), 7.52 (2H, d, J=8.6 Hz), 7.63 (1H, d, J=6.2 Hz), 7.94 (1H, d, J=6.2 Hz),-: 8·59 (1H，s)，8.89 (1H，s)，8·94 (1H，s)。 一 實施例739 Ν- (3二苯基）-Ν’- 塞吩并f 3,2-dl喊咱：-4-某氣基）策某） 默 以實施例73 7記載之方法同樣地，從4- (4-硝苯氧基）p塞吩 并[3,2-d]嘧啶375 mg，得到胺化合物310 mg。從該胺化合 物135 mg，藉由實施例737同樣之方法，使用異氰酸3 _氟苯 酉旨（90 /z 1) ’得到標題化合物250 mg。 h-NMR 光譜：（DMSO-d6) 6·72-7·56 (8H，m)，7.65 (1H，d， J=6.2 Hz), 8.44 (1H, d, J=6.2 Hz), 8.68 (1H, s), 8.86 (1H, s), 8.95 (1H，專- — 中間體係以以下之方法合成。 __- 753 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（748) 製造例739-1 4-(4 -石肖苯乳基）口塞吩并「3,2-dl 口密淀 藉由實施例737- 1記載之方法，從Seans Acad. Sci.，Ser， C( 1967)264( 1) 100中記載之化合物4-氯噻吩并[3,2-4]嘧啶 3 1 5 mg ’得到標題化合物3 82 mg。 iH-NMR光譜：（DMSO-d6) 7.63-7.69 (2H，m)，7.70 (1H，d，J= 6.1 Hz), 8.32-8.38 (2H, m), 8.51 (1H, d, J=6.1 Hz), 8.73 (1H, s) ° 實施例740 ' N_-〔4-氟苯基嘍吩并f3,2-dl嘧啶-4-甚氣）茉某）服 藉由與實施例737同樣之方法，使用異氰酸4-氟苯酯（94 # 1)從實施例739記載之胺化合物150 mg，得到標題化合物 135 mg 〇 一 W-NMR 光譜：（DMSO-d6) 7.00-7.56 (8H，m)，7.65 (1H，d， J=6.1 Hz), 8.44 (1H, d, J=6.1 Hz), 8.67 (1H, s), 8.73 (1H, s), 8·78 (1H，s) 〇 實施例741 N-(4-(6,7-二甲氧喹啉-4-基氣）苯某VN’-(3-甲碏醯苽某、 脲 將藉由WO 97/ 17329之方法得到之4-(6,7-二甲氧峻啉-4-基氧）苯胺（296 mg，1.00 mmol)及（3-甲磺醯苯基）胺甲酸苯 酯（291 mg，1.00 mmol)在二甲基亞諷（3 ml)中，在85°C加 熱攪拌2'M孝·。將反應液分溶於乙酸乙酯及水中，有機層用 1N氫氧化鈉水溶液、水及飽和食鹽水洗淨，用無水硫酸鎂 ___ - 754 __ 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（749 ) 二' 乾燥，濾除乾燥劑，以及將濾液減壓餾去。將得到之粗生 成物付諸於石夕凝膠管柱層析（溶出液為乙酸乙醋：甲醇 =30 : 1)，再將含有目的物之溶出份濃縮，懸浮於乙酸乙酯 中’再將其以己烷稀釋，濾取結晶及用己烷洗淨後，藉由 通風乾燥，得到為無色結晶之標題化合物（430 mg，〇.871 mmol _，87%) 〇 H-NMR 光譜（CDCl3)5(ppm): 3.16 (3H，s)，4.03 (3H，s)， 4·〇5 (3H，s)，6.46 (1H，d，J=5.2 Hz)，7.12-7.18 (2H，m)，7.41 (1H, s)5 7.50-7.62 (6H, m), 7.81 (1H, s), 7.93 (1H, s), 8.11-8.15 (1H，m)，8·48 (1H，d，J=5.2 Hz)。 實施例 ϋ:·(2_氣_4_((6·氰基- 7-M-六氤吡啶甲氣基p杏嗾篡）氧_ 基）笨某）-Ν·-甲基脲 -一 Ί 將Ν- (2-氯-4- ( 6-氰基_ 7- #垔峻琳-4-基氧）苯基）-Ν，-甲基 脉（125 mg)加入二甲基甲酿胺（ι·5 ml)中，於其中添加4· (溴T基）-1-六氫吡啶羧酸第三丁酯（141 mg)及碳酸鉀（93 mg) ’在60 C加熱3小時。於此反應液中加水且用乙酸乙酯 萃取，有機層依序用水及飽和食鹽水洗淨後，用無水硫酸 鋼乾燥’且減壓餾去溶媒。將得到之粗生成物於乙酸乙酯 中再結晶，得到為淡黃色結晶之4·“甲胺基） 羰基）胺苯氧基）-6 -氰基-7 -喹啉基）氧基）甲基）-i -六氫吡啶-: 羧酸第三丁酯（21 mg)。將其溶於三氟乙酸（1〇 ^1)，在室 溫擾拌10^-鐘，於其中加水2 ml並藉碳酸氫鈉中和，濾取 一 析出之結晶，得到標題化合物（16 mg)。 L _ - 755 - 尺度適财a ®家標準(CNS) A4規格(210 X 297公董) 1304061 A7 B7 五、發明説明（75〇) ^-NMR (DMSO-d6) 5 (ppm): 1.20-1.35 (4H, m), 1.70-1.80 (2H，m)，1.90-2.01(lH，m)，2.66(3H，d，J=4.4Hz)，2.95-3.05 (2H, m), 4.12 (2H, d, J=6.0 Hz), 6.58 (1H, d, J=5.2 Hz), 6.84-6.92 (1H, m), 7.21-7.26 (1H, m), 7.48 (1H, d, J=2.4 Hz), 7.59 (1H, s), 8.12 (1H, s), 8.22-8.28 (1H, m), 8.71-8.78 (2H, m) 〇 實施例743 N-(2-氯-4-((6-氨某- 7-((1-甲基-4-六氤吡啶基）甲氳基）-啉基）氣某）茏基）-Ν·-甲基脲 將Ν-(2-氯-4-((6-氰基-7-( 4-六氳吡啶甲氧基）-4-喳啉基） 氧基）苯基）-N*-甲基脲（15 mg)溶於四氳吱喃（0.5 ml)及甲 醇（0.5 ml)中後，於室溫添加37%甲醛水溶液（0.03 ml)、乙-酸（0.06 ml)及氰基硼氫鈉（5.0 mg)後，攪拌1小時。在~犮應： 液中加入水且用飽和碳酸氫鈉水溶液中和，並藉由乙酸乙 酯萃取。將有機層用水洗淨，餾去溶媒，得到粗生成物。 將其從乙酸乙酯中再結晶，得到為白色結晶之標題化合物 (10 mg) 〇 ^-NMR (DMSO-d6) 5 (ppm): 1.13-1.47 (2H? m), 1.75-1.95 (5H，m)，2·17 (3H，s)，2·68 (3H，s)，2.78-2.87 (2H，m)，4.17 (2H, d, J=6.0 Hz), 6.59 (1H, d, J=5.2 Hz), 6.95 (1H, br s), 7.22-7.28 (1H, m), 7.48 (1H, d, J=2.4 Hz), 7.61 (1H, s), 8.18 (1H，br s)，8·22·8·29 (1H，m)，8.72-8.77 (2H，m)。 以上之餐造例及實施例中所得到化合物之構造式，如以 下表4〜表5 1所示。 L__- 756 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7Wl.- The title compound - 1-92 mg 0 W-NMR was obtained from the title compound (yield: Spectrum: (DMSO-d6) 7·12 (2H, t, J = 9.6 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.46 (2H, dd, J = 9.6 Hz, 5.2 Hz), 7.52 ( 2H, d, J=8.6 Hz), 7.63 (1H, d, J=6.2 Hz), 7.94 (1H, d, J=6.2 Hz), -: 8·59 (1H, s), 8.89 (1H, s ), 8·94 (1H, s). Example 739 Ν-(3 diphenyl)-Ν'-cephene f 3,2-dl shouting: -4- a gas base) The method described in Example 73 7 is the same, From 375 mg of 4-(4-nitrophenoxy)p-seceno[3,2-d]pyrimidine, an amine compound 310 mg was obtained. From the 135 mg of the amine compound, the title compound (250 mg) was obtained by the procedure of Example 737, using 3- fluorophenyl phthalic acid (90 /z 1). h-NMR spectrum: (DMSO-d6) 6·72-7·56 (8H, m), 7.65 (1H, d, J = 6.2 Hz), 8.44 (1H, d, J = 6.2 Hz), 8.68 (1H , s), 8.86 (1H, s), 8.95 (1H, special - - The intermediate system is synthesized in the following way. __- 753 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. INSTRUCTION OF THE INVENTION (748) Production Example 737-1 4-(4-Dishylbenzene-based) ketone and "3,2-dl-peri-dense by the method described in Example 737-1, from Seans Acad. Sci., Ser, C (1967) 264(1) The compound 4-chlorothieno[3,2-4]pyrimidine 3 1 5 mg ', the title compound 3 82 mg. iH-NMR spectrum: (DMSO-d6) 7.63-7.69 (2H, m), 7.70 (1H, d, J = 6.1 Hz), 8.32-8.38 (2H, m), 8.51 (1H, d, J = 6.1 Hz), 8.73 (1H , s) ° Example 740 'N_-[4-fluorophenyl phenanthroline f3,2-dl pyrimidine-4-carbamate) Molybdenum) was used in the same manner as in Example 737, using isocyanic acid 4 -Fluorophenyl ester (94 #1) from the amine compound 150 mg as described in Example 739 to give the title compound 135 mg 〇-W-NMR spectrum: (DMSO-d6) 7.00-7.56 (8H, m), 7.65 (1H, d, J=6. 1 Hz), 8.44 (1H, d, J=6.1 Hz), 8.67 (1H, s), 8.73 (1H, s), 8·78 (1H, s) 〇 Example 741 N-(4-(6, 7-Dimethoxyquinolin-4-yl gas) Benzene VN'-(3-methyl hydrazine, urea will be obtained by the method of WO 97/17329 4-(6,7-dimethoxy Phenyl-4-yloxy)aniline (296 mg, 1.00 mmol) and phenyl (3-methylsulfonylphenyl) aminate (291 mg, 1.00 mmol) in dimethyl succinate (3 ml), at 85 The mixture was heated and stirred at 2 °M. The reaction solution was dissolved in ethyl acetate and water. The organic layer was washed with 1N sodium hydroxide aqueous solution, water and brine, and anhydrous magnesium sulfate ___ - 754 __ paper The scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Inventive Note (749) 2 'Dry, filter the desiccant, and distill off the filtrate under reduced pressure. The obtained crude product was subjected to a column chromatography (the eluate was ethyl acetate: methanol = 30:1), and the fraction containing the desired product was concentrated and suspended in ethyl acetate. The title compound (430 mg, 〇.871 mmol _, 87%) 〇H-NMR spectrum (CDCl3) was obtained. ) 5 (ppm): 3.16 (3H, s), 4.03 (3H, s), 4·〇5 (3H, s), 6.46 (1H, d, J = 5.2 Hz), 7.12-7.18 (2H, m) , 7.41 (1H, s)5 7.50-7.62 (6H, m), 7.81 (1H, s), 7.93 (1H, s), 8.11-8.15 (1H, m), 8.48 (1H, d, J= 5.2 Hz). Example ϋ:·(2_Gas_4_((6·Cyano-7-M-hexafluoropyridylmethyl-p-apricot) Oxygen _ group) stupid)-Ν·-methylurea-one Ί Add Ν-(2-chloro-4-(6-cyano-7-#垔垔琳-4-yloxy)phenyl)-indole,-methyl pulver (125 mg) to dimethyl ketoamine ( In ι·5 ml), 4·(bromo T-)-1-hexahydropyridinecarboxylic acid tert-butyl ester (141 mg) and potassium carbonate (93 mg) were added thereto and heated at 60 C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sulphuric acid steel. The obtained crude product was recrystallized from ethyl acetate to give a pale-yellow crystal of &lt;&quot;&quot;&quot;&&&&&&&&&&&&&&&&&&&& Base)-i-hexahydropyridine-: tert-butyl carboxylate (21 mg). Dissolve it in trifluoroacetic acid (1〇^1), stir it at room temperature for 10^-clock, add 2 ml of water to it. The title compound (16 mg) was obtained by neutralization with sodium hydrogencarbonate and filtered to give the title compound (16 mg). L _ - 755 - scales a ® standard (CNS) A4 size (210 X 297 dongdong) 1304061 A7 B7 V. Description of the invention (75〇) ^-NMR (DMSO-d6) 5 (ppm): 1.20-1.35 (4H, m), 1.70-1.80 (2H, m), 1.90-2.01 (lH, m), 2.66 ( 3H,d,J=4.4Hz), 2.95-3.05 (2H, m), 4.12 (2H, d, J=6.0 Hz), 6.58 (1H, d, J=5.2 Hz), 6.84-6.92 (1H, m ), 7.21-7.26 (1H, m), 7.48 (1H, d, J=2.4 Hz), 7.59 (1H, s), 8.12 (1H, s), 8.22-8.28 (1H, m), 8.71-8.78 ( 2H, m) 〇 Example 743 N-(2-chloro-4-((6-Ammonia-7-((1-methyl-4-hexapyridinyl)carboxamyl)))茏-)-Ν·-methylurea Ν-(2-chloro-4-((6-cyano-7-(4-hexa-pyridylmethoxy)-4-porphyrin) After the oxy)phenyl)-N*-methylurea (15 mg) was dissolved in tetrafuran (0.5 ml) and methanol (0.5 ml), 37% aqueous formaldehyde (0.03 ml) was added at room temperature. After adding ethyl acetate (0.06 ml) and sodium cyanoborohydride (5.0 mg), stir for 1 hour. Add water to the solution and neutralize with a saturated aqueous solution of sodium hydrogencarbonate and extract with ethyl acetate. The organic layer was washed with water, and the solvent was evaporated to give crystals crystals crystals crystals crystals crystals crystals crystals ): 1.13-1.47 (2H? m), 1.75-1.95 (5H, m), 2·17 (3H, s), 2·68 (3H, s), 2.78-2.87 (2H, m), 4.17 (2H , d, J=6.0 Hz), 6.59 (1H, d, J=5.2 Hz), 6.95 (1H, br s), 7.22-7.28 (1H, m), 7.48 (1H, d, J=2.4 Hz), 7.61 (1H, s), 8.18 (1H, br s), 8.22·8·29 (1H, m), 8.72-8.77 (2H, m). The above formulas and the structural formulas of the compounds obtained in the examples are shown in Table 4 to Table 5 1 below. L__- 756 - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7

本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（752This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of the invention (752

_- 758 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（753 【表6】_- 758 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (753 [Table 6]

本紙張尺度適用中國國家標準(CMS) A4規格(210X297公釐）This paper scale applies to the Chinese National Standard (CMS) A4 specification (210X297 mm)

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1304061 A7 B71304061 A7 B7

本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 B7 五、發明説明（755) 【表8】This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Invention description (755) [Table 8]

-761 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 A7-761 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7

本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 A7 B7This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7

本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 B7 五、發明説明（758 【表1 1】This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of invention (758 [Table 1 1]

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-764 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（759-764 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (759

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（76〇 【表1 3】This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (76〇 [Table 1 3]

766 -本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（761) 【表1 4】766 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (761) [Table 1 4]

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（762 【表1 5】This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention Description (762 [Table 15]

__- 768 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）__- 768 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

1304061 A7 B7 五、發明説明（763) 【表1 6】1304061 A7 B7 V. Description of invention (763) [Table 1 6]

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7

本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1304061 A7 B7This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7

本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 A7 B7 五、發明説明（766) 【表1 9】This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Invention description (766) [Table 1 9]

-772 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（767 【表20】-772 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (767 [Table 20]

本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1304061 A7 B7This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 B7

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1304061 A7 B7 五、發明説明（769 【表2 2】1304061 A7 B7 V. Description of invention (769 [Table 2 2]

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（77〇This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (77〇

本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（771 【表2 4】This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Invention description (771 [Table 2 4]

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（772This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (772

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__ - 778 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 B7 五、發明説明（773 【表2 6】__ - 778 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 B7 V. Invention description (773 [Table 2 6]

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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1304061 A7 B7 五、發明説明（774)1304061 A7 B7 V. Description of invention (774)

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本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（775 【表28】This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (775 [Table 28]

-781 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（776 【表2 9】-781 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (776 [Table 2 9]

_- 782 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（777_- 782 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (777

-783 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7-783 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7

本紙張尺度適用中國國家標準(CNS) A4規格(21〇x297公釐) 1304061 A7 B7 五、發明説明（779)This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇x297 mm) 1304061 A7 B7 V. Description of invention (779)

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（78〇)This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Description of invention (78〇)

_- 786 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（781_- 786 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Invention description (781

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（782 【表3 5】This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (782 [Table 3 5]

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本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7 五、發明説明（783) 【表3 6】This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (783) [Table 3 6]

_____- 789 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（784) 【表3 7】_____- 789 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (784) [Table 3 7]

本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 A7 B7This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7

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1304061 A7 B7 五、發明説明（786)【表3 9】1304061 A7 B7 V. INSTRUCTIONS (786) [Table 3 9]

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本紙張尺度通用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7This paper scale is common Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7

本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐) 1304061 A7 B7This paper size applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1304061 A7 B7

本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) 1304061 A7 B7 五、發明説明（789)This paper scale applies to China National Standard (CNS) A4 specification (210x 297 mm) 1304061 A7 B7 V. Invention description (789)

本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1304061 A7 B7 五、發明説明（790) 【表4 3】This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Invention description (790) [Table 4 3]

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7

本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1304061 A7 B7 五、發明説明（792)This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1304061 A7 B7 V. Invention description (792)

-798 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（793: 【表4 6】 nm^2i 実施例622 鄉例6 2 3-798 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (793: [Table 4 6] nm^2i 実Example 622 Township example 6 2 3

Me 鄉例e 2 雜例6 2 Λν) 0irV、 〇 o^Jo ¢0^ α Ί^9 缺β27 α Η „Νχδ. *Μ!62 c〇) mmz9Jx^ 乂：c〇 鄉例630Me Township e 2 Hybrid 6 2 Λν) 0irV, 〇 o^Jo ¢0^ α Ί^9 Missing β27 α Η „Νχδ. *Μ!62 c〇) mmz9Jx^ 乂:c〇 Township 630

or。 OH 方— 31irY、Or. OH side - 31irY,

鄉例6 3 2 91 Η H力丫、 OH ^fe^634 ^^635 M·、 2½ Λν 8、 、έ〇6 f Η H hr 、Μ· 1^)63( ^ixybTownship example 6 3 2 91 Η H 丫, OH ^fe^634 ^^635 M·, 21⁄2 Λν 8, έ〇6 f Η H hr , Μ · 1^) 63 ( ^ixyb

9» H9» H

JU 鄉例β37 UkO、·JU Township example β37 UkO,·

y、Me 1^638 f Η •ώττ a、 m ^0^639y, Me 1^638 f Η •ώττ a, m ^0^639

^m64Q 鄉拥6 4 1 π 織 Λ6 4 2^m64Q Township 6 4 1 π Weaving Λ 6 4 2

鄉例Μ 3Township example 3

Lf㈣ &amp;h&quot;Lf (four) &amp;h&quot;

本紙張尺度適用中國國家_(CNS) A4規格(210X297公釐） 799 - 1304061 A7 B7 五、發明説明（794This paper size applies to China's national _ (CNS) A4 specifications (210X297 mm) 799 - 1304061 A7 B7 V. Invention description (794

-800 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1304061 A7 B7-800 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7

本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 1304061 A7 B7 五、發明説明（796 【表4 9】This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1304061 A7 B7 V. Description of invention (796 [Table 4 9]

_ - 802 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1304061 A7 B7 五、發明説明（797 【表5 0】_ - 802 - This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 1304061 A7 B7 V. Invention description (797 [Table 5 0]

___- 803 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 A7 B7 五、發明説明（798 【表5 1】___- 803 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1304061 A7 B7 V. Invention description (798 [Table 5 1]

_ - 804 - 本紙張又度適用中國國家標準(CNS) A4規格(210X 297公釐） 130406 公告_ - 804 - This paper is again applicable to China National Standard (CNS) A4 specification (210X 297 mm) 130406 Announcement

f J L 申請曰期 90. 10. 19 案 號 090125928 類 別 A4 C4 中文說明書替換頁(95年12月） 發明 新型 專利説明書 中 文 含氮芳香環衍生物 名稱 英 文f J L Application Period 90. 10. 19 Case No. 090125928 Category A4 C4 Chinese Manual Replacement Page (December 95) Invention New Patent Specification Chinese Nitrogen-containing aromatic ring derivative Name English

NITROGEN-CONTAINING AROMATIC RING DERIVATIVES 姓 名 國 籍 1.鹤岡明彦 AKIHIKO TSURUOKA 3.羽田融 TORU HANEDA 5.鎌田淳一 JUNICHI KAMATA 7.松島知廣 2.松倉正幸 MASAYUKI MATSUKURA 4.福田吉男 YOSHIO FUKUDA 6.高橋惠子 KEIKO TAKAHASHI 8.宮崎和城 發明 創作&gt; 住、居所 TOMOfflRO MATSUSHIMA KAZUKI MIYAZAKI 均曰本 1. 日本國茨城縣筑波市吾妻3丁目19-1，2-203 2. 曰本國茨城縣筑波市東光台2丁目9-10 3. 日本國茨城縣牛久市神谷2丁目4-8 4. 曰本國茨城縣筑波市松代2丁目25-3-403 5. 日本國茨城縣筑波市天久保2丁目23-5-306 6·日本國茨城縣牛久市田宮3 丁目10-7-512 7. 曰本國茨城縣牛久市田宮2丁目10-2 8. 曰本國茨城縣筑波市稻荷前9-7, 2-211 姓 名 (名稱） 國 籍 曰商衛材R&amp;D企管股份有限公司 EISAI R&amp;D MANAGEMENT CO” LTD·NITROGEN-CONTAINING AROMATIC RING DERIVATIVES Name Nationality 1. Tsuruoka Akiko AKIHIKO TSURUOKA 3. Haneda Torio HANEDA 5. 镰田淳一 JUNICHI KAMATA 7. Matsushima Chihiro 2. Matsukura Masahiro MASAYUKI MATSUKURA 4. Fukuda Katsuyoshi YOSHIO FUKUDA 6. Takahashi Keiko KEIKO TAKAHASHI 8. Miyazaki and the city's inventions and creations ◎ Off l TOM TOM TOM TOM TOM TOM TOM TOM TOM TOM TOM TOM TOM TOM TOM TOM TOM TOM 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 9 9 9 9 9 9 9 -10 3. 4-8, Kamogawa 2, Kanagawa, Ibaraki, Ibaraki Prefecture, Japan 4 403 25-3-403, Matsuda-shi, Tsukuba, Ibaraki Prefecture, Japan.・10-7-512, Tamiya, Nikko-shi, Ibaraki, Ibaraki, Japan. 曰 10 10 -7 -7 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 9 9 9 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 Nationality 曰商卫材 R&amp;D Enterprise Management Co., Ltd. EISAI R&amp;D MANAGEMENT CO” LTD·

日本 JAPAN 三、申請人 住、居所 (事務所)Japan JAPAN III. Applicant Residence, Residence (Company)

日本國東京都文京區小石川四丁目6番10號 6-10? KOISHIKAWA 4-CHOME, BUNKYO-KU, TOKYO 112-8088, JAPAN 代表人 姓 名6-10, Ishikawa, Ishikawa, Bunkyo-ku, Tokyo 6-10? KOISHIKAWA 4-CHOME, BUNKYO-KU, TOKYO 112-8088, JAPAN Representative Name

吉松賢太郎 YOSHIMATSU, KENTARO 本紙張尺度適用中國國家襟準(CNS) A4規格(210 X 297公釐)吉松贤太郎 YOSHIMATSU, KENTARO This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

13 04ft6i)i25928鮮利申請案 中文申請專利範圍替換本(96年12月） 申請專利範圍 種通式（II)所示之化合物或其鹽或彼等之水合物， V 〇 ζ (II) 式中’ Α為以下式1)、式2)或式3)所示基團： 1)式13 04ft6i) i25928 Fresh Profit Application Chinese Patent Application Renewal (December 96) Patent application for a compound of the formula (II) or a salt thereof or a hydrate thereof, V 〇ζ (II) a group represented by the following formula 1), formula 2) or formula 3): 1) Ral3為氳原子；Ral2為氰基或下 [式中，W為碳原子 式所示之基團： 一 C一 N-〇-Va12 卜1-0 - Va12 13 &lt;—N—va11-Va12 &gt;13 -C - N—Va11—Va12 或 !a13 pC^N-Va12 ◊a13 (式中Val1為-CO- ; val2及val3各獨立為氫原子、可有 由取代基群A選出之1個以上取代基之c ! -6烷基、可有 由取代基群A選出之1個以上取代基之c3 8脂環式烴 基、吡咯啶基、可有由取代基群A選出之丨個以上取代 基之哌啶基、嗎福啉基、1，3 -二氧雜戊環· 2 -基、四氫 呋喃基、吡啶基、咪唑基或嘧唑基）；Ral1為式_Va21-Va22-Va23(式中，Va21為C、_6伸烷基、單鍵或下式所示 74525-961211.doc 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） A BCD 1304061 申請專利範圍 之基團： χΧλ Va22為單鍵、氧原子、硫原子、- S〇2-、式- CONRa14-、式-S02NRal4-、式 _NRal4s〇2_ 或式-NRal4·(式 中’ Ral4為氫原子、Cm烷基或C3-8脂環式烴基）； Va23為氫原子、可有由取代基群a選出之1個以上取代 基之C ! _6虎基、C3 _8脂環式烴基、苯基、可有由取代基 群A選出之1個以上取代基之吡p各啶基、可有由取代基 群A選出之1個以上取代基之喊啶基、可有由取代基群a 選出之1個以上取代基之哌嗪基、三唑基或吡啶基）]; 2)式 n^V\/v^Ral3 is a halogen atom; Ral2 is a cyano group or a lower group [wherein W is a group represented by a carbon atom formula: a C-N-〇-Va12 Bu 1-0 - Va12 13 &lt;-N-va11-Va12 &gt 13-C - N-Va11-Va12 or !a13 pC^N-Va12 ◊a13 (wherein Val1 is -CO-; val2 and val3 are each independently a hydrogen atom, and one or more selected from the substituent group A may be selected; a C 3 -6 alkyl group which may have one or more substituents selected from the substituent group A, a pyrrolidinyl group, or more than one substituent selected from the substituent group A a piperidinyl group, a morpholinyl group, a 1,3 -dioxapentane-2-yl group, a tetrahydrofuranyl group, a pyridyl group, an imidazolyl group or a pyrazolyl group; Ral1 is a formula of _Va21-Va22-Va23 (wherein Va21 is C, _6 alkyl, single bond or the following formula 74525-961211.doc This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) A BCD 1304061 Patent application group: χΧλ Va22 is a single bond, an oxygen atom, a sulfur atom, -S〇2-, a formula - CONRa14-, a formula -S02NRal4-, a formula of -NRal4s〇2_ or a formula -NRal4. (wherein Ral4 is a hydrogen atom, a Cm alkyl group or C3-8 alicyclic hydrocarbon Va23 is a hydrogen atom, may have one or more substituents selected from the substituent group a, C! _6, a C3-8 alicyclic hydrocarbon group, a phenyl group, and may be selected from the substituent group A. a pyridyl group of the above substituent, a pyridyl group which may have one or more substituents selected from the substituent group A, a piperazinyl group or a triazole which may have one or more substituents selected from the substituent group a Base or pyridyl)]; 2) formula n^V\/v^ 或·or· 個 [式中，W為可有由取代基群A選出之丨個以上取代基之 碳原子或氮原子；A…為⑴可有由取代基群A選出土之【 b11Wherein W is a carbon atom or a nitrogen atom which may have more than one substituent selected from the substituent group A; A... is (1) may be selected from the substituent group A [b11] R (式中，V-及V⑴各獨立為單鍵、_N (CH2)b-CCM式中，M0至6之整數 ，式 } κ 為早鍵、 -2- 74525-961211.doc 本紙張尺度適用中國國豕標準(CNS) Α4規格(210X297公复）.R (wherein, V- and V(1) are each a single bond, _N (CH2)b-CCM formula, an integer of M0 to 6, formula: κ is an early bond, -2- 74525-961211.doc applies to this paper scale China National Standard (CNS) Α 4 specifications (210X297 public). 申請專利範Patent application 匕1_6伸燒基、（：3_8脂環式炉其 之1個以上取代甚&gt; k m有由取代基群A選出 似以上取代基《吡咯啶基；Rb 原子、羥基、_辛原子^ ^ 各獨互為氫 以上取mr 有由取代基群A選出之1個 以上取代:：可有由取代基心選出之1個 、U 土1 3-8脂硪式烴基、可有由取代基群A選出 u個以上取代基之苯基 …選出 搜山士 吡哫基或可有由取代基群A &amp;出炙1個以上取代基之吡咯啶基）]; 3)式匕1_6 Stretching base, (:3_8 alicyclic furnace, one or more of them are substituted), km has a substituent group A selected from the above substituent "pyrrolidinyl; Rb atom, hydroxyl group, _ oct atom ^ ^ One or more substitutions selected from the substituents group A: There may be one selected from the substituent core, the U soil 1 3-8 lipid oxime hydrocarbon group, and the substituent group A may be used. Selecting a phenyl group having more than u substituents... selecting a sulfosylpyridinyl group or a pyrrolidinyl group which may have one or more substituents derived from the substituent group A &amp;); [式中，W為氮原子； 或（3)下式所示之基團 Rc 為（1)氫原子、（2)(^.6烷基 -vc21-n /Vc22\vc23 (式中=21為亞甲基；Vc22及vc23各獨立為u 基）、’ R為氫原子或可有由取代基群A選出之工個以上 取代基&lt;c1-6烷基；RCll為式_vell_vel2_vcl3所示基 團（式中’ V。11為單鍵、可有由取代基群A選出之1個以 上取代^之苯環、吡啶基或-C0- ; Vcl2為單键或氧原 子，V 為（1)可有由取代基群A選出之1個以上取代基 、1-6 k基（2)¾基、（3)幾基、（4) P比洛矣基、（5)可[wherein, W is a nitrogen atom; or (3) a group Rc represented by the following formula is (1) a hydrogen atom, (2) (^.6 alkyl-vc21-n /Vc22\vc23 (wherein 21 Is a methylene group; Vc22 and vc23 are each independently a U group), 'R is a hydrogen atom or may have a substituent selected by the substituent group A above &lt;c1-6 alkyl; RCll is represented by the formula _vell_vel2_vcl3 a group (wherein V.11 is a single bond, may have one or more substituted benzene rings, pyridyl groups or -C0- selected from the substituent group A; Vcl2 is a single bond or an oxygen atom, and V is (1) There may be one or more substituents selected from the substituent group A, a 1-6 k group (2) 3⁄4 group, a (3) group, a (4) P than a fluorenyl group, and (5) 本紙張尺度適用中國國豕標準(Cns) A4規格(21〇 X 297公釐) 1304061 六、申請專利範圍 A8 B8 C8 D8 (6)嗎 有由取代基群A選出之1個以上取代基之嗓嗪基 福啉基或（7 )氫原子）]; X為氧原子或硫原子； R1及R2各獨立為氫原子或烷基； E及Y係表示如下： ()一為A NR -(式巾，R之意義與前述定義相同）所 不基團，且Y為可有由取代基群A選出之1個以上取 代基之苯基、可有由取代基群A選出之i個以上取代 基之峨啶基或下式所示基團： /1 一W12This paper scale applies to China National Standard (Cns) A4 specification (21〇X 297 mm) 1304061 6. Patent application scope A8 B8 C8 D8 (6) There are more than one substituent selected by substituent group A Zrhofolinyl or (7) a hydrogen atom)]; X is an oxygen atom or a sulfur atom; R1 and R2 are each independently a hydrogen atom or an alkyl group; and E and Y are represented as follows: () one is A NR - (formula a towel, the meaning of R is the same as defined above, and Y is a phenyl group which may have one or more substituents selected from the substituent group A, and may have one or more substituents selected from the substituent group A Acridine group or a group of the formula: /1 a W12 (式中’W及w12各獨立為碳原子或氮原子） 或者為 (2)E為單鍵，且γ為下式所示基團：(wherein 'W and w12 are each independently a carbon atom or a nitrogen atom) or (2) E is a single bond, and γ is a group represented by the following formula: (式中，W13為可有由取代基群A選出之！個以上取 代基之碳原子）； Z為式-Z&quot;-Z12所示基團（式中，z&quot;為單键、氧原 子、硯原子、eC〇·、_S〇2-或Cb6伸燒基；Z12為 氫原子、可有由取代基群A選出之丨個以上取代基之 74525-961211.doc 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）. A8 B8 C8 D8(wherein, W13 is a carbon atom which may have one or more substituents selected from the substituent group A); Z is a group represented by the formula -Z&quot;-Z12 (wherein, z&quot; is a single bond, an oxygen atom, Helium atom, eC〇·, _S〇2- or Cb6 extension base; Z12 is a hydrogen atom, and may have more than one substituent selected from substituent group A. 74525-961211.doc This paper scale applies to Chinese national standards ( CNS) A4 size (210X297 mm). A8 B8 C8 D8 1304061 Ci·6烷基、可有由取代基群A選出之i個以上取代基 之可有取代基之C：3·8脂環式烴基、可有由取代基群 A選出之1個以上取代基之苯基、可有由取代基群a 選出之1個以上取代基之噻唑基、可有由取代基群A 選出之1個以上取代基之異噚唑基、吡啶基、苯并 咪唾基、2-經.喹啉基、ι，3·二氫苯并咪唑·2-酮 基、苯并嘮唑_ 2 -酮基或丨，3 _二氫吲哚_2 —酮基）； 其中，上述取代基群A為以下之基團： (1) _素原子、（2)羥基、（3)腈基、（4)側氧（oxo)基、 (5)脲基、（6)甲醯基、（7)可各經鹵化或氫氧化之 。1-6烷基、（：2_6晞基、C2.6炔基、c3_6環烷基、 C 1 -6燒氧基、C3 _6環烷氧基、c μ烷硫基或c ! _6伸 烷二氧基、（8 )苯基、（9 )吡咯啶基、（1 〇)旅啶基、 (11)嗎福淋基、（12)1，3_二氧雜戊環-2-基、（1 3) 四氫呋喃基、（14)哌嗪基、（1 5)羧基、（16)三氟甲 基、（1 7 ) C 2 _ 7燒氧羰基、（1 8 )胺基、（1 9 )燒胺基、 (20)二烷胺基、（21)烷磺醯基、（22)C2_7醯胺基。 2 ·如申請專利範圍第1項之化合物或其鹽或彼等之水合 物，其中Z為可有由取代基群A選出之1個以上取代基之 環丙基、可有由取代基群A選出之1個以上取代基之2· 嘧唑基或下式表示之基：1304061 Ci·6 alkyl group, C. 3·8 alicyclic hydrocarbon group which may have a substituent which may have one or more substituents selected from the substituent group A, may have one or more substituents selected from the substituent group A a phenyl group, a thiazolyl group which may have one or more substituents selected from the substituent group a, an isoxazolyl group which may have one or more substituents selected from the substituent group A, a pyridyl group, a benzopyrene Base, 2-trans. quinolinyl, iota, dihydrobenzimidazole-2-keto, benzoxazole-2-keto or oxime, 3 _dihydroanthracene-2-one); Wherein the above substituent group A is the following group: (1) a _ prime atom, (2) a hydroxyl group, a (3) nitrile group, (4) an oxo group, (5) a ureido group, (6) The formazan group and (7) may each be halogenated or oxidized. 1-6 alkyl, (: 2-6 fluorenyl, C 2.6 alkynyl, c 3-6 cycloalkyl, C 1 -6 alkoxy, C 3 -6 cycloalkoxy, c μ alkylthio or c ! -6 alkyl hexane Oxyl, (8) phenyl, (9) pyrrolidinyl, (1 fluorene) benzyl, (11) flufenyl, (12) 1,3-dioxalan-2-yl, ( 1 3) tetrahydrofuranyl, (14) piperazinyl, (1 5) carboxyl, (16) trifluoromethyl, (1 7 ) C 2 -7 alkoxycarbonyl, (1 8 ) amine, (1 9 ) An amine group, (20) a dialkylamino group, (21) an alkanesulfonyl group, (22) a C2-7 amidino group, a compound according to claim 1 or a salt thereof or a hydrate thereof, wherein Z is a cyclopropyl group which may have one or more substituents selected from the substituent group A, a pyridyl group which may have one or more substituents selected from the substituent group A, or a group represented by the following formula: (式中Z&quot;為腈基、甲績醯基或-NHCOCH3基）。 74525-961211.doc 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） A8 B8 C8(wherein Z&quot; is a nitrile group, a fluorenyl group or a -NHCOCH3 group). 74525-961211.doc This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) A8 B8 C8 1304061 3.:===合物…或彼等之水合1304061 3.:=== compound... or their hydration [式中： Ri，R2及Z12與申請專利範圍第1項中之r1，汉2及2!2具 有相同思我（但Z為卩比峻基之情況除外）； Yal為下式表示之基：[In the formula: Ri, R2 and Z12 have the same thoughts as r1, Han 2 and 2! 2 in the first item of the patent application scope (except when Z is a 卩 峻 峻 base); Yal is the base of the following formula; : {式中， W及W3 2各獨JL為碳原子或氮原子； R3 00及化3 01各獨立為氫原予、鹵素原子或可有由取 代基群A選出之1個以上取代基之Ci6烷基}; Ra 1 1及Ra 1 2具有與在申請專利範圍第1項中之1 1 及Ral2相同之意義； 限制條件為’在上述定義中，下述（1 )或（2 )之化合 74525-961211.doc -6- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) A8 B8 C8 D8 1304061 六、申請專利範圍 物除外： (1) Ra 12為下式表示之基： I—c—N—0—Val12 |all3 (式中Val12及Val13各獨立為氫原子、可有取代 基之q·6烷基、可有取代基之c：2·6晞基、可有 取代基之C 2 ·6決基、可有取代基之（：3-8脂環式 烴基、可有取代基之c6_14芳基、可有取代基之 5至14員雜環基或可有取代基之5至14員芳香族 雜壤基）， R1及R2為氫原子，而且 Z12為C6_14芳基、6至14員雜環基或6至14員芳 香族雜環基； (2) Ra 12為選自下式表示之基： Ο Ο I—C—0—val12 |—C—N—Val11—Val12 |all3 (式中 Val11 為-CO-或-so2_ ; val12 及 val13 之 意義分別與前述定義相同）， R2為氫原子，而且 Z12為（a)C6_14芳基，（b)5至14員雜環基，（c) 5至14員芳香族雜環基，（d)被5至10員雜環基 74525-961211.doc -7- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐). 申清專利範園 C 至式煙基取代之^境基，⑷被5 基，（f) ^基或CM0脂環式煙基取代之C2-6締 基 或 )被5至1〇員雜環甚戎ρ 取代之ρ 异衣基4C5-1〇脂環式烴 2-6炔基或者（g)被5至 4. 如申請2=1環式烴基取代之h脂環^二 物，並中RaUA昂3項之化合㈣其鹽或料之水¥ 4甲基、2·甲氧乙基或下式表示之基： Ra53，N、 ^853-^ N、 RaS2〆 R051 或 Ra52〆 L式中Ra53為甲基；Ra51為氫原子或經基； 咯啶基、 氧P比唉基、4 -嗎福，林基、 Ra52為1-吡 甲胺基或二乙 5. :申=义第3或4項之化合物或其鹽或彼等之水合 笨基。 ：、甲基、乙基、環丙基、2·噻唑基或4-氟 1申：ί利t圍第3或4項之化合物或其鹽或彼等之水合 物，其中Υ“為下式表示之基： t Ra61- h3c、 ch3 或 h3c、 氟甲基、氯原子或氟原 (式中Ra6i為氫原子、甲基、三 74525-961211.doc 本紙張尺度適用中國國家標準(CNS) A4^^i97公釐） 1304061 as B8 C8In the formula, W and W3 2 each independently JL is a carbon atom or a nitrogen atom; R3 00 and chemistry 3 01 are each independently a hydrogen atom, a halogen atom or a Ci6 which may have one or more substituents selected from the substituent group A; Alkyl}; Ra 1 1 and Ra 1 2 have the same meaning as 1 1 and Ral 2 in the first item of the patent application; the limitation is 'in the above definition, the combination of the following (1) or (2) 74525-961211.doc -6- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) A8 B8 C8 D8 1304061 VI. Except for patent application: (1) Ra 12 is the base of the following formula: I—c—N—0—Val12 |all3 (wherein Val12 and Val13 are each independently a hydrogen atom, a q.6 alkyl group which may have a substituent, a c:2·6 fluorenyl group which may have a substituent, may be substituted a C 2 ·6-bonded group, which may have a substituent (: 3-8 alicyclic hydrocarbon group, a c6-14 aryl group which may have a substituent, a 5- to 14-membered heterocyclic group which may have a substituent or may have a substituent 5 to 14 members of aromatic heterobasic), R1 and R2 are a hydrogen atom, and Z12 is a C6_14 aryl group, a 6 to 14 membered heterocyclic group or a 6 to 14 membered aromatic heterocyclic group; (2) Ra 12 is Selected from below The base of the formula: Ο Ο I—C—0—val12 |—C—N—Val11—Val12 |all3 (where Val11 is -CO- or -so2_; the meanings of val12 and val13 are the same as defined above), R2 Is a hydrogen atom, and Z12 is (a) C6_14 aryl, (b) 5 to 14 membered heterocyclic group, (c) 5 to 14 membered aromatic heterocyclic group, (d) is 5 to 10 membered heterocyclic group 74525 -961211.doc -7- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm). Shenqing Patent Fanyuan C to the type of smoke base replaced by ^, (4) is 5 base, (f) ^ Substituted or C10-6 phenyl group substituted by CM0 alicyclic ketone group or ρ substituted by 5 to 1 member heterocyclic ring 戎 异 4 4C5-1 〇 环 环 2 2 alkynyl or (g ) is 5 to 4. as claimed in the application of 2 = 1 cyclic hydrocarbyl substituted h alicyclic compound, and in the RaAA ang 3 compound (4) its salt or material water ¥ 4 methyl, 2 methoxyethyl or The base represented by the formula: Ra53, N, ^853-^ N, RaS2〆R051 or Ra52〆L wherein Ra53 is a methyl group; Ra51 is a hydrogen atom or a meridine; a pyridyl group, an oxygen P is a thiol group, 4 -福福, 林基, Ra52 is 1-pyridylamine or diethylene 5. :申=义第A compound of 3 or 4 or a salt thereof or a hydrated base thereof. : a methyl group, an ethyl group, a cyclopropyl group, a 2 thiazolyl group or a 4-fluoro 1 group: a compound of the 3rd or 4th or a salt thereof or a hydrate thereof, wherein Υ" is as follows Representation base: t Ra61- h3c, ch3 or h3c, fluoromethyl, chlorine atom or fluorocarbon (wherein Ra6i is hydrogen atom, methyl group, three 74525-961211.doc This paper scale applies to Chinese National Standard (CNS) A4 ^^i97 mm) 1304061 as B8 C8 子）。 7. 如申請專利範園第3或4；1頁之化合物或其鹽或彼等之水人 物6’2其中π&quot;為氰基或式-C〇NHRa62表示之基（式中 Ra62為氫原子、可有由如申請專利範圍第Η所述取 基Α選出1個以上取代基之烷基、可有由如申，專 利範圍第4所述取代基A選出！個以上取代基之C 環式烴基或C1-6烷氧基）。 31曰 8. 如申請專利範圍第〗項之化合物或其鹽或彼等之水合 物，其係以通式（Illb)表示： 。 〇 I~C一 N-0*~va12『—child). 7. For example, the compound or its salt or its water character 6'2, where π&quot; is a cyano group or a formula -C〇NHRa62 (wherein Ra62 is a hydrogen atom) There may be an alkyl group selected by one or more substituents as described in the scope of the patent application, and a C ring type which may be selected from the substituent A of the fourth aspect of the patent range. Hydrocarbyl or C1-6 alkoxy). 31曰 8. A compound of the formula Scope or a salt thereof or a hydrate thereof, which is represented by the formula (Illb): 〇 I~C-N-0*~va12『— [式中： Z21為可有由如申請專利範圍第i项所述取代基A選出工 個以上取代基之(^·6烷基、或C3·8脂環式烴基； R 2()為&quot;fL基或下式表示之基： 〇 c-o-v312[In the formula: Z21 is a (^.6 alkyl group or a C3.8 alicyclic hydrocarbon group which may be selected from the substituent A as described in the above-mentioned claim i, item i; R 2 () is &quot ;fL base or the base of the following formula: 〇co-v312 〇—va15 ο 卜芒-N—Va11—Va12 心13 Ο |-C-N-Va12 5 &gt;13 (式中 Val5 為 Cb6 烷基，val1，va 及val3具有與在 74525-961211.doc .9. 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐）.〇—va15 ο 卜芒-N—Va11—Va12 heart 13 Ο |-CN-Va12 5 &gt;13 (wherein Val5 is Cb6 alkyl, val1, va and val3 have the same as in 74525-961211.doc.9. The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm). 申請專利範園第1項中之Vall，及Val3相同之意 義）； R3G0及R301具有與在申請專利範圍第3項中之R300及 R3 G 1相同之意義； Ra 11具有與在申請專利範圍第1項中之Ra 1 1相同之意 義； 附帶條件為Ra 1 2 G及z 2 1具下列意義者被排除在外： Ral2G為選自下列式表示之基：Applying Vall in item 1 of the Patent Park, and the same meaning as Val3); R3G0 and R301 have the same meaning as R300 and R3 G 1 in item 3 of the patent application; Ra 11 has the same scope as in the patent application The meaning of Ra 1 1 in the 1 item is the same; the condition is that Ra 1 2 G and z 2 1 have the following meanings excluded: Ral2G is a base selected from the following formula: V c—N-Va112 及 Val13 (式中，val11、Vall2及Va113具有與在申請專利範 圍第3項中之val11、val12及val13相同之意義； val15為可有取代基iCi6烷基、可有取代基之c2_ 6烯基、可有取代基之c26炔基、可有取代基之 脂環式烴基）；而且 Z21為（a) C3_8脂環式烴基，被5至10員雜環基 或cv1G脂環式烴基取代之Ci 6烷基，（c)被5至1〇 員雜壤基或C5 · i G脂環式烴基取代之C2 _ 6烯基或（d) 被5至10員雜環基或CriG脂環式烴基取代之Q 6炔 基]。 _ 9· 一種通式（ΠΙΟ表示之化合物或其鹽或彼等之水合物， 74525-961211.docV c-N-Va112 and Val13 (wherein val11, Vall2 and Va113 have the same meaning as val11, val12 and val13 in item 3 of the patent application; val15 is a substitutable iCi6 alkyl group, which may be substituted a c2_6 alkenyl group, a c26 alkynyl group which may have a substituent, an optionally substituted alicyclic hydrocarbon group; and Z21 is a (a) C3_8 alicyclic hydrocarbon group, a 5 to 10 membered heterocyclic group or a cv1G grease a cyclic hydrocarbyl-substituted Ci 6 alkyl group, (c) a C 2 -6 alkenyl group substituted by 5 to 1 member hetero- or a C 5 · i G alicyclic hydrocarbon group or (d) a 5 to 10 membered heterocyclic group Or a CriG alicyclic hydrocarbon group substituted Q 6 alkynyl]. _ 9· A compound of the formula (ΠΙΟ represents a compound or a salt thereof or a hydrate thereof, 74525-961211.doc 1304061 申請專利範圍1304061 Patent application scope Z22 [式中·· z22為可有由如申請專利範圍第1項所述取代基A選出1 個以上取代基之苯基或嘧唑基； 〇300 ηη τ)3〇ΐ 及R 具有與在申請專利範圍第3項中之R r3 G 1相同之意義； Vdl3 3 0 0 及 為下列式表示之基： 卜或卜 (式中Val2及val3具有與在申請專利範園第1項中之 Val2及Val3相同之意義）； Vdn 為 Ci.6 伸烷基；vdl2 為（1)式·ΝΙ^&quot;Κ&lt;Π2(式中 R 及R 為氫原子或Cu燒基）；（2)?比ρ各淀基；或（3) 可有由如申請專利範圍第丨項所述取代基A選出1個以上 取代基之喊淀基]。 10·如申請專利範圍第1項之化合物或其鹽或彼等之水合 物，其係以通式（IIId)表示： 74525-961211.doc -11 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 、申請專利範園 〇300Z22 [wherein z22 is a phenyl or pyrazolyl group which may have one or more substituents selected from the substituent A as described in the first paragraph of the patent application; 〇300 ηη τ)3〇ΐ and R have The meaning of R r3 G 1 in the third paragraph of the patent application scope; Vdl3 3 0 0 and the base expressed by the following formula: Bu or Bu (in the formula Val2 and val3 have Val2 in the first item of the patent application) And Val3 has the same meaning); Vdn is Ci.6 alkyl; vdl2 is (1) ΝΙ^&quot;Κ&lt;Π2 (wherein R and R are hydrogen atoms or Cu alkyl groups); (2)? Each of the ruthenium groups; or (3) may have one or more substituents selected from the substituent A as described in the scope of the patent application. 10. The compound of claim 1 or a salt thereof or a hydrate thereof, which is represented by the formula (IIId): 74525-961211.doc -11 - This paper scale applies to the Chinese National Standard (CNS) A4 Specifications (210X297 mm), application for patent Fanyuan 〇300 (Hid) [式中·· 1項中之R1 R2 R ，R及Z12具有與在申請專利範圍第 及Z12相同之意義； w 1為碳原予或氮原子； Γ具有與在申請專利範圍第3項中之r3。。相同之意 y Ί與在申請專利範圍第i項中之Ra&quot;相同之土 我，Ral20具有與在申請專利範圍第思 之意義’· R相同 下述（1)或（2)之化合物被除 限制條件為上述定義中 外： (1)R2G為下式表示之基： !—C—N—0—Val12 ^all3 (式中V 112Ava113具有與在中請專利範圍第3 2Vall2lVa113相同之意義）， 、 R1及R2為氫原子，而且 1 2 Z為C6-&quot;芳基、ό至14員雜環基或6至14員 族雜環基； 胥(Hid) [R1 R2 R in the formula (1), R and Z12 have the same meanings as in the scope of application of the patent and Z12; w 1 is a carbon atom or a nitrogen atom; R3 of 3 items. . The same meaning y Ί is the same as the Ra&quot; in the scope of patent application i, Ral20 has the same as the following (1) or (2) in the meaning of the patent application scope. The restriction condition is the above definition: (1) R2G is the base represented by the following formula: !—C—N—0—Val12 ^all3 (wherein V 112Ava113 has the same meaning as the third patent of the patent range 3 2Vall2lVa113), R1 and R2 are a hydrogen atom, and 1 2 Z is a C6-&quot; aryl group, a fluorene to a 14-membered heterocyclic group or a 6 to 14 membered heterocyclic group; 本紙張尺度適用中國國家標準(CNS) Α4規格(21〇χ297公釐） 1304061 申請專利範園 A8 B8 C8 D8 (2) Ra G為選自下式表示之基： I —C—〇—val 12 |—ό—N—Val 11—val 12 I——〇—V -v τ_' ,al 12 -N—V |all3 (式中Val11，Vall2及vail3具有與在申請專利範圍 第3项中之Vain，yam及yam相同之意義， Val 15具有與在申請專利範圍第8項中之Val15相同 之意義）； R2為氫原子；而且 Z 為（a)c6-i4芳基，（b)5至14員雜環基，（c) 5至 14員方香族雜環基，（(1)被5至丨〇員雜環基或c5 i〇 脂環式烴基取代之Cl·6烷基，（e)被5至1〇員雜環 基或C5-1G脂環式烴基取代之C2-6烯基，被5至 1〇員雜環基或C5·&quot;脂環式烴基取代之^^炔基或者 (g)被5至1〇員雜環基或C5&quot;脂環式烴基取代之 C3·8脂環式烴基]。 11.This paper scale is applicable to China National Standard (CNS) Α4 specification (21〇χ297 mm) 1304061 Patent application A8 B8 C8 D8 (2) Ra G is a base selected from the following formula: I—C—〇—val 12 |—ό—N—Val 11—val 12 I—〇—V —v τ_′ ,al 12 —N—V |all3 (wherein Val11, Vall2, and vail3 have the Vain in item 3 of the scope of the patent application) , yam and yam have the same meaning, Val 15 has the same meaning as Val15 in item 8 of the patent application; R2 is a hydrogen atom; and Z is (a) c6-i4 aryl, (b) 5 to 14 a heterocyclic group, (c) a 5- to 14-membered aromatic heterocyclic group, ((1) a C 1-6 alkyl group substituted by a 5- to fluorene heterocyclic group or a c5 i fluorene cyclic hydrocarbon group, (e a C2-6 alkenyl group substituted by a 5 to 1 member heterocyclic group or a C5-1G alicyclic hydrocarbon group, substituted with a 5 to 1 member heterocyclic group or a C5&quot; alicyclic hydrocarbon group; Or (g) a C3·8 alicyclic hydrocarbon group substituted by 5 to 1 member heterocyclic group or C5&quot; alicyclic hydrocarbon group. 及 如申請專利範圍第1項之化合物或其鹽或彼等之水合 物，其係以下列通式表示： 口 Xy1And a compound or a salt thereof or a hydrate thereof as claimed in claim 1 which is represented by the following formula: mouth Xy1 74525-961211.doc74525-961211.doc 1313 [式中： W 1及W各獨立為可有如申請專利㈣第i項所述取代 基A選出1個以上取代基之碳原子或氮原子；限制條件 為W41及W不可同時為氮原予； Xyl為各可有由如申請專利範圍第卜頁所述取代基群A選 出1個以上取代基之下列式表示之基：[wherein: W 1 and W are each independently a carbon atom or a nitrogen atom which may have one or more substituents selected as the substituent A described in the above-mentioned patent (4) item i; the limitation is that W41 and W may not be simultaneously nitrogen; Xyl is a group represented by the following formula each of which may have one or more substituents selected from the substituent group A as described on the page of the patent application: ^式中，z12具有與在申請專利範圍第丨項中之相同之 意義；）；以及 Ab 11具有與在申請專利範圍第丄項中之Ab〗i相同之意 義]。 μ 12·如申請專利範圍第丨項之化合物或其鹽或彼等之水合 物，其係以通式（nif)表示：In the formula, z12 has the same meaning as in the third paragraph of the patent application scope;); and Ab 11 has the same meaning as Ab〗 i in the third paragraph of the patent application scope. μ 12· A compound or a salt thereof or a hydrate thereof according to the scope of the patent application, which is represented by the formula (nif): [式中： RCl3具有與在申請專利範圍第1項中之Rcl3相同之音 義； ^ X y 2為各可有由如申請專利範圍第1項所述取代基A群選 出1個以上取代基之下列式表示之基： 74525-961211.doc β 本紙張尺度適用中國國家標準(CNS) Α4規格(21〇 χ 297公釐） 1304061 A8 B8 C8 、申請專利範圍 XrV、z12[wherein: RCl3 has the same meaning as Rcl3 in the first item of the patent application; ^ X y 2 may each have one or more substituents selected from the group of substituents A as described in claim 1 of the scope of the patent application. The basis of the following formula: 74525-961211.doc β This paper scale applies to China National Standard (CNS) Α4 specification (21〇χ 297 mm) 1304061 A8 B8 C8, patent application scope XrV, z12 及 (式中 iH&lt;，! z 之ζ ，R及R2各具有與在申請專利範 圍第1 $頁中 子）； .’R1及R2相同之意義，以及WH為碳原子或氮原 R及Rc 12各具有與在申請專利範圍第i項中之rc 1〗 Rel2相同之意義； 限制條件為上述定義中，下述⑴或（2)之化合物除外： (1) R1及r2為氫原子，而且 z ‘（a)C6_14芳基，（b)5至14員雜環基，（〇)被5 至14員芳香族雜環基、5至1〇員雜環基或脂環 式基取代之Ci ·6烷基，（d)被5至1 〇員雜環基或 C5-1G脂環式烴基取代之C2-6烯基，（e)被5至1〇員 雜環基或CriG脂環式烴基取代之C2 6块基或（f)被 5至1 〇員雜環基或c5 _ i G脂環式煙基取代之C3 _ 8脂環 式烴基； (2) xy2為下式表示之基： Π ΗAnd (where iH&lt;,! z, R and R2 each have the same meaning as in the first corpus of the patent application scope: $1); .'R1 and R2, and WH is a carbon atom or a nitrogen source R and Rc 12 each has the same meaning as rc 1 〗 Rel2 in the i-th aspect of the patent application; the limitation is that in the above definition, the compounds of the following (1) or (2) are excluded: (1) R1 and r2 are hydrogen atoms, and z '(a) C6_14 aryl, (b) 5- to 14-membered heterocyclic group, (〇) Ci substituted by 5 to 14 membered aromatic heterocyclic group, 5 to 1 membered heterocyclic group or alicyclic group a 6-alkyl group, (d) a C2-6 alkenyl group substituted with a 5 to 1 member heterocyclic group or a C5-1G alicyclic hydrocarbon group, (e) a 5 to 1 member heterocyclic group or a CriG alicyclic group a hydrocarbyl-substituted C2 6 block or (f) a C3 -8 alicyclic hydrocarbon group substituted with a 5 to 1 fluorene heterocyclic group or a c5 _ i G alicyclic thiol group; (2) xy2 is a group represented by the following formula : Π Η (式中，Ζ12為（a)C6-14芳基，（b)5至14員雜環基， 15- 74525-961211.doc 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）. 1304061(wherein Ζ12 is (a) C6-14 aryl, (b) 5 to 14 membered heterocyclic group, 15- 74525-961211.doc This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) . 1304061 (〇 5至心芳香族雜環基，⑷心請員雜 或C5.,。脂環式烴基取代之A、燒基，⑷被土 貝雜環基或^。脂環式烴基取代之d希基 被5、至1〇員雜環基或C5_&quot;脂環式煙基取代之&amp; 基或（g) C3_8脂環式烴基）]。 13·如申請專利範圍第！或12項之化合物或其鹽或彼等之 合物，其中Rcl1為下式表示之基·· 7 vf12—vf1l-〇-|l(〇5 to a heart aromatic heterocyclic group, (4) a member of the heterogeneous or C5., an alicyclic hydrocarbon group substituted A, a pyridyl group, (4) a d-heterocyclic group or an alicyclic hydrocarbon group The group is substituted by a 5- to 1-membered heterocyclic group or a C5_&quot; alicyclic thiol group or (g) C3_8 alicyclic hydrocarbon group)]. 13·If you apply for a patent scope! Or a compound of 12 or a salt thereof or a compound thereof, wherein Rcl1 is a group represented by the following formula: 7 vf12-vf1l-〇-|l [式中 V 為單键、&lt;^_6伸烷基或下式表示之基 vfl2表示（1)氫原予’（2),比嘻啶基，（3)可有如申 請專利範圍第1項所述取代基A選出丨個以上取代基 之哌啶基，（4)式-NRf21Rf22(式中各&amp; 立為氫原子或C!. 6燒基）]。 14·如申請專利範圍第1項之化合物或其鹽或彼等之欠人 物，其係以通式（Illh)表示： R 300Wherein V is a single bond, &lt;^_6 alkyl or the formula vfl2 of the following formula represents (1) a hydrogenogen to '(2), a pyridyl group, and (3) may be as claimed in claim 1 The substituent A is selected from a piperidinyl group having at least one substituent, and (4) is a formula -NRf21Rf22 (wherein each &amp; is a hydrogen atom or a C!. 6 alkyl group). 14. The compound of claim 1 or a salt thereof or a owed person thereof, which is represented by the formula (Illh): R 300 -16- 74525-961211.doc 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1304061 as B8 C8-16- 74525-961211.doc This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304061 as B8 C8 Z z R R 12 3 0 0 3 0 0 R及R2各具有與在申請專利範圍第i項中之 Rl及R2相同之意義； 及R各具有與在申請專利範圍第3項中之 及R3 〇 1相同之意義； A32為下式表示之基：Z z RR 12 3 0 0 3 0 0 R and R2 each have the same meaning as R1 and R2 in the i-th scope of the patent application; and R each has the same as in the third paragraph of the patent application and R3 〇1 The same meaning; A32 is the basis of the following formula: (式中： W R ’ R 2及Ra 13分別具有與在申請專利範圍 第1項中之W，R“1，Ral2及Ral3相同之意義）]。 15·如申請專利範圍第！項之化合物或其藥理學上容許之鹽 或彼等之水合物，其選自下列化合物中之任一種： N-(4-(6·氰基-7-(3-(4-吡啶基）丙氧基）_4^奎啉基） 氧苯基）-N*-(4-甲氧苯基）脲， &gt;^-(4-(6_氰基-7-(2-(1，2,3-三峻-2-基）乙氧基）-4-喹啉基）氧苯基）-N’-(4-氟苯基）脲， Ν·(4·(6 -氰基- 7- (2-(1，2,3 -三峻 _ι_ 基）乙氧基）-4-喹啉基）氧苯基）-N'-(4-氟苯基）脲， Ν-(4·(6氰基- 7-(2-(1，2,3 -三唑 _2 -基）乙氧基）-4-喹啉基）氧苯基）-Nf-(2,4-二氟苯基）脲， Ν-(4-(6·氰基·7·(2·(1，2,3 -三唑-i_ 基）乙氧基）-4-喹啉基）氧苯基）-N’-(2,4-二氟苯基）脲， 17- 74525-961211.doc 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）· 1304061 六、申請專利範 A8 B8 C8 D8 圍 Νβ(4-(6-氰基-7·(2 -甲氧基乙氧基）-4-喹啉基）氧苯 基）'^,-(4-氟苯基）脲， Ν_(4·(6-氰基-7-(2 -甲氧基乙氧基）-4-喹啉基）氧苯 基）-N、（l，3-碟峻_2_基）脲， Νβ(4·(6-氰基-7_(2 -甲氧基乙氧基）-4-喹啉基）氧苯 基）以’-(3_氰基苯基）脲， Ν·(4-(6•氰基-7-(2-甲氧基乙氧基）_4·喹啉基）氧苯 基卜N’-(2气甲磺醯基）苯基）脲， 氰基-7-(2 -甲氧基乙氧基）-4-喹啉基）氧苯 基環丙脲， N_(4-(6 -氰基- 7·(2·甲氧基乙氧基）-4 -喹啉基）氧-八氟苯基）·Ν，_(1，3-嘧唑_2_基）脲， ^•(4、6-氰基-7-(2·甲氧基乙氧基）-4-喹啉基）氧- 氣苯基）-N，-環丙基脲， Ν_(4 _(6·氰基-7-(2 -甲氧基乙氧基）-4-喹啉基）氧苯 基）環丙甲基脲， Ν (4·(6 -氰基- 7_(3·(嗎福琳-4 -基）丙氧基）4淋-4_ 基氧）-2-氟苯基）_Ν，气2,4-二氟苯基）脲， Ν_ (4-(6-氰基_7·(3_(二乙胺）丙氧基）_4_喹啉氧基） 苯基）-Ν，-(4_氟苯基）脲， N_(4-(6 -氰基- 7-(3-(4 -嗎福啉基）丙氧基）-4 -喹啉 基）氧苯基）-Ν，-(4-氟苯基）脲， Ν-(4·(6-氰基-7-(2-甲氧基乙氧基）_4_喹啉基）氧· 2-氟苯基）-N’-(3-(曱磺醯基）苯基）脲， 74525-961211.doc -18- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐). ABCD 請專利範圍 N-(4-(6 -氰基-7-(3-(二乙胺基）丙氧基）_4·喹啉基） 氧_2-氟苯基）-N，-(2,4-二氟苯基）脲， N-(4-(6 -氰基-7-(3-(1-(4 -乙基六氫吡畊基））丙氧 基）-4 -喳啉基）氧苯基）_n，-(4 -甲氧苯基）脲， N-(4-(6-氰基-7-(3-氰基丙氧基）-4·喹啉基）氧-2-氟苯基）·Ν，-(2,4-二氟苯基）脲， Ν-(4-(6-氰基-7-(2-(甲磺醯基）乙氧基）_4_喹啉基） 氧_2 -氟苯基）-N’-(2,4·二氟苯基）脲， N-(4-(6-氰基-7-(2-(甲磺醯基）乙氧基）_4_喹啉基） 氣苯基）-N，-(4-氟苯基）脲， N-(4 _(6_氰基-7-(2-甲氧基乙氧基）-4-喹啉基）氧苯 基）-N，-苯基脲， N-(4-(6 -氰基- 7- (2 -甲氧基乙氧基）-4 -4琳基）氧-2·氟苯基）-N’-(2,4-二氟苯基）脲， Ν-(4-(6·氰基- 7- (3 -甲氧羰基丙氧基）-4-ρ奎琳基）氧 苯基）-Ν，-(4·甲氧苯基）脲， Ν-(4-(6·氰基- 7- (3·叛基丙氧基奎淋基）氧苯 基）_N，-(4-甲氧苯基）脲， N-(4-(6-氰基-7-(2-(2-羥基乙氧基）乙氧基）-4-喹 琳基）氧苯基）-N，-(4-甲氧苯基）脲， N-(4-(6 -氰基- 7- (3·(二乙胺基）丙氧基）-4_峻淋氧 基）苯基）-Ν'-(3-(甲橫醢）苯基）月尿， Ν-(4-(6·氰基-7-(3-(4 -嗎福淋基）丙氧基奎琳 基）氧苯基）-Ν’-(3·(甲磺醯基）苯基）脲， 74525-961211.doc -19- 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐). A BCD 1304061 六、申請專利範園 N-(4-(6 -氰基-7-(3-二乙胺基）丙氧基）-4·喹啉氧基) 苯基）-N’-苯基脲， N-(4-(6-氰基-7-(3-(4-嗎福啉基）丙氧基）-4-喹啉 基）氧苯基）-N’-苯基脲， N - (4 - ( 6 -氰基-7 - (3 - (4 -嗎福啉基）丙氧基）-4 -喳啉 基）氧苯基）-N ’ - (2 -酮基-1，2，3，4 -四氫-6 -喹啉基）脲， N-(4-(6-氰基-7-(2 -甲氧乙氧基）-4-喹啉基）氧苯 基）-N、（3-乙醯胺苯基）脲， ^^-(4-(6-孩1基-7-卞氧1基-4-峻1|7林基）氧-2-氣苯基）-N、（2,4-二氟苯基）脲， Ν-(4·(6-氰基-7-(2_甲氧乙氧基）-4-喳啉基）氧-2-氟苯基）-Ν^(4-氟苯基）脲， N-(4-(6-&quot;fL基- 7·(2 -甲氧ι乙氧》基）-4-峻ρ林基）乳-2_ 氟苯基）-N’-苯基脲， 4-(4-((4 -氟苯胺基)羰基）胺苯氧基）-7-(2 -甲氧乙氧 基）-6 - 4 p林叛酷胺， 7-(2 -甲氧乙氧基）-4-(4-((1，3-嘧唑-2-基胺基）羰基) 胺基苯氧基）-6-喹啉基羧醯胺， 4-(4-((苯胺羰基）胺基）-3 -氟苯氧基）-7-(2-甲氧乙 氧基）-6 · 4琳叛酸胺， 4-(4-((4 -鼠苯胺基）談基）胺基苯乳基）-7 -甲氧基-6_ 喹啉羧醯胺， 4_(4-((環丙胺基）羰基）胺基苯氧基）-7-(2-甲氧乙氧 基）-6-喹啉羧醯胺， 74525-961211.doc -20- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐）. 8 8 8 8 A BCD 1304061 六、申請專利範圍 7 -甲氧基-4 _ (4-((1,3-嘧唑-2-基胺基）羰基）胺基苯 氧基）-6 - p奎淋幾醯胺， 4-(4-( (2，4-二氟苯胺基）羰基）胺基-3-氟苯氧基）-7-甲氧基· 6 - p奎琳幾醯胺， 4_(4-((環丙胺基）羰基）胺苯氧基）_7_甲氧基-6-喹啉 羧醯胺， 4 - ( 5 -((苯胺羰基）胺基）· 2 -吡淀氧基）-7 -甲氧基-6 -p奎琳獲醯胺， 4-(4-(苯胺羰基）胺基苯氧基）_7_甲氧基喹啉羧醯 胺， 4-(4-(苯胺羰基）胺基苯氧基）-7-(2 -甲氧基乙氧基）_ 6-考琳叛醯胺， 4-(4-((2,4 -二氟苯胺基）羰基）胺基_3 -氟苯氧基）_7· (2 -甲氧基乙氧基）-6 -喹啉羧醯胺， 4-(4-((4 -氟苯胺基）羰基）胺基-3_氟苯氧基）_7-(2_ 甲氧基乙氧基）-6 -喳啉羧醯胺， 7-(2 -甲氧基乙氧基）-4-(4-((1，3·ρ塞唆_2_基胺基）羰 基）胺基-3-氟苯氧基）-6 -峻淋羧醯胺，及 4-(4-((4 -氟苯胺基）黢基）胺基-3-氟苯氧基）_7_甲氧 基-6 -峻p林叛酸胺。 16·如申請專利範圍第1項之化合物或其藥理學上容許之醆 或彼等之水合物，其選自下列化合物中之任一種： N-(4-(6 -氰基- 7·(2 -甲氧乙氧基）_4_喹啉基）氧_2_ 氟苯基）-Ν’-(4-氟苯基）脲， 74525-961211.doc -21 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) A8 B8 C8 D8 1304061 六、申請專利範圍 N-(2-氯-4-((6-氰基-7-((l_甲基·4_六氫吡啶基）甲 乳基）-4-p奎淋基）氧）苯基）-N' -環丙基脲， n_(4-((6-氰基-7-(((2R)_3-(二乙胺基）_2_羥基丙 基）氧）_4-如林基）氧）苯基）-N’-(4_氟苯基）脲， N - ( 4 _ (( 6 ·氰基-7 - (((2 R) - 2 _ 輕基 _ 3 _ (1 -吡咯違基） 丙基）氧）-4 - π奎琳基）氧）苯基）-N ’ - ( 4 -氟苯基）月尿， N-{4-[6 -氰基- 7- (2-#k基- 3-P比洛咬-1-基丙氧基）_ 峻琳-4-基氧]-2-甲基苯基}-化_環丙基脲， 4-(4-(4 -氟苯胺基）羰基）-4 -甲胺基苯氧基）-7_甲氧 基-6 - p奎琳羧酸胺， 4-(3 -氯- 4- (環丙胺窥基）胺苯氧基）_7_甲氧基6 -4琳 幾醯胺， 4-（3-'氯-4_(環丙胺羰基）胺苯氧基）-7-(2 -甲氧基乙 乳基）-6 -峻淋叛酿胺， N6·環丙基-4-(3-氯-4_(((環丙胺基）羰基）胺基）苯氧 基）-7 -甲氧基-6-4淋叛醯胺， N6-(2 -曱氧乙基）_4-(3 -氯_4-(((環丙胺基）羰基）胺 基）苯氧基）-7 -甲氧基-6 -喹啉羧醯胺， N6-(2-吡啶基）-4-(3-氯-4-(((環丙胺基）羰基）胺基） 苯氧基）-7 -甲氧基-6 _喹啉羧醯胺， N6-(2 -氟乙基）-4-(3 -氯-4-(((環丙胺基）羰基）胺基） 苯氧基）-7 -甲氧基-6 -喹啉羧醯胺， N6 -甲氧基-4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧 基）-7 -甲氧基-6-p奎琳竣酿胺’ -22- 74525-961211.doc 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）· ABC D 1304061 六、申請專利範圍 N6 -甲基-4-(3·氯-4-(((環丙胺基）羰基）胺基）苯氧 基）-7 -甲氧》基-6 -邊p林竣酿胺’ N6 -乙基-4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧 基）-7 -甲氧基-6-峻17林叛酿胺， 6 -胺甲醯基-4 - ( 1 -乙基胺甲醯基-1 Η _啕哚-5 -基氧）-7 -甲氧基ρ奎琳， 6 -胺甲醯基-7·甲氧基- 4- [1-丙基胺甲醯基_1Η -啕 嗓-5 -基氧]-ρ奎淋， 6 -胺甲醯基-7-甲氧基- 甲基）乙基胺甲醯基- 1Η-啕哚-5-基氧]喹啉， Ν4-(4-{4-[(苯胺羰基）胺基]-3·氯苯氧基卜2-吡啶 基）-1-甲基- 4- ΤΤ氯卩比淀幾酸胺， N1-苯基-3-氯_5_[(2-{[(1-甲基-4-六氫吡啶基）羰 基]胺基} - 4 -吡啶基）氧]-1 Η - 1 -峭哚羧醯胺， Ν4-[4_(3 -氣-4-{[(4 -氟苯胺基）羰基]胺基}苯氧 基）-2 -ρ比淀基]-1_甲基-4-六氫ρ比淀叛醯胺， 1-(2-氣-4-{6-[4_(2-二乙胺基乙氧基）苯基]-7H-毗 咯并[2,3-d]嘧啶-4-基氧}苯基）-3-環丙基脲， 1 { 2 ·鼠·4-[6 - [4-((2R)-2 -經基-3 -二乙胺基丙乳基） 苯基]-7H-吡咯并[2,3-(1]嘧啶-4-基氧]苯基}-3_環丙 基脲， 1 - (2-氯-4· { 6-[4-((2R)-2 -羥基-3·吡咯啶丙氧基） 苯基]-7H-吡咯并[2,3-d]嘧啶-4-基氧}苯基）-3-環丙 基月尿，以及 74525-961211.doc .23- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公羡） Αδ Βδ C8 D8 1304061 申請專利範圍 M2-氯-4_{ 6-[4-(2-二乙胺丙氧基）_苯基]-7H-吡 咯并[2,3-d]嘧啶-4-基氧}苯基）·3_環丙基脲。 17·如申請專利範圍第i項之化合物或其藥理學上容許之鹽 或彼等之水合物，其選自下列化合物中之任一種·· 4-(3-氯·4-(環丙胺羰基）胺苯氧基）_7_甲氧基_6•喹 4叛酸胺， 4 - ( 3 -氯· 4 _ (乙胺羰基）胺苯氧基）_ 7 _甲氧基_ 6 _喹啉 羧醯胺， Ν6 -甲氧基-4-(3-氯-4-(((環丙胺基）羰基）胺基）苯氧 基）-7_甲氧基- 6·ρ奎淋複酿胺， 4-(3-氯_4-(甲胺羰基）胺苯氧基）_7_甲氧基_6_喹啉 羧醯胺，以及 Ν6 -甲氧基- 4- (3 -氯- 4- (((乙胺基）羰基）胺基）苯氧 基）-7 -甲氧基-6 -喹啉羧醯胺。 1 8 ·如申请專利範圍第1項之化令物或其藥理學上容許之鹽 或彼等之水合物，該化合物為：4 - (3 -氯-4 -(環丙胺羰 基）胺苯氧基）-7 -甲氧基-6-喹啉羧醯胺。 1 9 ·如申請專利範圍第1項之化合物或其藥理學上容許之鹽 或彼等之水合物，該化合物為：4 - ( 3 -氯-4 -(乙胺羰基） 胺苯氧基）-7 -甲氧基-6 -喹啉羧醯胺。 2 0 ·如申請專利範圍第1項之化合物或其藥理學上容許之鹽 或彼等之水合物，該化合物為：N 6 -甲氧基-4 - ( 3 _氯一 4-(((環丙胺基）羰基）胺基）苯氧基）-7_甲氧基-6_喹啉 幾醯胺。 -24- 74525-961211.doc 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) !3〇4〇6ΐ(wherein: WR ' R 2 and Ra 13 respectively have the same meaning as W, R "1, Ral2 and Ral3 in the first item of the patent application scope)]. a pharmacologically acceptable salt or a hydrate thereof selected from any one of the following compounds: N-(4-(6-cyano-7-(3-(4-pyridyl)propoxy)) _4^ quinolinyl)oxyphenyl)-N*-(4-methoxyphenyl)urea, &gt;^-(4-(6-cyano-7-(2-(1,2,3-three) -2--2-yl)ethoxy)-4-quinolinyloxyphenyl)-N'-(4-fluorophenyl)urea, Ν·(4·(6-cyano-7-(2- (1,2,3 -三峻_ι_)ethoxy)-4-quinolinyloxyphenyl)-N'-(4-fluorophenyl)urea, Ν-(4·(6 cyano) - 7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolinyloxyphenyl)-Nf-(2,4-difluorophenyl)urea, Ν-(4-(6.Cyano7·(2,1,2,3-triazole-i-yl)ethoxy)-4-quinolinyl)oxyphenyl)-N'-(2 , 4-difluorophenyl)urea, 17- 74525-961211.doc This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) · 1304061 VI. Application for patent A8 B8 C8 D8 Νβ(4-(6-Cyano-7·(2-methoxyethoxy)-4-quinolinyl)oxyphenyl)'^,-(4-fluorophenyl)urea, Ν_(4 ·(6-Cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxyphenyl)-N, (l,3-disc-2-yl)urea, Νβ(4 · (6-Cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxyphenyl) as '-(3-cyanophenyl)urea, Ν·(4-(6• Cyano-7-(2-methoxyethoxy)_4·quinolinyloxyphenylene N'-(2 gassulfonyl)phenyl)urea, cyano-7-(2-A Oxyethoxy)-4-quinolinyloxyphenylcyclopropaneurea, N_(4-(6-cyano-7(2-methoxyethoxy)-4-quinolinyl)oxy - octafluorophenyl)·Ν, _(1,3-pyrazol-2-yl)urea, ^•(4,6-cyano-7-(2.methoxyethoxy)-4-quinoline Phenyl)oxy-oxyphenyl)-N,-cyclopropylurea, Ν_(4 _(6-cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxyphenyl Cyclopropylmethylurea, hydrazine (4·(6-cyano-7-(3·(moffin-4-yl)propoxy) 4 lysyl-4-yloxy)-2-fluorophenyl)-Ν, Gas 2,4-difluorophenyl)urea, Ν_ (4-(6-cyano-7)(3_(diethylamine)propoxy)_4_ Phenyloxy)phenyl)-indole,-(4-fluorophenyl)urea, N_(4-(6-cyano-7-(3-(4-)-norfosyl)propoxy)-4 Quinolinyl)oxyphenyl)-indole,-(4-fluorophenyl)urea, anthracene-(4.(6-cyano-7-(2-methoxyethoxy)-4-quinolinyl) Oxygen 2-fluorophenyl)-N'-(3-(decylsulfonyl)phenyl)urea, 74525-961211.doc -18- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 ABCD. Patent Range N-(4-(6-Cyano-7-(3-(diethylamino)propoxy)_4·quinolinyl)oxy-2-fluorophenyl)-N ,-(2,4-difluorophenyl)urea, N-(4-(6-cyano-7-(3-(1-(4-ethylhexahydropyrryl))propoxy)- 4-(porphyrinyl)oxyphenyl)_n,-(4-methoxyphenyl)urea, N-(4-(6-cyano-7-(3-cyanopropoxy)-4·quinoline Oxy-2-fluorophenyl)·Ν,-(2,4-difluorophenyl)urea, Ν-(4-(6-cyano-7-(2-(methylsulfonyl)) ethoxylate Base)_4_quinolinyl)oxy-2-fluorophenyl)-N'-(2,4.difluorophenyl)urea, N-(4-(6-cyano-7-(2-(A) Sulfhydryl)ethoxy)_4_quinolyl) gas phenyl)-N,-(4-fluorophenyl)urea, N-(4 _(6-cyano-7) -(2-methoxyethoxy)-4-quinolinyloxyphenyl)-N,-phenylurea, N-(4-(6-cyano-7-(2-methoxy) Oxy)-4-4(linyl)oxy-2.fluorophenyl)-N'-(2,4-difluorophenyl)urea, Ν-(4-(6.cyano-7-(3- Methoxycarbonylpropoxy)-4-ρ quinalyl)oxyphenyl)-indole,-(4.methoxyphenyl)urea, Ν-(4-(6.cyano-7-(3. Propyloxyquinolyloxyphenyl)-N,-(4-methoxyphenyl)urea, N-(4-(6-cyano-7-(2-(2-hydroxyethoxy)) Oxy)-4-quinolinyloxyphenyl)-N,-(4-methoxyphenyl)urea, N-(4-(6-cyano-7-(3)(diethylamino) Propoxy)-4_ 淋 氧基 oxy)phenyl)-Ν'-(3-(methyl 醢)phenyl) urinary, Ν-(4-(6·cyano-7-(3-( 4 - wholyl) propoxy quinolinyl) oxyphenyl)-Ν'-(3·(methylsulfonyl)phenyl)urea, 74525-961211.doc -19- This paper scale applies to China Standard (CNS) Α4 size (210X297 mm). A BCD 1304061 VI. Application for patent N-(4-(6-cyano-7-(3-diethylamino)propoxy)-4·quinine Phenyloxy)phenyl)-N'-phenylurea, N-(4-(6-cyano-7-(3- (4-oxalinyl)propoxy)-4-quinolinyloxyphenyl)-N'-phenylurea, N -(4-(6-cyano-7 - (3 - (4- Morpholinyl)propoxy)-4-carbino)oxyphenyl)-N '-(2-keto-1,2,3,4-tetrahydro-6-quinolinyl)urea, N -(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolinyl)oxyphenyl)-N, (3-acetamidophenyl)urea, ^^-( 4-(6-baby 1 -7-7-oxime 1 yl-4-Jun 1|7-linyl)oxy-2-phenylphenyl)-N, (2,4-difluorophenyl)urea, Ν- (4·(6-Cyano-7-(2-methoxyethoxy)-4-indolyl)oxy-2-fluorophenyl)-indole(4-fluorophenyl)urea, N-( 4-(6-&quot;fL-based - 7·(2-methoxyxyloxy)yl)-4-junphyrinyl)milk-2_fluorophenyl)-N'-phenylurea, 4-(4 -((4-fluoroanilino)carbonyl)amine phenoxy)-7-(2-methoxyethoxy)-6-4 plinamide, 7-(2-methoxyethoxy)- 4-(4-((1,3-pyrazol-2-ylamino)carbonyl)aminophenoxy)-6-quinolinylcarboxamide, 4-(4-((phenylaminocarbonyl)amino) -3 -Fluorophenoxy)-7-(2-methoxyethoxy)-6 · 4 linoleic acid, 4-(4-((4-)-anilino)-based phenyl styrene base -7-methoxy-6_quinolinecarboxamide, 4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinoline Carboxyguanamine, 74525-961211.doc -20- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm). 8 8 8 8 A BCD 1304061 VI. Patent scope 7-methoxy-4 _ (4-((1,3-Proazol-2-ylamino)carbonyl)aminophenoxy)-6-p-quinolamine, 4-(4-((2,4-difluoro) Anilino)carbonyl)amino-3-fluorophenoxy)-7-methoxy·6-p-quineinamine, 4-(4-((cyclopropylamino)carbonyl)amine phenoxy)_7_ Methoxy-6-quinoline carboxamide, 4-(5-((phenylaminocarbonyl)amino)-2-Pyratooxy)-7-methoxy-6-p-quineline, 4 -(4-(anilinecarbonyl)aminophenoxy)-7-methoxyquinoline carboxamide, 4-(4-(anilinecarbonyl)aminophenoxy)-7-(2-methoxyethyl Oxy) _ 6-Korline Resveramine, 4-(4-((2,4-difluoroanilino)carbonyl)amino)-3-fluorophenoxy)_7· (2-methoxyethoxy) -6-quinoline carboxamide, 4-(4-((4-fluoroanilino)carbonyl)amino-3-fluorobenzene )7-(2_methoxyethoxy)-6-porphyrin carboxamide, 7-(2-methoxyethoxy)-4-(4-((1,3·ρ塞唆_) 2_ylamino)carbonyl)amino-3-fluorophenoxy)-6-furanylcarboxamide, and 4-(4-((4-fluoroanilino)indolyl)-3-fluoro Phenoxy)_7_methoxy-6-junplin tetamine. 16. A compound according to claim 1 or a pharmacologically acceptable hydrazine or a hydrate thereof, which is selected from any one of the following compounds: N-(4-(6-cyano-7·( 2-methoxyethoxy)_4_quinolinyloxy-2_fluorophenyl)-indole-(4-fluorophenyl)urea, 74525-961211.doc -21 - This paper scale applies to Chinese national standards ( CNS) Α4 size (210X297 mm) A8 B8 C8 D8 1304061 VI. Patent application scope N-(2-chloro-4-((6-cyano-7-((l_methyl·4_hexahydropyridyl) )(Methyl)-4-p quinolyl)oxy)phenyl)-N'-cyclopropylurea, n_(4-((6-)-(2-(())) Amino)_2_hydroxypropyl)oxy)_4-(Linyl)oxy)phenyl)-N'-(4-fluorophenyl)urea, N-(4 _((6-cyano-7-) ((2 R) - 2 _ light base _ 3 _ (1 -pyrrole) propyl)oxy)-4 - π quinolinyl)oxy)phenyl)-N ' - (4-fluorophenyl) Urine, N-{4-[6-cyano-7-(2-#k-yl-3-P-Butyl-1-ylpropoxy)_Junlin-4-yloxy]-2-methyl Phenyl}-formation_cyclopropylurea, 4-(4-(4-fluoroanilino)carbonyl)-4-methylaminophenoxy)-7-methoxy-6-p-quine Carboxylic acid amine, 4-(3-chloro-4-(cyclopropylamine)aminophenoxy)_7-methoxy 6-1,4-linylamine, 4-(3-'chloro-4_(cyclopropylaminecarbonyl) Amine phenoxy)-7-(2-methoxyethyl lactyl)-6 - sulphonic amine, N6. cyclopropyl-4-(3-chloro-4_((cyclopropylamino)carbonyl) Amino)phenoxy)-7-methoxy-6-4 chlorpyrifos, N6-(2-oxoethyl)-4-(3-chloro-4-((cyclopropylamino)carbonyl) Amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, N6-(2-pyridyl)-4-(3-chloro-4-((cyclopropylamino)carbonyl) Amino) phenoxy)-7-methoxy-6-quinoline carboxamide, N6-(2-fluoroethyl)-4-(3-chloro-4-((cyclopropylamino)carbonyl) Amino) phenoxy)-7-methoxy-6-quinolinecarboxamide, N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl))amino)benzene Oxy)-7-methoxy-6-p-quineline indoleamine -22- 74525-961211.doc This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) · ABC D 1304061 6. Patent application scope N6-methyl-4-(3·chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy -6 - 边林林竣胺' N6 -ethyl-4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-jun 17Linden Amine, 6-Aminomethylmercapto-4 - (1-ethylamine-carbamoyl-1 Η _啕哚-5-yloxy)-7-methoxy hydroxyquine, 6-Amine Mercapto-7.methoxy- 4- [1-propylamine-methylindenyl-1Η-indol-5-yloxy]-r-quinidine, 6-aminoformamido-7-methoxy-A Ethylamine methyl hydrazino- 1 Η-啕哚-5-yloxy]quinoline, Ν4-(4-{4-[(phenylaminocarbonyl)amino]-3·chlorophenoxy b 2-pyridyl -1-methyl- 4-chloropurine succinic acid amine, N1-phenyl-3-chloro-5-[(2-{[(1-methyl-4-hexahydropyridyl)carbonyl]amine }- 4 -pyridyl)oxy]-1 Η - 1 - 哚 哚 carboxy guanamine, Ν 4-[4_(3 - qi-4-{[(4-fluoroanilino)carbonyl]amino}phenoxy -2 -ρ ratio aryl group -1 - methyl-4-hexahydro ρ than decidylamine, 1-(2- gas-4-{6-[4_(2-diethylamino ethoxy) Phenyl]-7H-pyrolo[2,3-d]pyrimidin-4-yloxy}phenyl)-3-cyclopropylurea, 1 { 2 ·rat·4-[6 - [4-( (2R)-2 -transmethyl-3-diethylaminopropyl lactyl)phenyl]-7H-pyrrolo[2,3-(1]pyrimidin-4-yloxy]benzene _}_cyclopropylurea, 1 - (2-chloro-4. { 6-[4-((2R)-2 -hydroxy-3.pyrrolidinyloxy)phenyl]-7H-pyrrole [2,3-d]pyrimidin-4-yloxy}phenyl)-3-cyclopropyl monthly urine, and 74525-961211.doc .23- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public)羡) Αδ Βδ C8 D8 1304061 Patent application range M2-chloro-4_{ 6-[4-(2-diethylaminopropyloxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-4 -yloxy}phenyl)·3_cyclopropylurea. 17. The compound of claim i or a pharmacologically acceptable salt thereof or a hydrate thereof, which is selected from any one of the following compounds: 4-(3-chloro-4-(cyclopropylaminecarbonyl) Amine phenoxy)_7_methoxy_6• quinolinate, 4 -( 3 -chloro· 4 _(ethylaminocarbonyl)amine phenoxy)-7 methoxy- 6 _quinoline Carboxylamidine, Ν6-methoxy-4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6·ρ quinidine complex amine , 4-(3-chloro- 4-(methylaminocarbonyl)amine phenoxy)-7-methoxy-6-quinoline carboxamide, and Ν6-methoxy-4-(3-chloro-4- (((Ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide. 1 8 · If the compound of claim 1 or its pharmacologically acceptable salt or hydrate thereof is used, the compound is: 4-(3-chloro-4-(cyclopropylaminecarbonyl)aminephenoxy Benzyl-7-methoxy-6-quinoline carboxamide. 1 9 If the compound of claim 1 or a pharmacologically acceptable salt thereof or a hydrate thereof is used, the compound is: 4-(3-chloro-4-(ethylaminecarbonyl)aminephenoxy) -7-methoxy-6-quinoline carboxamide. 2 0. If the compound of claim 1 or a pharmacologically acceptable salt thereof or a hydrate thereof, the compound is: N 6 -methoxy-4 - ( 3 _chloro- 4-((( Cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinamine. -24- 74525-961211.doc This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) !3〇4〇6ΐ 21. :申請專利範圍第！項之化合物或其藥理學上容許之鹽 :彼等之水合物’該化合物為：N6•甲氧基_4_(3_氯_ =(乙胺基）羧基）胺基）苯氧基）小甲氧基·6_喹琳幾 22. 23. :種醫藥組合物’其係用於血管新生抑料用能發揮效 理=疾病’其包含中請專利範圍第1項之化合物或其藥 一予上谷终之鹽或彼等之水合物作為有效成份。:種，藥組合物，其係用於血管新生抑制，其包含申請 、和園第1項之化合物或其藥理學上容許之鹽或彼等 '^水合物作為有效成份。 =醫藥組合物，其係用於抗腫瘤，其包含中請專利範 圍弟1項之化合物或其藥理學上容許之鹽或彼等之水合 物作為有效成份。 口 =醫藥組合物’其係用於血管瘤，其包含中請專利範 圍弟1項之化合物或其藥理學上容許之鹽或彼等之水合 物作為有效成份。 26· 27. 28. —種醫藥组合物’其係用於癌轉移抑制，其包含申請專 利範圍第【項之化合物或其藥理學上容許之鹽：彼；之 水合物作為有效成份。 一種醫藥組合物，其係用於網膜血f新生症或糖尿病性 網膜症，其包含申請專利範圍第i項之化合物或其藥理 學上容許之鹽或彼等之水合物作為有效成份。 -：醫藥組合物，其係用於發炎性疾病，其包含申請專 利範圍第1項之化合物或其藥理學上容許之鹽或彼等之 74525-961911 Hnr21. : Apply for patent scope! A compound or a pharmacologically acceptable salt thereof: a hydrate of the compound 'N6•methoxy_4_(3_chloro_=(ethylamino)carboxy)amino)phenoxy) small Methoxy 6-quinolin 22. 23. The pharmaceutical composition 'is used for angiogenesis and can be used as a disease = disease', including the compound of claim 1 or its drug The salt of the last season or the hydrate of them is used as an active ingredient. A medicinal composition for use in angiogenesis inhibition, which comprises the compound of the application, the compound of the first item or a pharmacologically acceptable salt thereof or the hydrates thereof as an active ingredient. A pharmaceutical composition for use in anti-tumor, which comprises a compound of the patent formula 1 or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient. Oral = pharmaceutical composition' is used for hemangioma, which comprises a compound of the patent application, or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient. 26.27. 28. A pharmaceutical composition for use in cancer metastasis inhibition comprising a compound of the above-mentioned patent application or a pharmacologically acceptable salt thereof; a hydrate thereof as an active ingredient. A pharmaceutical composition for retinal blood rejuvenation or diabetic retinopathy comprising a compound of claim i or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient. - a pharmaceutical composition for use in an inflammatory disease comprising a compound of claim 1 or a pharmacologically acceptable salt thereof or 74525-961911 Hnr 1304061 #、申請專利範圍 A8 B8 C8 D8 水合物作為有效成份。 •一種醫藥組合物，其係用於包含變形性關節炎、風濕性 關節炎、乾癖或延遲性過敏反應之發炎性疾病，其包含 申請專利範圍第1項之化合物或其藥理學上容許之鹽或 彼等之水合物作為有效成份。 30· —種醫藥組合物，其係用於粥腫性動脈硬化症，其包含 申請專利範圍第1項之化合物或其藥理學上容許之鹽或 彼等之水合物作為有效成份。 31· 種醫藥組合物，其係用於胰臟癌、胃癌、大腸癌、乳 癌、前列腺癌、肺癌、腎癌、腦腫瘤、血癌、或卵巢 癌’其包含申請專利範圍第Γ項之化合物或其藥理學上 容許之鹽或彼等之水合物作為有效成份。 32· —種醫藥組合物，其係用於基於血管新生抑制作用之腫 瘤’其包含申請專利範圍第1項之化合物或其藥理學上 容許之鹽或彼等之水合物作為有效成份。 74525-961211.doc • 26 -1304061 #, application patent range A8 B8 C8 D8 hydrate as an active ingredient. • A pharmaceutical composition for inflammatory diseases comprising osteoarthritis, rheumatoid arthritis, dryness or delayed allergic reactions, comprising a compound of claim 1 or a pharmacologically acceptable Salt or their hydrates are used as active ingredients. A pharmaceutical composition for use in atherosclerotic atherosclerosis comprising a compound of claim 1 or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient. 31. A pharmaceutical composition for pancreatic cancer, gastric cancer, colorectal cancer, breast cancer, prostate cancer, lung cancer, kidney cancer, brain tumor, blood cancer, or ovarian cancer, which comprises a compound of the scope of the patent application or The pharmacologically acceptable salts or their hydrates are used as active ingredients. A pharmaceutical composition for use in a tumor based on angiogenesis inhibition, which comprises the compound of claim 1 or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient. 74525-961211.doc • 26 -
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10822307B2 (en) 2014-08-28 2020-11-03 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor
US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer
US11598776B2 (en) 2011-06-03 2023-03-07 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds

Families Citing this family (273)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7517880B2 (en) * 1997-12-22 2009-04-14 Bayer Pharmaceuticals Corporation Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
JP2002534468A (en) 1999-01-13 2002-10-15 バイエル コーポレイション ω-Carboxyaryl-substituted diphenylureas as p38 kinase inhibitors
DK1415987T3 (en) * 2000-10-20 2007-07-02 Eisai R&D Man Co Ltd Nitrogen-containing aromatic ring compounds for use as anticancer agents
AU2002255284B2 (en) * 2001-04-27 2007-10-04 Kyowa Kirin Co., Ltd. Quinoline derivative having azolyl group and quinazoline derivative
DE60209721T2 (en) * 2001-05-14 2006-09-07 Novartis Ag OXAZOLO AND FUROPYRIMIDINES AND THEIR USE AS MEDICAMENTS AGAINST TUMORS
ATE443047T1 (en) 2001-06-22 2009-10-15 Kirin Pharma Kk QUINOLINE DERIVATIVE AND QUINAZOLINE DERIVATIVE INHIBITING THE SELF-PHOSPHORYLATION OF THE HEPATOCYTUS PROLIFERATOR RECEPTOR AND MEDICAL COMPOSITION CONTAINING THE SAME
US7323469B2 (en) 2001-08-07 2008-01-29 Novartis Ag 7H-pyrrolo[2,3-d]pyrimidine derivatives
GB0119249D0 (en) 2001-08-07 2001-10-03 Novartis Ag Organic compounds
EP1447405A4 (en) * 2001-10-17 2005-01-12 Kirin Brewery Quinoline or quinazoline derivatives inhibiting auto-phosphorylation of fibroblast growth factor receptors
AU2003209119A1 (en) 2002-02-11 2003-09-04 Bayer Pharmaceuticals Corporation Pyridine, quinoline, and isoquinoline n-oxides as kinase inhibitors
DK1478358T3 (en) 2002-02-11 2013-10-07 Bayer Healthcare Llc Sorafenibtosylate for the treatment of diseases characterized by abnormal angiogenesis
JP4542783B2 (en) * 2002-03-05 2010-09-15 エーザイ・アール・アンド・ディー・マネジメント株式会社 Antitumor agent comprising a combination of a sulfonamide-containing heterocyclic compound and an angiogenesis inhibitor
US7598258B2 (en) 2002-05-01 2009-10-06 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives inhibiting autophosphorylation of macrophage colony stimulating factor receptor
PE20040522A1 (en) * 2002-05-29 2004-09-28 Novartis Ag DIARYLUREA DERIVATIVES DEPENDENT ON PROTEIN KINASE
CN1694873A (en) 2002-08-08 2005-11-09 安姆根有限公司 Vanilloid receptor ligands and their use in treatments
RU2310651C2 (en) * 2002-08-30 2007-11-20 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Nitrogen-containing aromatic derivatives, pharmaceutical composition containing thereof, method for treatment and using
EP1559715B1 (en) 2002-10-21 2007-09-26 Kirin Beer Kabushiki Kaisha N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-n'-(5-methyl-3-isoxazolyl)urea salt in crystalline form
WO2004039782A1 (en) * 2002-10-29 2004-05-13 Kirin Beer Kabushiki Kaisha QUINOLINE DERIVATIVES AND QUINAZOLINE DERIVATIVES INHIBITING AUTOPHOSPHORYLATION OF Flt3 AND MEDICINAL COMPOSITIONS CONTAINING THE SAME
TW200418466A (en) * 2002-11-06 2004-10-01 Smithkline Beecham Corp Chemical compounds
US7557129B2 (en) 2003-02-28 2009-07-07 Bayer Healthcare Llc Cyanopyridine derivatives useful in the treatment of cancer and other disorders
WO2004080462A1 (en) * 2003-03-10 2004-09-23 Eisai Co., Ltd. c-Kit KINASE INHIBITOR
DK1611088T3 (en) * 2003-04-07 2009-10-19 Pharmacyclics Inc Hydroxymates as therapeutic agents
CN100586935C (en) * 2003-04-16 2010-02-03 亨斯迈先进材料（瑞士）有限公司 1-imidazolylmethyl-substituted-2-naphtols and their use as accelerators for low-temperature curing
US20070117842A1 (en) * 2003-04-22 2007-05-24 Itaru Arimoto Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
WO2004093812A2 (en) * 2003-04-22 2004-11-04 Irm Llc Compounds that induce neuronal differentiation in embryonic stem cells
TW200519106A (en) 2003-05-02 2005-06-16 Novartis Ag Organic compounds
EP1626714B1 (en) 2003-05-20 2007-07-04 Bayer Pharmaceuticals Corporation Diaryl ureas for diseases mediated by pdgfr
WO2006074147A2 (en) 2005-01-03 2006-07-13 Myriad Genetics, Inc. Nitrogen containing bicyclic compounds and therapeutical use thereof
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
BRPI0412219B8 (en) 2003-07-23 2021-07-27 Bayer Healthcare Llc fluoro substituted omega-carboxy aryl diphenyl urea compounds and pharmaceutical compositions comprising said compounds
MXPA05011286A (en) * 2003-08-20 2006-01-24 Axys Pharm Inc Acetylene derivatives as inhibitors of histone deacetylase.
WO2005030140A2 (en) * 2003-09-26 2005-04-07 Exelixis, Inc. C-met modulators and methods of use
JP2007533635A (en) * 2003-09-30 2007-11-22 アムジエン・インコーポレーテツド Vanilloid receptor ligands and their use in therapy
EP1683785B1 (en) * 2003-11-11 2013-10-16 Eisai R&D Management Co., Ltd. Urea derivative and process for producing the same
US20050267182A1 (en) * 2003-11-13 2005-12-01 Ambit Biosciences Corporation Urea derivatives as FLT-3 modulators
AU2004292773A1 (en) * 2003-11-28 2005-06-09 Novartis Ag Diaryl urea derivatives in the treatment of protein kinase dependent diseases
DE10357510A1 (en) * 2003-12-09 2005-07-07 Bayer Healthcare Ag Heteroaryl-substituted benzenes
AU2004309166B2 (en) 2003-12-23 2008-02-21 Pfizer Inc. Novel quinoline derivatives
EP1698623B1 (en) * 2003-12-25 2015-04-15 Eisai R&D Management Co., Ltd. Crystal of salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)amino-phenoxy)-7-methoxy-6-quinolinecarboxamide or of solvate thereof and processes for producing these
WO2005073224A2 (en) 2004-01-23 2005-08-11 Amgen Inc Quinoline quinazoline pyridine and pyrimidine counds and their use in the treatment of inflammation angiogenesis and cancer
CN1933839A (en) * 2004-01-23 2007-03-21 安进公司 Compounds and methods of use
EP1745034A1 (en) 2004-02-11 2007-01-24 Amgen Inc. Vanilloid receptor ligands and their use in treatments
MY139645A (en) 2004-02-11 2009-10-30 Amgen Inc Vanilloid receptor ligands and their use in treatments
TW200530236A (en) 2004-02-23 2005-09-16 Chugai Pharmaceutical Co Ltd Heteroaryl phenylurea
EP1719762B1 (en) * 2004-02-27 2012-06-27 Eisai R&D Management Co., Ltd. Novel pyridine derivative and pyrimidine derivative (1)
DE102004017438A1 (en) * 2004-04-08 2005-11-03 Bayer Healthcare Ag Hetaryloxy-substituted phenylaminopyrimidines
US7459562B2 (en) 2004-04-23 2008-12-02 Bristol-Myers Squibb Company Monocyclic heterocycles as kinase inhibitors
TW200538453A (en) 2004-04-26 2005-12-01 Bristol Myers Squibb Co Bicyclic heterocycles as kinase inhibitors
CN101010315A (en) 2004-04-30 2007-08-01 拜耳制药公司 Substituted pyrazolyl urea derivatives useful in the treatment of cancer
PL1746999T3 (en) * 2004-05-06 2012-07-31 Warner Lambert Co 4-phenylamino-quinazolin-6-yl-amides
WO2005113494A2 (en) 2004-05-07 2005-12-01 Amgen Inc. Nitrogenated heterocyclic derivatives as protein kinase modulators and use for the treatment of angiogenesis and cancer
WO2005121125A1 (en) * 2004-06-09 2005-12-22 Pfizer Inc. Ether-linked heteroaryl compounds
US7432373B2 (en) 2004-06-28 2008-10-07 Bristol-Meyers Squibb Company Processes and intermediates useful for preparing fused heterocyclic kinase inhibitors
US20050288290A1 (en) 2004-06-28 2005-12-29 Borzilleri Robert M Fused heterocyclic kinase inhibitors
US7439246B2 (en) 2004-06-28 2008-10-21 Bristol-Myers Squibb Company Fused heterocyclic kinase inhibitors
EP1773826A4 (en) * 2004-07-02 2009-06-03 Exelixis Inc C-met modulators and method of use
US7507748B2 (en) * 2004-07-22 2009-03-24 Amgen Inc. Substituted aryl-amine derivatives and methods of use
WO2006010264A1 (en) * 2004-07-30 2006-02-02 Methylgene, Inc. Inhibitors of vegf receptor and hgf receptor signaling
US8772269B2 (en) 2004-09-13 2014-07-08 Eisai R&D Management Co., Ltd. Use of sulfonamide-including compounds in combination with angiogenesis inhibitors
WO2006030941A1 (en) * 2004-09-13 2006-03-23 Eisai R & D Management Co., Ltd. Simultaneous use of sulfonamide-containing compound and angiogenesis inhibitor
PE20060664A1 (en) 2004-09-15 2006-08-04 Novartis Ag BICYCLE AMIDAS AS KINASE INHIBITORS
AU2005283422C1 (en) 2004-09-17 2017-02-02 Eisai R & D Management Co., Ltd. Medicinal composition
GB0421525D0 (en) * 2004-09-28 2004-10-27 Novartis Ag Inhibitors of protein kineses
US20070054916A1 (en) * 2004-10-01 2007-03-08 Amgen Inc. Aryl nitrogen-containing bicyclic compounds and methods of use
CA2586056C (en) 2004-11-02 2012-03-13 Banyu Pharmaceutical Co., Ltd. Aryloxy-substituted benzimidazole derivative
US7652009B2 (en) 2004-11-30 2010-01-26 Amgem Inc. Substituted heterocycles and methods of use
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
AU2006221065A1 (en) * 2005-02-03 2006-09-14 Vertex Pharmaceuticals Incorporated Pyrrolopyrimidines useful as inhibitors of protein kinase
US7301022B2 (en) 2005-02-15 2007-11-27 Amgen Inc. Vanilloid receptor ligands and their use in treatments
JO2787B1 (en) 2005-04-27 2014-03-15 امجين إنك, Substituted Amid derivatives & methods of use
ATE540948T1 (en) 2005-05-20 2012-01-15 Vertex Pharma PYRROLOPYRIDINES AS PROTEIN KINASE INHIBITORS
US8093264B2 (en) * 2005-05-20 2012-01-10 Methylgene Inc. Fused heterocycles as inhibitors of VEGF receptor and HGF receptor signaling
WO2006137474A1 (en) 2005-06-23 2006-12-28 Eisai R & D Management Co., Ltd. Amorphous salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)­aminophenoxy)-7-methoxy-6-quinolinecarboxamide and process for producing the same
US7550483B2 (en) 2005-06-23 2009-06-23 Eisai R&D Management Co., Ltd. Amorphous salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and process for preparing the same
AU2006265835B2 (en) 2005-06-30 2012-05-03 Amgen Inc. Bis-aryl kinase inhibitors and their use in the treatment of inflammation, angiogenesis and cancer
TW200740820A (en) * 2005-07-05 2007-11-01 Takeda Pharmaceuticals Co Fused heterocyclic derivatives and use thereof
US7994331B2 (en) 2005-07-13 2011-08-09 Msd K.K. Heterocycle-substituted benzimidazole derivative
JP5066446B2 (en) * 2005-08-01 2012-11-07 エーザイ・アール・アンド・ディー・マネジメント株式会社 Methods for predicting the effects of angiogenesis inhibitors
EP2281901B1 (en) 2005-08-02 2013-11-27 Eisai R&D Management Co., Ltd. Anti-tumour pharmaceutical composition with angiogenesis inhibitors
WO2007018137A1 (en) 2005-08-05 2007-02-15 Chugai Seiyaku Kabushiki Kaisha Multikinase inhibitor
US7605154B2 (en) * 2005-08-08 2009-10-20 Janssen Pharmaceutica N.V. Substituted Thiazolo [4,5-d]pyrimidines as protein kinase inhibitors
BRPI0616799B8 (en) 2005-08-24 2021-05-25 Eisai R&D Man Co Ltd pyridine derivative and pyrimidine derivative, pharmaceutical compositions, uses, angiogenesis inhibitors, against hepatocyte growth factor receptor and against cancer metastasis, and antitumor agent
WO2007026864A1 (en) * 2005-09-01 2007-03-08 Eisai R & D Management Co., Ltd. Method for preparation of pharmaceutical composition having improved disintegradability
GT200600411A (en) * 2005-09-13 2007-05-21 Novartis Ag COMBINATIONS THAT INCLUDE AN INHIBITOR OF THE RECEIVER OF THE VASCULAR ENDOTELIAL GROWTH FACTOR
CA2623958C (en) 2005-09-30 2013-05-28 Banyu Pharmaceutical Co., Ltd. 2-heteroaryl-substituted indole derivative
AU2006309171A1 (en) * 2005-10-28 2007-05-10 Irm Llc Compounds and compositions as protein kinase inhibitors
KR101353763B1 (en) * 2005-11-07 2014-01-21 에자이 알앤드디 매니지먼트 가부시키가이샤 USE OF COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND c-kit KINASE INHIBITOR
EP1964837A4 (en) * 2005-11-22 2010-12-22 Eisai R&D Man Co Ltd Anti-tumor agent for multiple myeloma
TW200804288A (en) * 2005-12-12 2008-01-16 Astrazeneca Ab Alkylsulphonamide quinolines
ME00011A (en) * 2005-12-21 2009-02-10 Novartis Ag Pyrimidinyl aryl urea derivatives being fgf inhibitors
JP5331485B2 (en) * 2005-12-21 2013-10-30 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Substituted pyrimidine derivatives useful for the treatment of cancer and other disorders
TW200804349A (en) * 2005-12-23 2008-01-16 Kalypsys Inc Novel substituted pyrimidinyloxy ureas as inhibitors of protein kinases
US7868177B2 (en) 2006-02-24 2011-01-11 Amgen Inc. Multi-cyclic compounds and method of use
EP1991531A1 (en) * 2006-02-28 2008-11-19 Amgen Inc. Cinnoline and quinoxaline derivates as phosphodiesterase 10 inhibitors
UY30183A1 (en) * 2006-03-02 2007-10-31 Astrazeneca Ab QUINOLINE DERIVATIVES
GB0604937D0 (en) * 2006-03-10 2006-04-19 Novartis Ag Organic compounds
GB0605120D0 (en) 2006-03-14 2006-04-26 Novartis Ag Organic Compounds
PE20080145A1 (en) 2006-03-21 2008-02-11 Janssen Pharmaceutica Nv TETRAHYDRO-PYRIMIDOAZEPINE AS MODULATORS OF TRPV1
US7692024B2 (en) * 2006-05-05 2010-04-06 Tk Holdings, Inc. Gas generant compositions
US7914632B2 (en) * 2006-05-05 2011-03-29 Tk Holdings, Inc. Gas generant compositions
US20090209580A1 (en) 2006-05-18 2009-08-20 Eisai R & D Management Co., Ltd. Antitumor agent for thyroid cancer
WO2008035209A2 (en) * 2006-05-30 2008-03-27 Methylgene Inc. Inhibitors of protein tyrosine kinase activity
US20090203693A1 (en) * 2006-06-29 2009-08-13 Eisai R & D Management Co., Ltd. Therapeutic agent for liver fibrosis
EP2044086A2 (en) * 2006-06-30 2009-04-08 Janssen Pharmaceutica N.V. Thiazolopyrimidine modulators of trpv1
CA2659971A1 (en) 2006-08-04 2008-02-07 Takeda Pharmaceutical Company Limited Fused heterocyclic derivative and use thereof
CA2661333C (en) 2006-08-23 2014-08-05 Eisai R&D Management Co., Ltd. Salt of phenoxypyridine derivative or crystal thereof and process for producing the same
JP5368096B2 (en) 2006-08-28 2013-12-18 エーザイ・アール・アンド・ディー・マネジメント株式会社 Anti-tumor agent for undifferentiated gastric cancer
KR101432318B1 (en) 2006-08-31 2014-08-20 에자이 알앤드디 매니지먼트 가부시키가이샤 Method for producing phenoxypyridine derivative
US7790885B2 (en) * 2006-08-31 2010-09-07 Eisai R&D Management Co., Ltd. Process for preparing phenoxypyridine derivatives
DE112007002257T5 (en) * 2006-09-30 2009-07-30 TK Holdings, Inc., Armada Gas generating compositions
EP2077262A4 (en) 2006-10-23 2011-12-28 Takeda Pharmaceutical Iminopyridine derivative and use thereof
US8563573B2 (en) 2007-11-02 2013-10-22 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
CA2672903C (en) 2006-12-20 2012-10-23 Amgen Inc. Heterocyclic compounds and their use in treating inflammation, angiogenesis and cancer
BRPI0720741A2 (en) 2006-12-22 2014-01-28 Hoffmann La Roche PRIMIDILA DERIVATIVES AS PROTEIN KINASE INHIBITORS.
CA2674084C (en) * 2006-12-26 2013-05-14 Pharmacyclics, Inc. Method of using histone deacetylase inhibitors and monitoring biomarkers in combination therapy
CA2675736A1 (en) 2007-01-19 2008-07-24 Eisai R&D Management Co., Ltd. Composition for treatment of pancreatic cancer
CA2676796C (en) * 2007-01-29 2016-02-23 Eisai R & D Management Co., Ltd. Composition for treatment of undifferentiated gastric cancer
KR101483805B1 (en) * 2007-01-30 2015-01-16 파마시클릭스, 인코포레이티드 Methods for determining cancer resistance to histone deacetylase inhibitors
JP2010517935A (en) * 2007-02-09 2010-05-27 武田薬品工業株式会社 Fused ring compounds as partial agonists of PPAR-gamma
US8148532B2 (en) 2007-03-14 2012-04-03 Guoqing Paul Chen Spiro substituted compounds as angiogenesis inhibitors
US20110189167A1 (en) * 2007-04-20 2011-08-04 Flynn Daniel L Methods and Compositions for the Treatment of Myeloproliferative Diseases and other Proliferative Diseases
BRPI0807717A2 (en) * 2007-04-20 2014-05-20 Deciphera Pharmaceuticals Llc KINASE INHIBITORS USEFUL FOR TREATMENT OF MYELOPROLIFERATIVE DISEASES AND OTHER PROLIFERATIVE DISEASES.
US20110160305A1 (en) * 2007-05-01 2011-06-30 Marty Jones Oral Delivery of Therapeutic Doses of Glutathione
AR066845A1 (en) 2007-06-05 2009-09-16 Takeda Pharmaceutical DERIVATIVES OF TRIAZOLOPIRIDINE AND IMIDAZOPIRIDINE A PHARMACEUTICAL COMPOSITION THAT INCLUDES THEM AND THEIR USE IN THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF CANCER
US8324395B2 (en) * 2007-08-23 2012-12-04 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
JP5656634B2 (en) 2007-08-29 2015-01-21 メチルジーン インコーポレイテッド Inhibitors of protein tyrosine kinase activity
WO2009035949A2 (en) * 2007-09-13 2009-03-19 Arete Therapeutics, Inc. Soluble epoxide hydrolase inhibitors
SI2214487T1 (en) 2007-10-11 2014-03-31 Glaxosmithkline Llc Novel seh inhibitors and their use
AU2008319366B2 (en) * 2007-10-29 2012-03-01 Amgen Inc. Benzomorpholine derivatives and methods of use
TWI440638B (en) * 2007-10-30 2014-06-11 Otsuka Pharma Co Ltd Heterocyclic compound and pharmaceutical composition thereof
WO2009060945A1 (en) 2007-11-09 2009-05-14 Eisai R & D Management Co., Ltd. Combination of anti-angiogenic substance and anti-tumor platinum complex
KR101585848B1 (en) * 2007-11-16 2016-01-15 애브비 인코포레이티드 Method of treating arthritis
BRPI0820171B8 (en) * 2007-11-16 2021-05-25 Rigel Pharmaceuticals Inc carboxamide, sulfonamide and amine compounds for metabolic disorders, pharmaceutical composition, and use thereof
JP2009132660A (en) 2007-11-30 2009-06-18 Eisai R & D Management Co Ltd Composition for treating esophageal cancer
US8129390B2 (en) * 2007-12-12 2012-03-06 Rigel Pharmaceuticals, Inc. Carboxamide, sulfonamide and amine compounds and methods for using the same
PE20091102A1 (en) 2007-12-17 2009-07-25 Janssen Pharmaceutica Nv IMIDAZOLO-, OXAZOLO-, AND THIAZOLOPYRIMIDINE MODULATORS OF TRPV1
PE20091523A1 (en) 2007-12-20 2009-10-29 Novartis Ag THIAZOL DERIVATIVES AS INHIBITORS OF THE ENZYME PHOSPHATIDYLINOSITOL 3-KINASE (PI3K)
WO2009094427A1 (en) 2008-01-23 2009-07-30 Bristol-Myers Squibb Company 4-pyridinone compounds and their use for cancer
KR101506062B1 (en) 2008-01-29 2015-03-25 에자이 알앤드디 매니지먼트 가부시키가이샤 Combined use of angiogenesis inhibitor and taxane
JP2009203226A (en) * 2008-01-31 2009-09-10 Eisai R & D Management Co Ltd Receptor tyrosine kinase inhibitor containing pyridine derivative and pyrimidine derivative
EP2248810A4 (en) * 2008-02-18 2011-05-25 Eisai R&D Man Co Ltd Method for producing phenoxypyridine derivative
WO2009109035A1 (en) * 2008-03-05 2009-09-11 Methylgene Inc. Inhibitors of protein tyrosine kinase activity
CN106146484A (en) * 2008-03-17 2016-11-23 埃姆比特生物科学公司 Quinazoline derivant is as RAF kinase modulator and their method and purposes
WO2009125597A1 (en) * 2008-04-10 2009-10-15 大鵬薬品工業株式会社 Acylthiourea compound or salt thereof, and use of the compound or the salt
US8193202B2 (en) * 2008-04-21 2012-06-05 Lexicon Pharmaceuticals, Inc. LIMK2 inhibitors, compositions comprising them, and methods of their use
US20110039892A1 (en) * 2008-04-23 2011-02-17 Takeda Pharmaceutical Company Limited Iminopyridine derivative and use thereof
CA2722139C (en) 2008-04-23 2017-04-11 Rigel Pharmaceuticals, Inc. Carboxamide compounds for the treatment of metabolic disorders
AR071392A1 (en) * 2008-04-23 2010-06-16 Takeda Pharmaceutical IMINOPIRIDINE DERIVATIVES AND THEIR USE
US8481569B2 (en) 2008-04-23 2013-07-09 Takeda Pharmaceutical Company Limited Iminopyridine derivatives and use thereof
CN102014627B (en) * 2008-04-30 2014-10-29 国家卫生研究院 Fused bicyclic pyrimidine compounds as aurora kinase inhibitors
CA2722734C (en) 2008-05-05 2013-11-05 Merck Frosst Canada Ltd. 3,4-substituted piperidine derivatives as renin inhibitors
WO2009151910A2 (en) * 2008-05-25 2009-12-17 Wyeth Combination product of receptor tyrosine kinase inhibitor and fatty acid synthase inhibitor for treating cancer
KR20110025856A (en) * 2008-07-03 2011-03-11 메르크 파텐트 게엠베하 Naphthyridininones as aurora kinase inhibitors
US8211911B2 (en) 2008-08-19 2012-07-03 Guoqing Paul Chen Compounds as kinase inhibitors
CN102131812B (en) 2008-08-20 2014-04-09 硕腾有限责任公司 Pyrrolo[2,3-d]pyrimidine compounds
UA104147C2 (en) 2008-09-10 2014-01-10 Новартис Аг Pyrrolidine dicarboxylic acid derivative and use thereof in the treatment of proliferative diseases
EP2331530B8 (en) 2008-09-26 2013-12-25 National Health Research Institutes Fused multicyclic compounds as protein kinase inhibitors
EP2340244A4 (en) * 2008-10-14 2012-07-25 Ning Xi Compounds and methods of use
WO2010064611A1 (en) 2008-12-01 2010-06-10 武田薬品工業株式会社 Heterocyclic compound and use thereof
JO3101B1 (en) 2008-12-02 2017-09-20 Takeda Pharmaceuticals Co Benzothiazole derivatives as anticancer agents
JO3265B1 (en) 2008-12-09 2018-09-16 Novartis Ag Pyridyloxyindoles Inhibitors of VEGF-R2 and Use Thereof for Treatment of Disease
NZ618004A (en) 2009-01-16 2015-06-26 Exelixis Inc Malate salt of n-(4-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} phenyl)-n’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer
JP5583751B2 (en) * 2009-03-21 2014-09-03 クイ ニング Amino ester derivatives, salts thereof, and methods of use
WO2010108503A1 (en) 2009-03-24 2010-09-30 Life & Brain Gmbh Promotion of neuronal integration in neural stem cell grafts
US8603521B2 (en) 2009-04-17 2013-12-10 Pharmacyclics, Inc. Formulations of histone deacetylase inhibitor and uses thereof
CN101671301B (en) * 2009-05-05 2014-02-26 江苏省药物研究所有限公司 Heterocyclic substituent acardite derivate and application thereof
US8293753B2 (en) 2009-07-02 2012-10-23 Novartis Ag Substituted 2-carboxamide cycloamino ureas
US20110112121A1 (en) * 2009-07-06 2011-05-12 Joerg Berghausen Pharmaceutical Compositions and Solid Forms
UA108618C2 (en) 2009-08-07 2015-05-25 APPLICATION OF C-MET-MODULATORS IN COMBINATION WITH THEMOSOLOMID AND / OR RADIATION THERAPY FOR CANCER TREATMENT
JP5048871B2 (en) * 2009-08-19 2012-10-17 エーザイ・アール・アンド・ディー・マネジメント株式会社 Quinoline derivative-containing pharmaceutical composition
MX2012002596A (en) * 2009-09-03 2012-07-03 Allergan Inc Compounds as tyrosine kinase modulators.
US8802868B2 (en) 2010-03-25 2014-08-12 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide
EP2560954B1 (en) 2010-04-22 2016-10-05 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
KR101677790B1 (en) 2010-06-25 2016-11-18 에자이 알앤드디 매니지먼트 가부시키가이샤 Antitumor agent using compounds having kinase inhibitory effect in combination
EP2594566A4 (en) 2010-07-16 2014-10-01 Kyowa Hakko Kirin Co Ltd Nitrogenated aromatic heterocyclic ring derivative
KR101032732B1 (en) * 2010-07-29 2011-05-06 김선자 Window frame for crime prevention
EP2423208A1 (en) 2010-08-28 2012-02-29 Lead Discovery Center GmbH Pharmaceutically active compounds as Axl inhibitors
CA2826773C (en) * 2011-02-24 2019-07-16 Emory University Jab1 blocking compositions for ossification and methods related thereto
CN103402519B (en) * 2011-04-18 2015-11-25 卫材R&D管理有限公司 tumor therapeutic agent
EP2718270B1 (en) * 2011-06-10 2022-04-27 Merck Patent GmbH Compositions and methods for the production of pyrimidine and pyridine compounds with btk inhibitory activity
UA110853C2 (en) 2011-09-13 2016-02-25 Фармасайклікс, Інк. Dosage forms histone deacetylase inhibitor in combination with bendamustine and their use
US8841301B2 (en) 2011-09-26 2014-09-23 Bristol-Myers Squibb Company Selective NR2B antagonists
TWI594986B (en) * 2011-12-28 2017-08-11 Taiho Pharmaceutical Co Ltd Antineoplastic agent effect enhancer
CN103508961B (en) 2012-06-26 2015-07-22 中美冠科生物技术（太仓）有限公司 Antitumor drug
JP2015530378A (en) * 2012-08-29 2015-10-15 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ DDR2 inhibitors for the treatment of osteoarthritis
JPWO2014098176A1 (en) * 2012-12-21 2017-01-12 エーザイ・アール・アンド・ディー・マネジメント株式会社 Amorphous quinoline derivative and method for producing the same
AR094812A1 (en) 2013-02-20 2015-08-26 Eisai R&D Man Co Ltd DERIVED FROM MONOCYCLIC PYRIDINE AS AN FGFR INHIBITOR
CA2909752A1 (en) 2013-04-19 2014-10-23 Astrazeneca Ab A nk3 receptor antagonist compound (nk3ra) for use in a method for the treatment of polycystic ovary syndrome (pcos)
CN105264380B (en) 2013-05-14 2017-09-05 卫材R&D管理有限公司 Pleasure is cut down for the biological marker of Buddhist nun's compound response for predicting and evaluating carcinoma of endometrium subject
RU2672585C2 (en) 2013-06-26 2018-11-16 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Use of eribulin and lenvatinib as combination therapy for treatment of cancer
AR097204A1 (en) 2013-08-02 2016-02-24 Pharmacyclics Inc SOLID TUMORS TREATMENT METHODS
CN103509005B (en) * 2013-09-26 2015-04-08 苏州海特比奥生物技术有限公司 Quinazoline compound as well as preparation method and application thereof
LT3536685T (en) * 2014-04-04 2022-04-25 Pfizer Inc. Bicyclic-fused heteroaryl or aryl compounds and their use as irak4 inhibitors
SI3925607T1 (en) 2014-04-15 2023-10-30 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
BR112017002268B1 (en) 2014-08-18 2022-11-08 Eisai R&D Management Co., Ltd MONOCYCLIC PYRIDINE DERIVATIVE SALT AND ITS CRYSTAL
MA40774A (en) 2014-10-01 2017-08-08 Respivert Ltd DIARYLEUREA DERIVATIVES AS KINASE P38 INHIBITORS
CN105985289B (en) * 2015-02-15 2018-12-21 正大天晴药业集团股份有限公司 A kind of pleasure cuts down the preparation method for Buddhist nun
JP6617155B6 (en) * 2015-04-07 2020-01-22 グアンドン・レイノーヴェント・バイオテック・カンパニー・リミテッド Tyrosine kinase inhibitor and pharmaceutical composition containing the same
SG11201801083UA (en) 2015-08-20 2018-03-28 Eisai R&D Man Co Ltd Tumor therapeutic agent
US10174000B2 (en) * 2015-08-27 2019-01-08 Pfizer Inc. Bicyclic-fused heteroaryl or aryl compounds as IRAK4 modulators
CN107266363A (en) * 2016-04-06 2017-10-20 杭州华东医药集团新药研究院有限公司 Methanesulfonic acid pleasure is cut down for the preparation method of Buddhist nun's impurity of the drug
CZ2016240A3 (en) 2016-04-27 2017-11-08 Zentiva, K.S. Salts of lenvatinib
EA202092442A3 (en) 2016-06-07 2021-08-31 Джакобио Фармасьютикалс Ко., Лтд. NEW HETEROCYCLIC DERIVATIVES USED AS SHP2 INHIBITORS
CN106243124B (en) * 2016-07-29 2018-03-09 湖北民族学院 A kind of Thienopyrimidine carbamide compounds and its preparation method and application
US9957233B1 (en) 2016-08-05 2018-05-01 Calitor Sciences, Llc Process for preparing substituted quinolin-4-ol compounds
WO2018028591A1 (en) * 2016-08-09 2018-02-15 殷建明 Quinoline derivative and use thereof
TWI603962B (en) 2016-09-10 2017-11-01 國立清華大學 Thioxo-containiing oxazine compound and the synthesis method thereof
WO2018059534A1 (en) * 2016-09-30 2018-04-05 广东众生药业股份有限公司 Crystal form and salt form of and preparation method for tyrosine kinase inhibitor
CN106854180B (en) * 2016-11-30 2018-08-31 济南轩德化工有限公司 A kind of preparation method of the chloro- 7- methoxy quinolines -6- amides of 4-
CN110191705A (en) 2016-12-01 2019-08-30 亚尼塔公司 The method for the treatment of cancer
BR112019013581A2 (en) * 2016-12-29 2020-01-07 Dr. Reddy’S Laboratories Limited FORMS IN THE SOLID STATE OF LENVATINIBE MESILATE
CN108299294A (en) * 2017-01-11 2018-07-20 江苏恒瑞医药股份有限公司 A kind of pleasure is cut down for the preparation method of Buddhist nun's impurity
CN106810512B (en) * 2017-01-18 2019-09-10 江苏省中医药研究院 IDH2 mutant inhibitor and application thereof
US10800741B2 (en) 2017-02-07 2020-10-13 Ancureall Pharmaceutical (Shanghai) Co., Ltd. Quinoline compound, preparation method and medical use therefor
BR112019014127A2 (en) 2017-02-08 2020-02-11 Eisai R&D Management Co., Ltd. PHARMACEUTICAL COMPOSITION FOR TUMOR TREATMENT
JP6771594B2 (en) 2017-02-15 2020-10-21 大鵬薬品工業株式会社 Pharmaceutical composition
WO2018157411A1 (en) * 2017-02-28 2018-09-07 深圳市塔吉瑞生物医药有限公司 Substituted nitrogen-containing aromatic compound and application thereof
MA49013A (en) 2017-03-23 2021-05-05 Jacobio Pharmaceuticals Co Ltd NEW HETEROCYCLIC DERIVATIVES USEFUL AS SHP2 INHIBITORS
CN107115344B (en) * 2017-03-23 2019-06-14 广东众生睿创生物科技有限公司 Tyrosine kinase inhibitor is preparing the purposes in the drug for preventing and/or treating fibrotic disease
EP3384901B1 (en) 2017-04-04 2024-08-14 Synthon B.V. Pharmaceutical composition comprising lenvatinib mesylate
JP2021506735A (en) * 2017-05-26 2021-02-22 イクノス サイエンシズ エスエー New MAP4K1 inhibitor
CN107513057A (en) * 2017-09-06 2017-12-26 南京医科大学 One kind pleasure is cut down for the weary oxygen activation prodrug of Buddhist nun and its application
WO2019062637A1 (en) * 2017-09-28 2019-04-04 南京明德新药研发股份有限公司 Quinoline derivative and application thereof as tyrosine kinase inhibitor
CN107739335A (en) * 2017-12-01 2018-02-27 南京奇可药业有限公司 A kind of pleasure cuts down the synthetic method for Buddhist nun
WO2019121406A1 (en) * 2017-12-18 2019-06-27 Chiesi Farmaceutici S.P.A. Azaindole derivatives as rho-kinase inhibitors
WO2019119486A1 (en) * 2017-12-21 2019-06-27 中国科学院合肥物质科学研究院 Class of pyrimidine derivative kinase inhibitors
MA51570A (en) 2018-01-10 2020-11-18 Eisai R&D Man Co Ltd POLYTHERAPIES FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA
MA51679A (en) 2018-01-26 2020-12-02 Exelixis Inc COMPOUNDS INTENDED FOR THE TREATMENT OF KINASE-DEPENDENT DISORDERS
JP7321165B2 (en) * 2018-01-26 2023-08-04 エグゼリクシス， インコーポレイテッド Compounds for treating kinase dependent disorders
US10583133B2 (en) 2018-03-12 2020-03-10 Shilpa Medicare Limited Pharmaceutical compositions of lenvatinib
CN108623521B (en) * 2018-03-22 2020-09-04 盐城师范学院 Preparation method of lenvatinib
KR20200135945A (en) 2018-03-28 2020-12-04 에자이 알앤드디 매니지먼트 가부시키가이샤 Hepatocellular carcinoma treatment
WO2019222075A1 (en) 2018-05-14 2019-11-21 Merck Sharp And Dohme Corp. Biomarkers for a combination therapy comprising lenvatinib and a pd-1 antagonist
CN110483482A (en) * 2018-05-15 2019-11-22 北京诺诚健华医药科技有限公司 Indoline -1- Carbox amide, preparation method and its in application pharmaceutically
CN110590839B (en) * 2018-06-13 2022-04-05 四川海思科制药有限公司 Levatinib derivative and preparation method and application thereof
CN108570044A (en) * 2018-07-02 2018-09-25 秦继伟 A kind of purposes of amides compound and its synthetic method and treating cancer
CN108690013A (en) * 2018-07-02 2018-10-23 秦继伟 Ben Bing &#91;d&#93;Thiazole and its application as EGFR inhibitor in treatment of cancer
CN110845408A (en) * 2018-08-20 2020-02-28 润佳（苏州）医药科技有限公司 Isotopically enriched lenvatinib
PT3620452T (en) 2018-09-07 2021-07-06 Indena Spa Process for the preparation of lenvatinib
KR20210137422A (en) 2018-09-25 2021-11-17 블랙 다이아몬드 테라퓨틱스, 인코포레이티드 Quinazoline derivatives, compositions, methods for their preparation and uses thereof as tyrosine kinase inhibitors
ES2922903T3 (en) 2018-10-04 2022-09-21 Synthon Bv Pharmaceutical composition comprising salts of lenvatinib
AU2019352722A1 (en) 2018-10-04 2021-04-01 Synthon B.V. Crystalline forms and processes of lenvatinib besylate
WO2020071457A1 (en) 2018-10-05 2020-04-09 Eisai R&D Management Co., Ltd. Biomarkers for a combination therapy comprising lenvatinib and everolimus
WO2020071451A1 (en) 2018-10-05 2020-04-09 Eisai R&D Management Co., Ltd. Biomarkers for a therapy comprising a sorafenib compound
CN111116468A (en) * 2018-10-31 2020-05-08 正大天晴药业集团股份有限公司 Quinolines or pharmaceutically acceptable salts thereof for the treatment of pancreatic cancer
BR112021011894A2 (en) 2018-12-21 2021-09-08 Daiichi Sankyo Company, Limited PHARMACEUTICAL COMPOSITION
JP2020100598A (en) 2018-12-25 2020-07-02 公益財団法人応用生化学研究所 Lenvatinib derivative, and composition for pharmaceutical research and tumor therapeutic agent using the same
CN115838369A (en) 2019-03-19 2023-03-24 株式会社沃若诺伊 Heteroaryl derivatives, process for preparing the same, and pharmaceutical composition containing the same as active ingredient
CN109776432B (en) * 2019-03-21 2020-07-24 广州六顺生物科技股份有限公司 Multi-target kinase inhibitor, pharmaceutical composition, preparation method and application of multi-target kinase inhibitor
EP3949990A4 (en) 2019-04-01 2023-02-08 Chiome Bioscience, Inc Medicament for treating cancer
CN113924288B (en) * 2019-04-03 2024-04-05 北京普祺医药科技股份有限公司 Quinolinyl-containing compound, pharmaceutical composition and application thereof
CN114144410A (en) 2019-07-19 2022-03-04 阿纳格纳斯生物技术股份有限公司 Polyarylurea derivatives and their use in the treatment of muscular diseases
MX2022001321A (en) 2019-08-02 2022-05-20 Akeso Pharmaceuticals Inc Anti-ctla4-anti-pd-1 bispecific antibody and uses thereof.
AU2020324185A1 (en) 2019-08-02 2022-03-03 CTTQ-Akeso (ShangHai) Biomed. Tech. Co., Ltd. Anti-PD-1 antibody and medical use thereof
CN110437223B (en) * 2019-08-06 2022-11-25 江苏千之康生物医药科技有限公司 Thiazolone derivative of lenetinic acid and application thereof
WO2021217537A1 (en) * 2020-04-30 2021-11-04 天津睿创康泰生物技术有限公司 Crystal form of lenvatinib free base and preparation method therefor
CN115843272A (en) 2020-05-08 2023-03-24 哈利亚治疗公司 Inhibitors of NEK7 kinase
WO2021226547A2 (en) * 2020-05-08 2021-11-11 Halia Therapeutics, Inc. Targeted nek7 inhibition for modulation of the nlrp3 inflammasome
CN112194623A (en) * 2020-10-16 2021-01-08 四川伊诺达博医药科技有限公司 Synthetic method of key intermediate of lenvatinib derivative
CA3200386A1 (en) * 2020-12-29 2022-07-07 Seo Jung Han Novel naphthyridinone derivative having inhibitory activity against ectonucleotide pyrophosphatase-phosphodiesterase and use thereof
EP4029501A1 (en) 2021-01-19 2022-07-20 Anagenesis Biotechnologies Combination of polyaromatic urea derivatives and glucocorticoid or hdac inhibitor for the treatment of diseases or conditions associated with muscle cells and/or satellite cells
WO2022226182A1 (en) * 2021-04-22 2022-10-27 Halia Therapeutics, Inc. Nek7 inhibitors
CN113372270A (en) * 2021-06-24 2021-09-10 江西国药有限责任公司 Lunvatinib and preparation method thereof
CN113582924A (en) * 2021-09-09 2021-11-02 四川国康药业有限公司 Multi-target tyrosine kinase inhibitor and preparation method and application thereof
EP4147689A1 (en) 2021-09-13 2023-03-15 Lotus Pharmaceutical Co., Ltd. Lenvatinib formulation
CA3237696A1 (en) 2021-11-08 2023-05-11 Progentos Therapeutics, Inc. Platelet-derived growth factor receptor (pdgfr) alpha inhibitors and uses thereof
CN115124534B (en) * 2021-11-23 2023-09-15 中山大学 Non-nucleotide PRMT5 small molecule inhibitor, preparation method and application
AU2023242146A1 (en) 2022-03-31 2024-09-05 Eisai R&D Management Co., Ltd. Liposome composition and liposome-containing pharmaceutical composition
WO2023225300A2 (en) * 2022-05-20 2023-11-23 Emory University Compounds and pharmaceutical compositions useful for managing sickle cell disease and conditions related thereto
WO2023228095A1 (en) 2022-05-24 2023-11-30 Daiichi Sankyo Company, Limited Dosage regimen of an anti-cdh6 antibody-drug conjugate
EP4289427A1 (en) * 2022-06-10 2023-12-13 Anagenesis Biotechnologies Dihydro[1,8]naphthyridin-7-one and pyrido[3,2-b][1,4]oxazin-3-one for use in treating cancer, and metastases in particular.
CN116751161A (en) * 2023-06-28 2023-09-15 中国人民解放军军事科学院军事医学研究院 Quinoline compound, preparation method thereof, pharmaceutical composition and medical application

Family Cites Families (193)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US189629A (en) * 1877-04-17 Improvement in adjustable elastic buckets for chain-pumps
CU22545A1 (en) 1994-11-18 1999-03-31 Centro Inmunologia Molecular OBTAINING A CHEMICAL AND HUMANIZED ANTIBODY AGAINST THE RECEPTOR OF THE EPIDERMAL GROWTH FACTOR FOR DIAGNOSTIC AND THERAPEUTIC USE
US4526988A (en) 1983-03-10 1985-07-02 Eli Lilly And Company Difluoro antivirals and intermediate therefor
DE3587022T2 (en) 1984-02-17 1993-06-17 Genentech Inc HUMAN TRANSFORMATION GROWTH FACTOR AND PRECURSOR OR FRAGMENT THEREOF, CELLS, DNA, VECTORS AND METHODS FOR THE PRODUCTION THEREOF, COMPOSITIONS AND PRODUCTS THAT CONTAIN THESE, AND ANTI-OXIDERS AND DIAGNOSTICS DERIVED FROM THEM.
US4716102A (en) * 1984-08-15 1987-12-29 Regents Of The University Of California Purified AIDS-associated virus ARV-2
IL77133A (en) 1984-12-04 1991-01-31 Lilly Co Eli Antineoplastic pharmaceutical compositions containing pentofuranoside derivatives,some new such compounds and their preparation
JPS62168137A (en) * 1985-12-20 1987-07-24 Fuji Photo Film Co Ltd Silver halide color photographic sensitive material and its processing method
CA1339136C (en) 1987-07-01 1997-07-29 Sailesh Amilal Varia Amorphous form of aztreonam
AU4128089A (en) 1988-09-15 1990-03-22 Rorer International (Overseas) Inc. Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same
US4983615A (en) 1989-06-28 1991-01-08 Hoechst-Roussel Pharmaceuticals Inc. Heteroarylamino- and heteroaryloxypyridinamine compounds which are useful in treating skin disorders
JPH0340486A (en) 1989-07-07 1991-02-21 Asahi Chem Ind Co Ltd Printed wiring board
JP2980326B2 (en) 1989-08-31 1999-11-22 株式会社東芝 Disk controller
US5180818A (en) 1990-03-21 1993-01-19 The University Of Colorado Foundation, Inc. Site specific cleavage of single-stranded dna
GB9105677D0 (en) 1991-03-19 1991-05-01 Ici Plc Heterocyclic compounds
US5367057A (en) 1991-04-02 1994-11-22 The Trustees Of Princeton University Tyrosine kinase receptor flk-2 and fragments thereof
US5409930A (en) 1991-05-10 1995-04-25 Rhone-Poulenc Rorer Pharmaceuticals Inc. Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
US5710158A (en) 1991-05-10 1998-01-20 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
US5721237A (en) 1991-05-10 1998-02-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties
JPH04341454A (en) 1991-05-16 1992-11-27 Canon Inc Sheet storing device
US5750376A (en) 1991-07-08 1998-05-12 Neurospheres Holdings Ltd. In vitro growth and proliferation of genetically modified multipotent neural stem cells and their progeny
CA2137275A1 (en) 1992-06-03 1993-12-09 Richard L. Eckert Bandage for continuous application of biologicals
GB9221220D0 (en) 1992-10-09 1992-11-25 Sandoz Ag Organic componds
GB9323290D0 (en) 1992-12-10 1994-01-05 Zeneca Ltd Quinazoline derivatives
JPH07176103A (en) 1993-12-20 1995-07-14 Canon Inc Magneto-optical recording/reproducing system magnetic head and magneto-optical recording medium used therefor
GB9326136D0 (en) 1993-12-22 1994-02-23 Erba Carlo Spa Biologically active 3-substituted oxindole derivatives useful as anti-angiogenic agents
IL112249A (en) 1994-01-25 2001-11-25 Warner Lambert Co Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds
US6811779B2 (en) 1994-02-10 2004-11-02 Imclone Systems Incorporated Methods for reducing tumor growth with VEGF receptor antibody combined with radiation and chemotherapy
JP3660391B2 (en) 1994-05-27 2005-06-15 株式会社東芝 Manufacturing method of semiconductor device
JPH0848078A (en) 1994-08-05 1996-02-20 Nippon Paper Ind Co Ltd Heat-sensitive recorder
GB9510757D0 (en) 1994-09-19 1995-07-19 Wellcome Found Therapeuticaly active compounds
US5656454A (en) 1994-10-04 1997-08-12 President And Fellows Of Harvard College Endothelial cell-specific enhancer
IL115256A0 (en) 1994-11-14 1995-12-31 Warner Lambert Co 6-Aryl pyrido (2,3-d) pyrimidines and naphthyridines and their use
GB9424249D0 (en) 1994-12-01 1995-01-18 T & N Technology Ltd Brake pads
JPH08176138A (en) 1994-12-19 1996-07-09 Mercian Corp Isocumarin derivative
US5658374A (en) 1995-02-28 1997-08-19 Buckman Laboratories International, Inc. Aqueous lecithin-based release aids and methods of using the same
US5624937A (en) 1995-03-02 1997-04-29 Eli Lilly And Company Chemical compounds as inhibitors of amyloid beta protein production
US6579314B1 (en) 1995-03-10 2003-06-17 C.R. Bard, Inc. Covered stent with encapsulated ends
DE122005000053I2 (en) 1995-03-30 2008-01-17 Pfizer Prod Inc quinazoline derivatives
GB9508538D0 (en) 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivatives
US5880141A (en) 1995-06-07 1999-03-09 Sugen, Inc. Benzylidene-Z-indoline compounds for the treatment of disease
ES2203642T3 (en) 1995-06-07 2004-04-16 Pfizer Inc. HETEROCICLIC PYRIMIDINE DERIVATIVES WITH CONDENSED RINGS.
GB9514265D0 (en) 1995-07-13 1995-09-13 Wellcome Found Hetrocyclic compounds
JP3493903B2 (en) * 1995-09-29 2004-02-03 株式会社デンソー Semiconductor device
GB9520822D0 (en) 1995-10-11 1995-12-13 Wellcome Found Therapeutically active compounds
AR004010A1 (en) 1995-10-11 1998-09-30 Glaxo Group Ltd HETERO CYCLIC COMPOUNDS
US6346398B1 (en) 1995-10-26 2002-02-12 Ribozyme Pharmaceuticals, Inc. Method and reagent for the treatment of diseases or conditions related to levels of vascular endothelial growth factor receptor
US6143764A (en) * 1995-11-07 2000-11-07 Kirin Beer Kabushiki Kaisha Quinoline and quinazoline derivatives inhibiting platelet-derived growth factor receptor autophosphorylation and pharmaceutical compositions containing the same
US5849759A (en) 1995-12-08 1998-12-15 Berlex Laboratories, Inc. Naphthyl-substituted benzimidazole derivatives as anti-coagulants
JPH09176103A (en) 1995-12-28 1997-07-08 Nitto Chem Ind Co Ltd Production of halomethylbiphenyl derivative
GB9604361D0 (en) 1996-02-29 1996-05-01 Pharmacia Spa 4-Substituted pyrrolopyrimidine compounds as tyrosine kinase inhibitors
JP2002503207A (en) 1996-04-17 2002-01-29 デュポン ファーマシューティカルズ カンパニー N- (amidinophenyl) -N '-(substituted) -3H-2,4-benzodiazepin-3-one derivatives as factor Xa inhibitors
JP2000514061A (en) 1996-06-28 2000-10-24 メルク エンド カンパニー インコーポレーテッド Fibrinogen receptor antagonist
ES2191187T3 (en) 1996-07-13 2003-09-01 Glaxo Group Ltd BICYCLE HETEROAROMATIC COMPOUNDS AS INHIBITORS OF PROTEIN TIROSIN-QUINASA.
HRP970371A2 (en) 1996-07-13 1998-08-31 Kathryn Jane Smith Heterocyclic compounds
PT912559E (en) 1996-07-13 2003-03-31 Glaxo Group Ltd HETEROCYCLIC COMPOUNDS FUSED AS PROTEIN INHIBITORS TYROSINE KINASE
US6809097B1 (en) 1996-09-25 2004-10-26 Zeneca Limited Quinoline derivatives inhibiting the effect of growth factors such as VEGF
WO1998014437A1 (en) 1996-09-30 1998-04-09 Nihon Nohyaku Co., Ltd. 1,2,3-thiadiazole derivatives and salts thereof, disease controlling agents for agricultural and horticultural use, and method for the use thereof
EP0837063A1 (en) 1996-10-17 1998-04-22 Pfizer Inc. 4-Aminoquinazoline derivatives
IL129825A0 (en) 1996-11-27 2000-02-29 Pfizer Fused bicyclic pyrimidine derivatives
CA2275777A1 (en) 1997-01-29 1998-07-30 Louise Richman Levine Treatment for premenstrual dysphoric disorder
CO4950519A1 (en) 1997-02-13 2000-09-01 Novartis Ag PHTHALAZINES, PHARMACEUTICAL PREPARATIONS THAT UNDERSTAND THEM AND THE PROCESS FOR THEIR PREPARATION
JP4495257B2 (en) * 1997-02-19 2010-06-30 バーレツクス ラボラトリーズ インコーポレーテツド N-heterocyclic derivatives as NOS inhibitors
US6090556A (en) 1997-04-07 2000-07-18 Japan Science & Technology Corporation Method for quantitatively determining the expression of a gene
AU7526798A (en) 1997-04-18 1998-11-27 Smithkline Beecham Plc Acetamide and urea derivatives, process for their preparation and their use in the treatment of cns disorders
ES2151467T3 (en) 1997-05-23 2005-03-01 Bayer Corporation ARILURES FOR THE TREATMENT OF INFLAMMATORY OR IMMUNOMODULATING DISEASES.
US6093742A (en) 1997-06-27 2000-07-25 Vertex Pharmaceuticals, Inc. Inhibitors of p38
WO1999001738A2 (en) 1997-06-30 1999-01-14 University Of Maryland, Baltimore Heparin binding-epidermal growth factor in the diagnosis of interstitial cystitis
JP3765918B2 (en) 1997-11-10 2006-04-12 パイオニア株式会社 Light emitting display and driving method thereof
JP4194678B2 (en) * 1997-11-28 2008-12-10 キリンファーマ株式会社 Quinoline derivative and pharmaceutical composition containing the same
BR9814374B1 (en) 1997-12-22 2013-09-17 "Substituted heterocyclic ureas and compositions comprising them"
MXPA00006233A (en) 1997-12-22 2002-09-18 Bayer Ag INHIBITION OF p38 KINASE ACTIVITY USING SUBSTITUTED HETEROCYCLIC UREAS.
AU762077B2 (en) 1997-12-22 2003-06-19 Bayer Healthcare Llc Inhibition of p38 kinase activity using aryl and heteroaryl substituted heterocyclic ureas
IL136690A0 (en) 1997-12-22 2001-06-14 Bayer Ag Inhibition of raf kinase using symmetrical and unsymmetrical substituted diphenyl ureas
RS49779B (en) 1998-01-12 2008-06-05 Glaxo Group Limited, Byciclic heteroaromatic compounds as protein tyrosine kinase inhibitors
GB9800575D0 (en) 1998-01-12 1998-03-11 Glaxo Group Ltd Heterocyclic compounds
BR9908275A (en) 1998-02-25 2000-10-24 Genetics Inst Phospholipase enzyme inhibitors
UA60365C2 (en) 1998-06-04 2003-10-15 Пфайзер Продактс Інк. Isothiazole derivatives, a method for preparing thereof, a pharmaceutical composition and a method for treatment of hyperproliferative disease of mammal
HUP0104211A3 (en) 1998-11-19 2003-01-28 Warner Lambert Co N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases and pharmaceutical composition containing it
WO2000042012A1 (en) 1999-01-13 2000-07-20 Bayer Corporation φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
UA73492C2 (en) 1999-01-19 2005-08-15 Aromatic heterocyclic compounds as antiinflammatory agents
HU230789B1 (en) * 1999-01-22 2018-05-02 Kyowa Hakko Kirin Co Quinoline derivatives and quinazoline derivatives, pharmaceutical compositions containing them and their use
JP3270834B2 (en) 1999-01-27 2002-04-02 ファイザー・プロダクツ・インク Heteroaromatic bicyclic derivatives useful as anticancer agents
UA71945C2 (en) 1999-01-27 2005-01-17 Pfizer Prod Inc Substituted bicyclic derivatives being used as anticancer agents
ATE482946T1 (en) 1999-02-10 2010-10-15 Astrazeneca Ab QUINAZOLINE DERIVATIVES AS ANGIOGENESIS INHIBITORS AND INTERMEDIATE PRODUCTS THEREFOR
GB9904103D0 (en) 1999-02-24 1999-04-14 Zeneca Ltd Quinoline derivatives
JP2000328080A (en) 1999-03-12 2000-11-28 Shin Etsu Chem Co Ltd Agent for low friction treatment of seat belt
YU13200A (en) 1999-03-31 2002-10-18 Pfizer Products Inc. Process and intermediates for preparing anti-cancer compounds
BR0010017A (en) 1999-04-28 2002-06-11 Univ Texas Compositions and processes for the treatment of cancer by selective vegf inhibition
WO2000071097A1 (en) 1999-05-20 2000-11-30 Takeda Chemical Industries, Ltd. Composition containing ascorbic acid salt
JP4304357B2 (en) 1999-05-24 2009-07-29 独立行政法人理化学研究所 How to create a full-length cDNA library
PE20010306A1 (en) 1999-07-02 2001-03-29 Agouron Pharma INDAZOLE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM USEFUL FOR THE INHIBITION OF PROTEIN KINASE
US6534535B1 (en) 1999-08-12 2003-03-18 Millennium Pharmaceuticals, Inc. Inhibitors of factor Xa
GT200000158A (en) 1999-09-28 2002-03-16 PIRIDINES AND REPLACED PYRIDACINES WITH ANGIOGENESIS INHIBITION ACTIVITY.
UA75054C2 (en) 1999-10-13 2006-03-15 Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг Substituted in position 6 indolinones, producing and use thereof as medicament
JP2001131071A (en) 1999-10-29 2001-05-15 Meiji Seika Kaisha Ltd Amorphous substance and medical composition containing amorphous substance
JP2003525595A (en) 1999-11-01 2003-09-02 キュラゲン コーポレイション Differentially expressed gene involved in angiogenesis, polypeptide encoded thereby, and method using the same
US20080241835A1 (en) * 1999-11-01 2008-10-02 Genentech, Inc. Differentially expressed genes involved in angiogenesis, the polypeptides encoded thereby, and methods of using the same
AU1617901A (en) * 1999-11-16 2001-05-30 Boehringer Ingelheim Pharmaceuticals, Inc. Urea derivatives as anti-inflammatory agents
UA75055C2 (en) 1999-11-30 2006-03-15 Пфайзер Продактс Інк. Benzoimidazole derivatives being used as antiproliferative agent, pharmaceutical composition based thereon
ES2267605T3 (en) * 1999-12-22 2007-03-16 Sugen, Inc. USE OF INDOLINONE COMPOUNDS FOR THE MANUFACTURE OF PHARMACEUTICAL PRODUCTS INTENDED TO MODULATE THE FUNCTION OF C-KIT-TYROSIN-PROTEIN-KINASE.
US7135466B2 (en) 1999-12-24 2006-11-14 Kirin Beer Kabushiki Kaisha Quinoline and quinazoline derivatives and drugs containing the same
US7005430B2 (en) 1999-12-24 2006-02-28 Kyowa Hakko Kogyo Co., Ltd. Fused purine derivatives
AU2001239770B2 (en) 2000-02-15 2006-01-05 Pharmacia & Upjohn Company Pyrrole substituted 2-indolinone protein kinase inhibitors
CA2411278A1 (en) 2000-06-09 2001-12-20 Corixa Corporation Compositions and methods for the therapy and diagnosis of colon cancer
AU2001277621A1 (en) 2000-08-09 2002-03-04 Astrazeneca Ab Antiangiogenic bicyclic derivatives
DK1415987T3 (en) * 2000-10-20 2007-07-02 Eisai R&D Man Co Ltd Nitrogen-containing aromatic ring compounds for use as anticancer agents
TWI283575B (en) 2000-10-31 2007-07-11 Eisai Co Ltd Medicinal compositions for concomitant use as anticancer agent
TW558430B (en) * 2000-11-01 2003-10-21 Kao Corp Cleaning device
AU2002223684A1 (en) 2000-11-22 2002-06-03 Novartis Pharma Gmbh Combination comprising an agent decreasing vegf activity and an agent decreasing egf activity
EP1341771A2 (en) 2000-11-29 2003-09-10 Glaxo Group Limited Benzimidazole derivatives useful as tie-2 and/or vegfr-2 inhibitors
AU2002254152A1 (en) 2001-03-08 2002-09-24 Millennium Pharmaceuticals (homo) piperazine substituted quinolines for inhibiting the phosphorylation of kinases
SI1385551T1 (en) 2001-04-06 2008-12-31 Wyeth Five Giralda Farms Antineoplastic combinations comprising cci-779 (rapamycin derivative) together with gemcitabine or fluorouracil
AU2002255284B2 (en) * 2001-04-27 2007-10-04 Kyowa Kirin Co., Ltd. Quinoline derivative having azolyl group and quinazoline derivative
JP4477303B2 (en) 2001-05-16 2010-06-09 ノバルティス アーゲー N- {5- [4- (4-Methyl-piperazino-methyl) -benzoylamide] -2-methylphenyl} -4- (3-pyridyl) -2-pyrimidin-amine and a combination comprising a chemotherapeutic agent Agent
ATE443047T1 (en) 2001-06-22 2009-10-15 Kirin Pharma Kk QUINOLINE DERIVATIVE AND QUINAZOLINE DERIVATIVE INHIBITING THE SELF-PHOSPHORYLATION OF THE HEPATOCYTUS PROLIFERATOR RECEPTOR AND MEDICAL COMPOSITION CONTAINING THE SAME
GB0117144D0 (en) 2001-07-13 2001-09-05 Glaxo Group Ltd Process
GB0119467D0 (en) 2001-08-09 2001-10-03 Smithkline Beecham Plc Novel compound
AU2002333526B2 (en) 2001-09-10 2008-01-17 Meso Scale Technologies, Llc. Methods and apparatus for conducting multiple measurements on a sample
JP2005511506A (en) 2001-09-20 2005-04-28 アブ サイエンス Use of a potent, selective and non-toxic c-kit inhibitor for treating interstitial cystitis
WO2003027102A1 (en) 2001-09-27 2003-04-03 Allergan, Inc. 3-(arylamino)methylene-1, 3-dihydro-2h-indol-2-ones as kinase inhibitors
JP4130179B2 (en) 2001-09-27 2008-08-06 ノバルティス アクチエンゲゼルシャフト Use of c-kit inhibitors to treat myeloma
EP1435959A2 (en) 2001-10-09 2004-07-14 University of Cincinnati Inhibitors of the egf receptor for the treatment of thyroid cancer
EP1447405A4 (en) 2001-10-17 2005-01-12 Kirin Brewery Quinoline or quinazoline derivatives inhibiting auto-phosphorylation of fibroblast growth factor receptors
DE60221886D1 (en) 2001-11-27 2007-09-27 Wyeth Corp 3-CYANOCHINOLINE AS INHIBITORS OF EGF-R AND HER2 KINASES
GB0201508D0 (en) * 2002-01-23 2002-03-13 Novartis Ag Organic compounds
JP4542783B2 (en) 2002-03-05 2010-09-15 エーザイ・アール・アンド・ディー・マネジメント株式会社 Antitumor agent comprising a combination of a sulfonamide-containing heterocyclic compound and an angiogenesis inhibitor
EP1488239A2 (en) 2002-03-20 2004-12-22 Dana-Farber Cancer Institute, Inc. Methods and compositions for the identification, assessment, and therapy of small cell lung cancer
US7598258B2 (en) 2002-05-01 2009-10-06 Kirin Beer Kabushiki Kaisha Quinoline derivatives and quinazoline derivatives inhibiting autophosphorylation of macrophage colony stimulating factor receptor
UA77303C2 (en) 2002-06-14 2006-11-15 Pfizer Derivatives of thienopyridines substituted by benzocondensed heteroarylamide useful as therapeutic agents, pharmaceutical compositions and methods for their use
WO2004006862A2 (en) 2002-07-16 2004-01-22 Children's Medical Center Corporation A method for the modulation of angiogenesis
US7169936B2 (en) 2002-07-23 2007-01-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments
RU2310651C2 (en) 2002-08-30 2007-11-20 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Nitrogen-containing aromatic derivatives, pharmaceutical composition containing thereof, method for treatment and using
GB0223380D0 (en) 2002-10-09 2002-11-13 Astrazeneca Ab Combination therapy
JP2006504745A (en) 2002-10-09 2006-02-09 コーザン バイオサイエンシス インコーポレイテッド Epo D and 5-FU / gemcitabine
JP4749660B2 (en) 2002-10-16 2011-08-17 武田薬品工業株式会社 Stable solid formulation
EP2596792A1 (en) 2002-10-16 2013-05-29 Takeda Pharmaceutical Company Limited Stable solid preparations
WO2004039782A1 (en) 2002-10-29 2004-05-13 Kirin Beer Kabushiki Kaisha QUINOLINE DERIVATIVES AND QUINAZOLINE DERIVATIVES INHIBITING AUTOPHOSPHORYLATION OF Flt3 AND MEDICINAL COMPOSITIONS CONTAINING THE SAME
WO2004041308A1 (en) 2002-11-06 2004-05-21 Cyclacel Limited Pharmaceutical composition comprising a cdk inhibitor and gemcitabine
GB0226434D0 (en) 2002-11-13 2002-12-18 Astrazeneca Ab Combination product
ITSV20020056A1 (en) 2002-11-14 2004-05-15 Alstom Transp Spa DEVICE AND METHOD OF VERIFICATION OF LOGIC SOFTWARE MOTORS TO COMMAND RAILWAY SYSTEMS, IN PARTICULAR OF STATION SYSTEMS
AR042042A1 (en) 2002-11-15 2005-06-08 Sugen Inc COMBINED ADMINISTRATION OF AN INDOLINONE WITH A CHEMOTHERAPEUTIC AGENT FOR CELL PROLIFERATION DISORDERS
AU2004206860B2 (en) 2003-01-14 2010-03-18 Cytokinetics, Inc. Compounds, compositions and methods
NL1022425C2 (en) 2003-01-17 2004-08-03 Trespa Int Bv Phenolic resin, use of such a phenolic resin and a molded part produced therewith.
JP3581361B1 (en) 2003-02-17 2004-10-27 株式会社脳機能研究所 Brain activity measurement device
TWI355936B (en) 2003-02-18 2012-01-11 Helsinn Healthcare Sa Uses of palonosetron hydrochloride
KR20050117533A (en) 2003-03-05 2005-12-14 셀진 코포레이션 Diphenylethylene compounds and uses thereof
WO2004080462A1 (en) 2003-03-10 2004-09-23 Eisai Co., Ltd. c-Kit KINASE INHIBITOR
RU2312109C2 (en) 2003-03-14 2007-12-10 Тайсо Фармасьютикал Ко., Лтд. Monoclonal antibody and hybridoma producing its
NZ542304A (en) 2003-03-14 2009-07-31 Ono Pharmaceutical Co Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient
DE10317649A1 (en) 2003-04-17 2004-11-04 Robert Bosch Gmbh Method and device for operating an internal combustion engine in push mode
US20070117842A1 (en) 2003-04-22 2007-05-24 Itaru Arimoto Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
JP2005008534A (en) * 2003-06-17 2005-01-13 Soc De Conseils De Recherches & D'applications Scientifiques (Scras) Anticancer agent and method for treating cancer
AU2004255022B2 (en) 2003-07-10 2007-08-23 Astrazeneca Ab Use of the quinazoline derivative ZD6474 combined with platinum compounds and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability
WO2005016323A2 (en) 2003-08-15 2005-02-24 Ab Science Use of c-kit inhibitors for treating type ii diabetes
AP2006003549A0 (en) 2003-08-21 2006-04-30 Osi Pharm Inc N-substituted benzimidazolyl C-kit inhibitors.
MXPA06003163A (en) 2003-09-23 2006-06-05 Novartis Ag Combination of a vegf receptor inhibitor with a chemotherapeutic agent.
WO2005030140A2 (en) 2003-09-26 2005-04-07 Exelixis, Inc. C-met modulators and methods of use
JP2005124034A (en) 2003-10-20 2005-05-12 Nippon Telegr & Teleph Corp <Ntt> Line setting method for specifying caller and carrying out callback to caller
EP1683785B1 (en) 2003-11-11 2013-10-16 Eisai R&D Management Co., Ltd. Urea derivative and process for producing the same
AU2004292773A1 (en) 2003-11-28 2005-06-09 Novartis Ag Diaryl urea derivatives in the treatment of protein kinase dependent diseases
RU2402567C2 (en) 2003-12-05 2010-10-27 Бристоль-Майерз Сквибб Компани Inhibitors of receptors of type 2 vessel endothelium growth factor
EP1698623B1 (en) 2003-12-25 2015-04-15 Eisai R&D Management Co., Ltd. Crystal of salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)amino-phenoxy)-7-methoxy-6-quinolinecarboxamide or of solvate thereof and processes for producing these
EP1719762B1 (en) 2004-02-27 2012-06-27 Eisai R&D Management Co., Ltd. Novel pyridine derivative and pyrimidine derivative (1)
KR20050091462A (en) 2004-03-12 2005-09-15 한국과학기술연구원 Furopyrimidine compound and ddr2 tyrosine kinase activity inhibitor comprising the same
JP2008501652A (en) 2004-06-03 2008-01-24 エフ．ホフマン−ラ　ロシュ　アーゲー Treatment with gemcitabine and EGFR inhibitors
US8772269B2 (en) 2004-09-13 2014-07-08 Eisai R&D Management Co., Ltd. Use of sulfonamide-including compounds in combination with angiogenesis inhibitors
WO2006030941A1 (en) 2004-09-13 2006-03-23 Eisai R & D Management Co., Ltd. Simultaneous use of sulfonamide-containing compound and angiogenesis inhibitor
AU2005283422C1 (en) 2004-09-17 2017-02-02 Eisai R & D Management Co., Ltd. Medicinal composition
WO2006036941A2 (en) 2004-09-27 2006-04-06 Kosan Biosciences Incorporated Specific kinase inhibitors
AU2005336924A1 (en) 2004-11-22 2007-04-12 King Pharmaceuticals Research & Development, Inc. Enhancing treatment of cancer and HIF-1 mediated disoders with adenosine A3 receptor antagonists
CA2589274A1 (en) 2004-12-07 2006-06-15 Locus Pharmaceuticals, Inc. Inhibitors of protein kinases
JP5106098B2 (en) 2005-02-28 2012-12-26 エーザイ・アール・アンド・ディー・マネジメント株式会社 New combination of sulfonamide compounds with anticancer agents
PL1859793T3 (en) 2005-02-28 2011-09-30 Eisai R&D Man Co Ltd Novel combinational use of a sulfonamide compound in the treatment of cancer
DE102005017446B4 (en) * 2005-04-15 2008-06-05 Südzucker AG Mannheim/Ochsenfurt Temperature control during alkaline extraction
WO2006137474A1 (en) 2005-06-23 2006-12-28 Eisai R & D Management Co., Ltd. Amorphous salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)­aminophenoxy)-7-methoxy-6-quinolinecarboxamide and process for producing the same
US7550483B2 (en) 2005-06-23 2009-06-23 Eisai R&D Management Co., Ltd. Amorphous salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and process for preparing the same
US20080219977A1 (en) 2005-07-27 2008-09-11 Isaiah Josh Fidler Combinations Comprising Gemcitabine and Tyrosine Kinase Inhibitors for the Treatment of Pancreatic Cancer
JP5066446B2 (en) 2005-08-01 2012-11-07 エーザイ・アール・アンド・ディー・マネジメント株式会社 Methods for predicting the effects of angiogenesis inhibitors
EP2281901B1 (en) 2005-08-02 2013-11-27 Eisai R&D Management Co., Ltd. Anti-tumour pharmaceutical composition with angiogenesis inhibitors
KR101353763B1 (en) 2005-11-07 2014-01-21 에자이 알앤드디 매니지먼트 가부시키가이샤 USE OF COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND c-kit KINASE INHIBITOR
EP1964837A4 (en) 2005-11-22 2010-12-22 Eisai R&D Man Co Ltd Anti-tumor agent for multiple myeloma
AR059066A1 (en) * 2006-01-27 2008-03-12 Amgen Inc COMBINATIONS OF THE ANGIOPOYETINE INHIBITOR -2 (ANG2) AND THE VASCULAR ENDOTELIAL GROWTH FACTOR INHIBITOR (VEGF)
US20090209580A1 (en) 2006-05-18 2009-08-20 Eisai R & D Management Co., Ltd. Antitumor agent for thyroid cancer
US8238322B2 (en) * 2006-06-30 2012-08-07 Nokia Corporation Optimizing of channel allocation in a wireless communications system
JP5368096B2 (en) 2006-08-28 2013-12-18 エーザイ・アール・アンド・ディー・マネジメント株式会社 Anti-tumor agent for undifferentiated gastric cancer
US20080057195A1 (en) * 2006-08-31 2008-03-06 United Technologies Corporation Non-line of sight coating technique
CA2675736A1 (en) 2007-01-19 2008-07-24 Eisai R&D Management Co., Ltd. Composition for treatment of pancreatic cancer
CA2676796C (en) * 2007-01-29 2016-02-23 Eisai R & D Management Co., Ltd. Composition for treatment of undifferentiated gastric cancer
CA2680122A1 (en) 2007-03-05 2008-09-18 Kyowa Hakko Kirin Co., Ltd. Pharmaceutical composition
EP2543390A1 (en) 2007-03-05 2013-01-09 Kyowa Hakko Kirin Co., Ltd. Pharmaceutical composition
WO2009060945A1 (en) 2007-11-09 2009-05-14 Eisai R & D Management Co., Ltd. Combination of anti-angiogenic substance and anti-tumor platinum complex
WO2009111648A1 (en) * 2008-03-05 2009-09-11 Vicus Therapeutics, Llc Compositions and methods for mucositis and oncology therapies
MX2010012290A (en) 2008-05-14 2011-02-21 Amgen Inc Combinations vegf(r) inhibitors and hepatocyte growth factor (c-met) inhibitors for the treatment of cancer.

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11598776B2 (en) 2011-06-03 2023-03-07 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
US10822307B2 (en) 2014-08-28 2020-11-03 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
TWI721954B (en) * 2014-08-28 2021-03-21 日商衛材R&D企管股份有限公司 High-purity quinoline derivative and production method thereof
US11186547B2 (en) 2014-08-28 2021-11-30 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer
US12083112B2 (en) 2015-03-04 2024-09-10 Eisai R&D Management Co., Ltd. Combination of a PD-1 antagonist and a VEGFR/FGFR/RET tyrosine kinase inhibitor for treating cancer
US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor

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